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Optimizing the Management of Acute Myeloid Leukemia: Individualized Therapy Optimizing the Management of Acute Myeloid Leukemia: Individualized Therapy 1 Learning Objectives Describe diagnostic testing for risk stratification in AML and

  1. Optimizing the Management of Acute Myeloid Leukemia: Individualized Therapy Case Study 1: Tom, 58 Years Old • Presents to ED complaining of • Laboratory results: extreme fatigue and abrupt onset of – WBCs: 120,000 cells/mm 3 shortness of breath – Hgb: 6.9 g/dL • 2-week history of worsening exercise – Platelets: 27,000/mm 3 tolerance – Blasts: 47% • No significant past medical history • Admitted to hospital for further • Enjoys bicycling, swimming, and testing painting Hgb = hemoglobin. 10 10 Diagnostic Testing and Karyotyping for Risk Stratification • Bone marrow core biopsy and aspirate analysis, including immunophenotyping and cytochemistry • Molecular analyses: FLT3 (ITD and TKD), NPM1, CEBPA, IDH1, IDH2, TP53, c-KIT, RUNX1, ASXL1 • Karyotyping is an important prognostic factor for predicting remission rates, relapse risk, and OS ‒ Complex karyotype: independent unfavorable risk factor • With each additional karyotype abnormality, the risk of failing to achieve CR increases • SWOG analysis: • Complex cytogenetics without involvement of chromosome 5 or 7: CR 50%; OS 20% • Complex cytogenetics + involvement of chromosome 5 or 7: CR 37%; OS 3% ‒ Monosomal karyotype: very poor prognosis • 4-year OS 4% OS = overall survival; SWOG = Southwest Oncology Group. NCCN Guidelines. Acute myeloid leukemia. www.nccn.org/professionals/physician_gls/pdf/aml.pdf. Accessed Mar 20, 2020; Orozco JJ, et al. 11 Oncology (Williston Park) . 2012;26:706-712; Slovak ML, et al. Blood . 2000;96:4075-4083; Xu J, et al. Turk J Haematol . 2017;34:126-130. 11 AML Disease Prognosis Influenced by Genetic Abnormalities Risk Category Genetic Abnormality 5-Year Survival • t(8;21)(q22;q22.1); RUNX1-RUNX1T1 • inv(16)(p13.1q22) or t(16;16)(p13.1;q22); CBFB-MYH11 Favorable 34% to 65% • Mutated NPM1 without FLT3 -ITD or with FLT3 -ITD low • Biallelic mutated CEBPA • Mutated NPM1 and FLT3 -ITD high • Wild-type NPM1 without FLT3 -ITD or with FLT3 -ITD low (without adverse-risk genetic lesions) Intermediate 13% to 41% • t(9;11)(p21.3;q23.3); MLLT3-KMT2A • Cytogenetic abnormalities not classified as favorable or adverse • t(v;11q23.3); KMT2A rearranged • t(6;9)(p23;q34.1); DEK-NUP214 • Wild-type NPM1 and FLT3 -ITD high • t(9;22)(q34.1;q11.2); BCR-ABL1 • Mutated RUNX1 • inv(3)(q21.3q26.2) or t(3;3)(q21.3;q26.2); Poor/Adverse • Mutated ASXL1 2% to 14% GATA2,MECOM(EVI1) Mutated TP53 • –5 or del(5q); –7; –17/abn(17p) • Complex karyotype, monosomal karyotype 12 NCCN Guidelines. Acute myeloid leukemia. www.nccn.org/professionals/physician_gls/pdf/aml.pdf. Accessed Mar 20, 2020. 12 2020 Spring PCE Oncology Series 4

  2. Optimizing the Management of Acute Myeloid Leukemia: Individualized Therapy MRCs in AML • MRCs are characterized by a history of myelodysplastic syndrome (MDS), significant morphologic dysplasia, or MDS-related cytogenetic features • Patients with MRCs have a worse prognosis • Can occur in patients with or without a history of MDS or myeloproliferative neoplasms (MPN) • Also includes AML with morphologic features or cytogenetic abnormalities characteristic of MDS National Cancer Institute. www.cancer.gov/publications/dictionaries/cancer-terms/def/aml-mrc. Accessed Mar 20, 2020; NCCN Guidelines. Acute myeloid leukemia. www.nccn.org/professionals/physician_gls/pdf/aml.pdf. Accessed Mar 20, 2020. 13 13 Optimizing Testing • Communication between clinician and pathologist ensures necessary testing ‒ Pertinent patient history • Prior hematologic disorder or known predisposing conditions • Prior malignancy • Exposure to cytotoxic therapy, immunotherapy, radiotherapy, or other possibly toxic substances • Presence or absence of MRC ‒ Comprehensive genomic profiling at diagnosis for disease classification, risk stratification, prognosis, and treatment selection NCCN Guidelines. Acute myeloid leukemia. www.nccn.org/professionals/physician_gls/pdf/aml.pdf. Accessed Mar 20, 2020. Waterhouse M, et al. 14 Biol Blood Marrow Transplant . 2011;17:1450-1459. 14 Case Study (cont’d): Tom’s Test Results • ECOG PS: 1 • Cytogenetics: diploid karyotype 46,XY[20] • Bone marrow core biopsy: hypercellular marrow (90% cellularity) with 56% myeloblasts • Flow cytometry: CD33+/CD117+/HLA-DR+/MPO+/CD34− • Molecular studies: ‒ Wild-type CEBPA and NPM1 ‒ FLT3- ITD/wildtype allelic ratio of 0.55 15 ECOG PS = Eastern Cooperative Oncology Group performance status. 15 2020 Spring PCE Oncology Series 5

  3. Optimizing the Management of Acute Myeloid Leukemia: Individualized Therapy RATIFY: Frontline Standard 7+3 ± Midostaurin in FLT3 -ITD and FLT3 -TKD Mutated Disease Median OS: Months (95% CI) Midostaurin Placebo 100 Complete remission by day 60 59% 53% 80 Probability of Survival (%) Midostaurin 74.7 (31.5-NR) Event-free survival (EFS) 8 months 3 months Placebo 25.6 (18.6-42.9) 60 4-year OS 51% 44% 40 Midostaurin is indicated for use in patients with FLT3 -mutated AML in combination with standard 20 cytarabine and daunorubicin induction therapy 1-sided P = .009 by stratified log-rank test and cytarabine consolidation therapy. 0 0 12 24 36 48 60 72 84 90 Months Patients at Risk, n Midostaurin 360 269 208 181 151 97 37 1 Placebo 357 221 163 147 129 80 30 1 CI = confidence interval; NR = not reported. Rydapt [prescribing information]. Novartis Pharmaceuticals; 2019; Stone RM, et al. N Engl J Med . 2017;377:454-464. 16 16 Case Study (cont’d) • Because Tom has a FLT3- ITD mutation, induction chemotherapy is initiated with 7+3 (daunorubicin 60 mg/m 2 ) and midostaurin 50 mg orally twice a day on days 8 to 21 17 17 Standard 7+3 ± Midostaurin: AEs • No statistically significant differences in grade 5 AEs between midostaurin and placebo ‒ Significantly more grade ≥3 anemia and rash vs placebo ‒ Significantly more nausea with placebo • AEs with 7+3 and midostaurin: febrile neutropenia, nausea, mucositis, vomiting, headache, petechiae, musculoskeletal pain, epistaxis, device-related infection, hyperglycemia, and upper respiratory tract infection • Administer prophylactic antiemetics before treatment with midostaurin • Instruct patients to take with food; do not open or crush capsules • Consider interval assessments of QT if taken concurrently with medications that can prolong the QT interval AE = adverse event. Cessna MH, et al. www.hematology.org/Clinicians/Guidelines-Quality/Quick-Reference.aspx. Accessed Mar 20, 2020; NCCN Guidelines. Acute myeloid leukemia. www.nccn.org/professionals/physician_gls/pdf/aml.pdf. Accessed Mar 20, 2020; Rydapt [prescribing Information]. Novartis; 2019; 18 Stone RM, et al. Blood . 2015;126:6; Stone RM, et al. N Engl J Med . 2017;377:454-464. 18 2020 Spring PCE Oncology Series 6

  4. Optimizing the Management of Acute Myeloid Leukemia: Individualized Therapy Gemtuzumab Ozogamicin + Chemotherapy: OS by Risk Category Annual event rates: Years 1 to 5 Years 6+ • Approved for newly diagnosed and R/R GO 5.8% SD 1.1 2.3% SD 1.3 CD33+ AML No GO 14.1% SD 1.9 0.0% SD 0.0 ‒ May be used in combination with 7+3 100 or as monotherapy in certain patients 77.5% 75.5% 80 Estimated % Still Alive • Meta-analysis of 5 randomized controlled trials (N = 3325) 60 • Absolute survival benefit at 6 years 55.0% 54.8% 40 especially apparent in patients with favorable cytogenetic characteristics 20 – allocated GO (% ± SD) 20.7% SD 6.5 – allocated No GO (% ± SD) (log-rank P = .0006) 0 0 1 2 3 4 5 6+ Years Deaths/person-years: Favorable cytogenics GO 12/117 7/104 6/93 1/81 1/70 3/129 No GO 20/109 18/93 10/76 5/61 1/45 0/84 GO = gemtuzumab ozogamicin; SD = standard deviation. Hill RK, et al. Lancet Oncol . 2014;15:986-996; Mylotarg [prescribing information]. Pfizer Inc; 2018. 19 19 Gemtuzumab Ozogamicin: AEs • Prescribing information carries a boxed warning for hepatotoxicity, including severe or fatal VOD, also known as sinusoidal obstruction syndrome • VOD risk higher in patients: ‒ With moderate or severe hepatic impairment prior to receiving gemtuzumab ozogamicin ‒ Treated with gemtuzumab ozogamicin before or after HSCT • Assess ALT, AST, total bilirubin, and alkaline phosphatase prior to each dose • After treatment, monitor frequently for VOD signs/symptoms ‒ Elevations in ALT, AST, and total bilirubin ‒ Hepatomegaly ‒ Rapid weight gain ‒ Ascites ALT = alanine transaminase; AST = aspartate aminotransferase; VOD = veno-occlusive disease. 20 Hill RK, et al. Lancet Oncol . 2014;15:986-996; Mylotarg [prescribing information]. Pfizer Inc; 2018. 20 CPX-351: Median OS in Newly Diagnosed Older Patients With High-risk Secondary AML • Approved for newly diagnosed, therapy- Events/No. Median survival 100 (95% Cl), months of patients related, or AML-MRC CPX-351 104/153 9.56 (6.60 to 11.86) 7+3 132/156 5.95 (4.99 to 7.75) 80 HR, 0.69 • Improved OS vs standard 7+3 in older One-sided P = .003 patients with high-risk secondary AML 60 OS (%) • Better outcomes after allogeneic HSCT 40 in older patients with high-risk AML, including 53% fewer deaths within 100 20 days of transplant 0 3 6 9 12 15 18 21 24 27 30 33 36 Time Since Random Assignment (months) No. at risk CPX-351 153 122 92 79 62 46 34 21 16 11 5 1 7+3 156 110 77 56 43 31 20 12 7 3 2 0 21 Lancet JE, et al. J Clin Oncol . 2018;36:2684-2692. 21 2020 Spring PCE Oncology Series 7

  5. Optimizing the Management of Acute Myeloid Leukemia: Individualized Therapy CPX-351: AEs • Reported AEs are generally consistent with the known safety profile of cytarabine and daunorubicin therapy • Boxed warning against interchanging with other products containing daunorubicin or cytarabine • Associated with delayed neutrophil and platelet count recovery of 6 to 7 days • Administered as 90-minute infusion; potential to be given in outpatient setting Lancet JE, et al. Blood . 2016;128:906; Lancet JE, et al. J Clin Oncol. 2016 ; 34(15 Suppl):7000. US Food and Drug Administration. www.fda.gov/newsevents/newsroom/pressannouncements/ucm569883.htm. Accessed March 20, 2020; Vyxeos [prescribing information]. Jazz Pharmaceuticals; 2019. 22 22 Case Conclusion • After treatment with 7+3 and midostaurin, Tom achieves a CR as assessed by repeat bone marrow biopsy following recovery of blood count • Manageable side effects − Myelosuppression managed with transfusions, growth factors − Nausea and vomiting managed with antiemetic combinations • Tom is sent for allogeneic HSCT 23 23 Case Study 2: Edith, 68 Years Old • History of AML ‒ CR 4 months ago following 1 cycle of cytarabine with idarubicin and 3 cycles of intermediate-dose cytarabine for consolidation • Presents with extreme fatigue and pallor, sudden onset of shortness of breath ‒ ECOG PS: 2 ‒ Comorbid COPD • Complete blood count: ‒ WBCs: 1300 cells/mm 3 ; absolute neutrophils: 570 cells/mcL; Hgb: 8.3 g/dL; platelets: 95,000/mm 3 • Bone marrow biopsy consistent with relapse ‒ 80% cellular with 16% myeloblasts 24 24 2020 Spring PCE Oncology Series 8

  6. Optimizing the Management of Acute Myeloid Leukemia: Individualized Therapy Case Study (cont’d): Edith’s Test Results • Molecular studies: ‒ IDH1 mutation-positive ‒ FLT3 negative ‒ NPM1 negative • Cytogenetics: 46,XX[20] 25 25 Targeting IDH Mutations: Ivosidenib and Enasidenib in R/R AML Ivosidenib Enasidenib • First-in-class oral targeted IDH1 inhibitor for R/R AML • First-in-class oral targeted IDH2 inhibitor for R/R AML • Also approved for newly diagnosed adults aged ≥75 years or • Single-arm trial in adult patients with R/R AML and with comorbidities precluding intensive induction chemotherapy IDH2 mutation • Single-arm trial in adult patients with R/R AML and • 19.3% of 176 patients achieved CR IDH1 mutation − 6.8% experienced CRp/CRi • 24.7% of 174 patients achieved CR • Boxed warning: IDH-DS ‒ 8.0% experienced CRh • Most common AEs of any grade: • Boxed warning: IDH-DS − Nausea, vomiting, diarrhea, elevated bilirubin, decreased • Most common AEs of any grade: appetite ‒ Fatigue, leukocytosis, arthralgia, diarrhea, dyspnea, edema, nausea, mucositis, ECG QT prolongation, rash, pyrexia, cough, constipation CRh = complete remission with partial hematologic recovery; CRi = complete remission with incomplete hematologic recovery; CRp = complete remission with incomplete platelet recovery. DiNardo CD, et al. N Engl J Med . 2018;378:2386-2398; Idhifa [prescribing information]. Celgene Corporation; 2019; Stein EM, et al. Blood. 26 2017;130:722-731; Tibsovo [prescribing information]. Agios Pharmaceuticals; 2019. 26 Case Study (cont’d): Edith’s Second-line Therapy • You start Edith on ivosidenib for her relapsed AML • 4 weeks later, she is admitted to the hospital with shortness of breath, cough, diarrhea, and rapid weight gain despite loss of appetite • She believes the therapy is making her sicker and asks to discontinue treatment 27 27 2020 Spring PCE Oncology Series 9

  7. Optimizing the Management of Acute Myeloid Leukemia: Individualized Therapy IDH-DS: Signs and Symptoms • Leukocytosis, lung infiltrates, pleural or pericardial effusions, rapid weight gain, edema, azotemia • Monitor closely when diagnosis is uncertain, as patients can rapidly deteriorate • For severe or rapidly progressing IDH-DS, hospitalize patient for management DiNardo CD, et al. N Engl J Med . 2018;378:2386-2398; Stein EM, et al. Blood. 2017;130:722-731. 28 28 Clinical Management of IDH-DS • Promptly initiate corticosteroids when IDH-DS is first suspected; upon improvement, progressively reduce steroid dose ‒ Interrupt IDH inhibitor therapy at clinician’s discretion or if severe pulmonary symptoms and/or renal dysfunction persist after 48 hours of treatment ‒ Resume therapy when symptoms improve • In patients with elevated WBC count, promptly initiate hydroxyurea • Furosemide may be used for substantial fluid accumulations • Monitor patients with rapidly increasing peripheral blood cells for disseminated intravascular coagulopathy and hemorrhage 29 DiNardo CD, et al. N Engl J Med . 2018;378:2386-2398; Fathi AT. ASCO 2017; Stein EM, et al. Blood. 2017;130:722-731. 29 Case Study (cont’d) • Dexamethasone 10 mg is initiated • Differentiation syndrome resolves after 48 hours of therapy • Edith agrees to continue ivosidenib • CR is achieved after 5 months of treatment 30 30 2020 Spring PCE Oncology Series 10

  8. Optimizing the Management of Acute Myeloid Leukemia: Individualized Therapy Venetoclax: CR/CRi and OS in Elderly or Frail Patients BCL-2 inhibitor for newly diagnosed AML in adults age ≥75 or with comorbidities that preclude intensive induction therapy in combination with azacitidine, decitabine, or LDAC Multicenter, Phase 1b Dose-escalation and Expansion Study Composite Response Overall Response Rate Median Duration of Median OS Cohort N Rate, (CR + CRi) n (%) (CR + CRi + PR) n (%) CR + CRi (95% CI) (95% CI) All patients 145 97 (67) 99 (68) 11.3 (8.9-NR) 17.5 (12.3-NR) VEN 400 mg + HMA 60 44 (73) 44 (73) 12.5 (7.8-NR) NR (11.0-NR) VEN 800 mg + HMA 74 48 (65) 50 (68) 11.0 (6.5-12.9) 17.5 (10.3-NR) • Common AEs (>30%): nausea, diarrhea, constipation, febrile neutropenia, fatigue, hypokalemia, decreased appetite, and decreased WBC count • FDA warning of increased risk of death in investigational use in R/R multiple myeloma but not in approved indications HMA = hypomethylating agent; VEN = venetoclax. DiNardo CD, et al. Blood. 2019;133:7-17; US Food and Drug Administration. www.fda.gov/Drugs/DrugSafety/ucm634120.htm. Accessed Mar 20, 2020. 31 31 Phase 1b/2 Study: Venetoclax + Low-dose Cytarabine in Previously Untreated Patients With AML • Median OS = 10.1 months • Common grade ≥3 AEs: • Median DOR = 8.1 months – Febrile neutropenia (42%) • 54% of patients achieved CR/CRi – Thrombocytopenia (38%) • Patients without prior HMA exposure – Decreased WBC count (34%) – CR/CRi = 62% – Median DOR = 14.8 months – Median OS = 13.5 months DOR = duration of response. 32 Wei AH, et al. J Clin Oncol . 2019;37:1277-1284. 32 BRIGHT: Glasdegib in Elderly or Frail Newly Diagnosed Patients Hedgehog pathway inhibitor; for newly diagnosed AML in adults aged ≥75 years or with comorbidities • CR that preclude intensive induction therapy − Glasdegib/LDAC: 17.0% (15/88) of • In combination with LDAC patients vs LDAC: 2.3% (1/44 ) of patients ( P <.05) • Most common AEs (>20%) Randomized, International, Phase 2 BRIGHT 1003 Trial − Anemia, fatigue, hemorrhage, febrile 1.0 Median OS, months (80%) neutropenia, musculoskeletal pain, Glasdegib/LDAC 8.8 (6.9-9.9) Survival Probability nausea, edema, thrombocytopenia, 0.8 LDAC 4.9 (3.5-6.0) dyspnea, decreased appetite, HR = 0.513 0.6 80% CI: 0.394-0.666, P = .0004 dysgeusia, mucositis, constipation, rash • Boxed warning 0.4 Glasdegib/LDAC − Embryo-fetal death or severe birth 0.2 LDAC defects when administered to pregnant 0.0 women 0 5 10 15 20 25 30 35 40 Time (months) HR = hazard ratio. 33 Cortes JE, et al. Leukemia. 2019;33:379-389. 33 2020 Spring PCE Oncology Series 11

  9. Optimizing the Management of Acute Myeloid Leukemia: Individualized Therapy ADMIRAL: Gilteritinib vs Salvage Chemotherapy Kinase inhibitor for R/R FLT3+ AML Phase 3, open-label, multicenter, randomized trial Patients with FLT3 -ITD or -TKD mutations randomized to gilteritinib (n = 347) or SC (n = 124) • Efficacy: ‒ OS: 9.3 months GIL; 5.6 SC (HR for death = 0.637; P = .0007) ‒ CR/CRh rate: 34.0% GIL; 15.3% SC ( P = .0001) ‒ Median EFS: 2.8 months GIL; 0.7 months SC (HR 0.793; P = .0830) • Common grade ≥3 AEs for GIL: anemia (19.5%), febrile neutropenia (15.4%), thrombocytopenia (12.2%), decreased platelet count (12.2%) ‒ Serious treatment-emergent AEs less common with GIL (7.1%) vs SC (9.2%) • Boxed warning for GIL: differentiation syndrome GIL = gilteritinib; SC = salvage chemotherapy (LDAC, azacitidine, mitoxantrone/etoposide/cytarabine, or fludarabine/cytarabine/GCSF/idarubicin). Perl AE, et al. AACR 2019. Abstract CT184; Xospata [prescribing information]. Astellas Pharma US, Inc; 2019. 34 34 AML and Patient Counseling • In one survey, 67% of patients aged ≥60 years did not realize that there was more than one treatment option ‒ Respondents failed to understand their chances of cure, 1-year survival, or treatment-related mortality, regardless of final treatment choice • Educate patients and families on all appropriate treatments: risks and benefits, length of treatment, AE management, treatment expectations and perceptions ‒ Compared with chemotherapy, patients take longer to achieve CR on biologics such as enasidenib • Address any misconceptions and specific needs ‒ Financial assistance available for many therapies ‒ Current evidence on allogeneic HSCT in elderly patients with AML Devillier R. https://ashpublications.org/blood/article/132/Supplement%201/209/261662/Allogeneic-Hematopoietic-Stem-Cell-Transplantation. Accessed March 20, 2020; LeBlanc TW, et al. J Clin Oncol . 2019;37(suppl):7040; Sekeres MA, et al. Leukemia . 2004;18:809-816; Stein 35 EM, et al. Blood. 2017;130:722-731. 35 Case Conclusion • Edith continues ivosidenib • Following blood count recovery, she proceeds to allogeneic HSCT 36 36 2020 Spring PCE Oncology Series 12

  10. Optimizing the Management of Acute Myeloid Leukemia: Individualized Therapy Investigational Treatment Approaches in AML • Second-generation FLT3 inhibitors • Immunotherapeutic agents − Crenolanib ‒ Bispecific T-cell engager − Quizartinib ‒ Dual affinity retargeting − CG-806 ‒ PD-1 inhibitors ‒ CTLA-4 inhibitors ‒ Chimeric antigen receptor therapies PD-1 = programmed cell death protein 1. Broderick JM. www.onclive.com/web-exclusives/fda-panel-votes-against-quizartinib-approval-for-aml. Accessed Mar 20, 2020; Cortes JE, et al. Leukemia . 2019;33:379-389; Lichtenegger FS, et al. J Hematol Oncol . 2017;10:142; Liu H, et al. Front Immunol . 2017;8:38; Montesinos P, et al. J Clin Oncol . 2019;37(15 suppl):TPS7063. Papayannidis C, et al. Int J Mol Sci . 2019;20:e2721; Ternyila D. www.targetedonc.com/news/daver- investigates-combination-therapy-in-tp53-flt3mutated-aml. Accessed Mar 20, 2019; Zhang H, et al. AACR 2019. 37 37 QUAZAR AML Maintenance Trial: Design and Methods • Randomized, double-blind, placebo-controlled trial investigating the epigenetic modifier CC-486 (oral formulation of azacitidine) in patients aged ≥55 years with AML in first remission following induction chemotherapy • Primary endpoint ‒ OS • Secondary endpoints ‒ RFS, health-related quality of life, safety • Patients randomized to receive CC-486 300 mg or placebo once daily on days 1 to 14 of repeated 28-day treatment cycles RFS = relapse-free survival. 38 Roboz GJ, et al. Future Oncol . 2016;12(3):293-301; Wei AH, et al. Blood . 2019;134(suppl 2):LBA-3. 38 QUAZAR AML Maintenance Trial: Results • 472 patients (median age, 68 years) were randomized to receive CC-486 (n = 238) or placebo (n = 234) ‒ At median follow-up of 42 months, median OS from time of randomization with CC-486 and placebo was 24.7 months vs 14.8 months, respectively ‒ Median RFS with CC-486 and placebo was 10.2 months vs 4.8 months, respectively ‒ Most common grade 3/4 AEs: neutropenia (CC-486, 41%; placebo, 24%), thrombocytopenia (23% and 22%, respectively), and anemia (14% and 13%, respectively) 39 Roboz GJ, et al. Future Oncol . 2016;12(3):293-301; Wei AH, et al. Blood . 2019;134(suppl 2):LBA3. 39 2020 Spring PCE Oncology Series 13

  11. Optimizing the Management of Acute Myeloid Leukemia: Individualized Therapy CC-486 Maintenance Trial After A llogeneic HSCT : Design and Methods • Phase 1/2 dose-finding study of CC-486 maintenance therapy after allogeneic HSCT in patients with AML or MDS who were in morphologic CR at the time of treatment initiation • Patients received 1 of 4 CC-486 dosing schedules per 28-day cycle for up to 12 cycles • Endpoints: safety, pharmacokinetics, incidence of graft-versus-host disease, relapse/progression rate, and survival de Lima M, et al. Biol Blood Marrow Transplant . 2018;24:2017-2024. 40 40 CC-486 Maintenance Trial After A llogeneic HSCT: Results • The intention-to-treat population consisted of 30 patients (median age, 64.5 years) who received ≥1 dose of CC-486 between July 2013 and November 2015 • At 19-month follow-up, median OS was not reached 1.0 Median OS was not reached in any dosing cohort; the range for all patients was (NR, 95% CI 15.1 months, NR) 0.9 86 to 1324 days Survival Probability 0.8 0.7 • Rate of relapse or progressive disease during 0.6 treatment in 28 assessable patients: 21% 0.5 • 1-year cumulative incidence of acute or chronic 0.4 graft-versus-host disease: 50% 0.3 Censored • Grade 3/4 AEs were uncommon and occurred with 0.2 0.1 similar frequency across the dosing regimens 0.0 0 6 12 18 24 30 36 42 48 Patients 12 5 3 1 30 25 23 19 at Risk Time (months) 41 de Lima M, et al. Biol Blood Marrow Transplant . 2018;24:2017-2024. 41 PCE Action Plan  Consider patient factors and preferences when establishing treatment goals for AML  Risk-stratify patients by karyotype and genetic abnormalities in order to help predict remission, relapse, and OS  Order comprehensive genomic profiling at both diagnosis and relapse, as genomic alterations can evolve throughout the disease course  Enhance shared decision-making by addressing patient and family perceptions and knowledge of all appropriate treatments PCE Promotes Practice Change 42 42 2020 Spring PCE Oncology Series 14

  12. New Treatment Paradigms in Relapsed/Refractory Multiple Myeloma: Integrating Novel Agents Into Clinical Practice New Treatment Paradigms in Relapsed/Refractory Multiple Myeloma: Integrating Novel Agents Into Clinical Practice 1 Learning Objectives • Identify novel agents used in the treatment of relapsed/refractory (RR) multiple myeloma (MM) and guideline recommendations for their use • Apply established criteria to identify patients who have developed RRMM and individualize therapy based on relevant patient- and disease-related characteristics • Use current recommendations for monitoring and managing treatment-related AEs in patients with RRMM 2 AE = adverse event. 2 Multiple Myeloma • B-cell–derived plasma cell disorder ‒ Clonal proliferation of immunoglobulin (Ig)-secreting malignant plasma cells in bone marrow ‒ Secretion of M-protein into blood or urine • Abnormal Ig or Ig fragment; also called monoclonal protein, myeloma protein, or paraprotein ‒ Associated end-organ dysfunction • 32,270 new cases expected in the United States in 2020 • Median age at diagnosis is ~69 years, but 37% of patients are aged <65 years • Novel treatments have improved survival for newly diagnosed MM, but relapse is still expected ‒ 2-year survival rate (all patients): 87.1% in 2012, up from 69.9% in 2006 ‒ 5-year survival rate (all patients): 54% in 2009-2015, up from 27% in 1987-1989 • Important to use the best therapies in front-line treatment: treatment-free intervals are shorter with each subsequent line of therapy American Cancer Society. www.cancer.org/research/cancer-facts-statistics/all-cancer-facts-figures/cancer-facts-figures-2020.html. Accessed Mar 23, 2020; Durie BGM. www.myeloma.org/sites/default/files/images/publications/UnderstandingPDF/concisereview.pdf. Accessed Mar 23, 2020; Fonseca R, et al. Leukemia. 2017;31:1915-1921; NCCN Guidelines. Multiple myeloma. www.nccn.org/professionals/physician_gls/default.aspx. 3 Accessed Mar 23, 2020; Palumbo A, Anderson K. N Engl J Med. 2011;364:1046-1060; Yong K, et al. Br J Haematol . 2016;175:252-254. 3 2020 PCE Spring Oncology Series 1

  13. New Treatment Paradigms in Relapsed/Refractory Multiple Myeloma: Integrating Novel Agents Into Clinical Practice Progress in Treating Multiple Myeloma Preclinical and Clinical Studies Leading to FDA Approvals in MM Improvement in OS From Median 2006 2012, 2015 2012, 2015 2015 2020 of 3 to 8 to 10 Years Thalidomide Carfilzomib Carfilzomib Panobinostat Isatuximab 1.0 1960-65 0.9 1965-70 2005 2010 2015 2020 1970-75 0.8 1975-80 Proportion Surviving 1980-85 0.7 2007 2003, 2005, 2008 2003, 2005, 2008 2013, 2015 2019 1985-90 Doxil + Bortezomib (BTZ) Bortezomib (BTZ ) Pomalidomide Selinexor 0.6 1990-95 BTZ 1995-00 0.5 2015 2000-05 2015 Ixazomib 2005-10 Ixazomib 0.4 2006, 2014 2015 2015 0.3 Lenalidomide Daratumumab Elotuzumab 0.2 0.1 Immunomodulatory agent Proteasome inhibitor XPO1 inhibitor 0.0 Monoclonal antibody HDAC inhibitor 0 2 4 6 8 10 12 14 16 18 20 Follow-up From Diagnosis (years) OS = overall survival; XPO1 = exportin 1. Adapted with permission from Anderson KC. Clin Cancer Res . 2016;22:5419-5427 . 4 4 Myeloma Can Be Treated, But Not Cured Asymptomatic Symptomatic Relapsing Refractory Disease may respond or become refractory at any point Relapse M-Protein Level → Active myeloma Relapse MGUS or indolent myeloma Remission 1st-line 2nd- or 3rd- 4th-line 4th-20th-line therapy line therapy therapy therapy ← 2-3 years ← 1-2 years ← 1-2 years ← 6 months-1 year → → → → MGUS = monoclonal gammopathy of unknown significance. 5 Adapted from: Durie BGM. www.myeloma.org/sites/default/files/images/publications/UnderstandingPDF/concisereview.pdf. Accessed Mar 23, 2020. 5 Response and Survival in RRMM Median Response Duration (months) Response Duration With Subsequent Survival Outcomes 100 12 Lines of Treatment Median, Months 10 80 Events, n/N (range) Patients (%) 170/286 9 (7-11) OS 8 217/286 5 (4-6) EFS 60 6 40 4 20 2 0 0 0 12 24 36 48 60 First Second Third Fourth Fifth Sixth Treatment Regimen Months EFS = event-free survival. 6 Kumar SK, et al. Leukemia . 2012;26:149-157; Kumar SK, et al. Mayo Clin Proc . 2004;79:867-874. 6 2020 PCE Spring Oncology Series 2

  14. New Treatment Paradigms in Relapsed/Refractory Multiple Myeloma: Integrating Novel Agents Into Clinical Practice International Myeloma Working Group: Standard Response Criteria Criteria Definition MRD-negative In patients who have achieved ≥CR, MRD negative in bone marrow by NGS plus disappearance of areas of disease previously seen on FPG-PET/CT Stringent CR CR and normal FLC ratio, absence of clonal cells in bone marrow biopsy by IHC CR Negative immunofixation on serum and urine, and disappearance of any soft tissue plasmacytomas, and <5% plasma cells in bone marrow aspirate VGPR Serum and urine M-protein detectable on immunofixation but not on electrophoresis, or ≥90% reduction in serum M-protein plus urine M-protein <100 mg/24 h PR ≥50% reduction of serum M-protein plus ≥90% reduction in urine M-protein or to <200 mg/24 h Minimal response ≥25% but ≤49% reduction in serum M-protein and reduction in 24 h urine M-protein of 50% to 89% Stable disease No evidence of disease response or progression CR = complete response; FDG PET/CT = fluorodeoxyglucose positron emission tomography-computed tomography; FLC = free light chain; IHC = immunohistochemistry; MRD = minimal residual disease; NGS = next-generation sequencing; PR = partial response; VGPR = very good partial response. Kumar S, et al. Lancet Oncol. 2016;17:e328-e346. 7 7 Major Classes of Treatment Used in Multiple Myeloma IMiDs PIs mAbs Others Agents in • Lenalidomide (R) • Bortezomib (V) • Daratumumab (D) • HDI: Panobinostat (F) class • Pomalidomide (P) • Carfilzomib (K) • Isatuximab • XPO1: Selinexor (abbreviation) • Thalidomide (T) • Ixazomib (N, I) • Elotuzumab (E) Mechanism of • Antiangiogenic and • Promote apoptosis • Daratumumab • Panobinostat: action anti-inflammatory • Inhibit osteoclast and Isatuximab: Damages DNA and properties formation CD38-mediated upregulates apoptosis- • CD-4+/CD-8+ T-cell • Increase osteoblast apoptosis promoting proteins enhancement creation and • Selinexor : Inhibits • Elotuzumab : • NK cell function growth and promotes SLAMF7-mediated augmentation apoptosis by blocking NK cell actions of XPO1 enhancement HDI = histone deacetylase inhibitor; mAbs = monoclonal antibodies; NK = natural killer; PI = protease inhibitor; SLAMF7 = signaling activation molecule F7. Bahlis NJ, et al. Blood. 2018;132:2546-2554; Cook G, et al. Crit Rev Oncol Hematol. 2018;121:74-89; Palumbo A, Anderson K. N Engl J Med. 8 2011;364:1046-1060. 8 Current Treatment Paradigm for Active Myeloma SCT Eligible Induction SCT/Consolidation Maintenance Managing Diagnosis and Risk Relapse Stratification Induction Followed by SCT Continuous Maintenance Therapy Ineligible Tumor Burden 9 SCT = stem-cell transplant. 9 2020 PCE Spring Oncology Series 3

  15. New Treatment Paradigms in Relapsed/Refractory Multiple Myeloma: Integrating Novel Agents Into Clinical Practice Case Study 1: Jean, 68 Years Old History • Diagnosed with MM 4 years ago • Standard-risk cytogenetics: t(6;14) • Front-line treatment ‒ Bortezomib/lenalidomide/low-dose dexamethasone (VRd): achieved VGPR ‒ Successful ASCT with melphalan 200 mg/m 2 : achieved CR ‒ Lenalidomide 10 mg maintenance treatment Finding 4 Months Ago 2 Months Ago Serum M-protein 0.1 g/dL 0.2 g/dL Serum creatinine 0.7 mg/dL 1.2 mg/dL Hgb 12.5 g/dL 10.9 g/dL Bone lesions None None ASCT = autologous stem-cell transplant; Hgb = hemoglobin. 10 10 Case Study (cont’d): Today’s Visit • 20 months after starting lenalidomide maintenance, Jean presents with pain in her ribs and back • Otherwise good health, but has residual PN from VRd; Jean says it is still slowly improving • Bone marrow biopsy: 14% bone marrow plasma cells, 50% increase over last biopsy • ECOG PS = 1 Finding 4 Months Ago 2 Months Ago Today Serum M-protein 0.1 g/dL 0.2 g/dL 0.9 g/dL Serum creatinine 0.7 mg/dL 1.2 mg/dL 2.0 mg/dL Hgb 12.5 g/dL 10.9 g/dL 9.5 g/dL Bone lesions None None Osteolytic lesions on X-ray 11 ECOG PS = Eastern Cooperative Oncology Group performance status; PN = peripheral neuropathy. 11 MM Cytogenetic Changes Over Time May Impact Prognosis • Myeloma evolves over time in response to treatment, epigenetics, and other factors • Presence of high-risk cytogenetics at diagnosis is associated with higher rates of clonal evolution • High-risk clones can develop de novo after successful front-line therapy and ASCT ‒ High-risk deletion 17p and gain 1q21 mutations • Development of high-risk mutations associated with poor prognosis • Acquired del17p associated with significantly shorter PFS and OS ‒ Lower-risk translocations; eg, t(11;14) or t(6;14) (rare) PFS = progression-free survival. Bianchi G, Ghobrial M. Curr Cancer Ther Rev. 2014;10:70-79; Lakshman A, et al. Blood Adv. 2019;3:1930-1938; Merz M, et al. Haematologica. 12 2017;102:1432-1438. 12 2020 PCE Spring Oncology Series 4

  16. New Treatment Paradigms in Relapsed/Refractory Multiple Myeloma: Integrating Novel Agents Into Clinical Practice mSMART: Risk Classification of MM Standard Risk High Risk** • All others, including: High-risk genetic • RISS stage 3 abnormalities by FISH or – Trisomies • High plasma-cell S phase equivalent – t(11:14)* • Gene expression profiling: • t(4:14) High-risk signature – t(6:14) • t(14:16) • Double-hit: any 2 high-risk Jean now • t(14:20) genetic abnormalities Jean at diagnosis • del(17p) • Triple-hit: ≥3 high-risk genetic abnormalities • p53 mutation • 1q gain *t(11;14) may be associated with plasma cell leukemia; **Trisomies may ameliorate risk. FISH = fluorescent in situ hybridization; mSMART = Mayo Stratification of Myeloma and Risk-Adapted Therapy; RISS = Revised International Staging System. Mayo Clinic.static1.squarespace.com/static/5b44f08ac258b493a25098a3/t/5b802d8270a6adbc6a79a678/ 13 1535126914646/Risk+Strat+3.0rev_svr.pdf. Accessed Mar 23, 2020. 13 Relapse Patterns in Multiple Myeloma Clinically symptomatic disease with increase Extramedullary disease in M-protein Four patterns of relapse Asymptomatic disease Plasma cell leukemia characterized by increase in M-protein 14 Alegre, et al . Haemotologica. 2002; 87:609-614. 14 Biochemical Relapse: IMWG Criteria Biochemical relapse identified due to improved monitoring can catch progression before development of clinical symptoms • 25% increase from the lowest response value in ≥1of the following: ‒ Serum M-protein • Absolute increase ≥0.5 g/dL or • Increase ≥1 g/dL if the lowest M-protein level was ≥5 g/dL ‒ Urine M-protein: absolute increase ≥200 mg/24 hours ‒ For patients without measurable serum or urine M-protein levels • Difference between involved and uninvolved FLC levels: absolute increase >10 mg/dL • Absolute increase >10% in percentage of bone marrow plasma cells • Development of new lesions, increase in size of existing lesions,* or ≥50% increase in circulating plasma cells (minimum 200 cells/mcL) if only measure of disease *50% increase from nadir in SPD of >1 lesion, or ≥50% increase in the longest diameter of a previous lesion >1 cm in the short axis. IMWG = International Myeloma Working Group; SPD = sum of the products of the maximal perpendicular diameters. 15 Kumar S, et al. Lancet Oncol. 2016;17:e328-e346. 15 2020 PCE Spring Oncology Series 5

  17. New Treatment Paradigms in Relapsed/Refractory Multiple Myeloma: Integrating Novel Agents Into Clinical Practice Clinical Relapse: IMWG Criteria ≥1 of the following: CRAB criteria: a mnemonic for myeloma-related organ dysfunction: • CRAB features C = calcium elevation: >11.5 mg/dL • Size* increase in existing (or development R = renal disease: serum Cr >2 mg/dL of new) soft tissue plasmacytomas or A = anemia: Hgb <10 g/dL or >2 g/dL bone lesions (not new osteoporotic fractures) below LLN • Hgb reduction ≥2 g/dL unrelated to MM B = bone lesions: ≥1 osteolytic lesion therapy or other conditions • Serum creatinine increase ≥2 mg/dL attributable to MM • Hyperviscosity related to serum paraprotein *50% (and ≥1 cm) increase as measured serially by the SPD of the measurable lesion. Kumar S, et al. Lancet Oncol. 2016;17:e328-e346. 16 16 IMWG: High-Risk Disease Characteristics in Relapsed or Relapsed/Refractory Disease • Adverse cytogenetic features • Complex karyotypes • High β 2 microglobulin (>5.5 mg/L) or low albumin (<3.5 mg/dL) • LDH above normal • Circulating plasma cells • Extramedullary disease • Short duration of response (DOR) to prior therapy or progression on current therapy • Aggressive clinical features: rapid symptom onset, extensive disease, CRAB features LDH = lactate dehydrogenase. 17 Dingli D, et al. Mayo Clin Proc. 2017;92:578-598; Laubach J, et al. Leukemia. 2016;30:1005-1017. 17 IMWG: Principles of Treating Progressive Disease When to Treat • Clinical (symptomatic) relapse: CRAB criteria • Rapidly rising M-protein levels (eg, monoclonal peak doubling time ≤3 months) • Extramedullary disease • Early relapse, high-risk cytogenetics • Threatened organ function (ie, renal dysfunction) 18 Laubach L, et. al Leukemia. 2016;30:1005-1017. 18 2020 PCE Spring Oncology Series 6

  18. New Treatment Paradigms in Relapsed/Refractory Multiple Myeloma: Integrating Novel Agents Into Clinical Practice Before Changing or Initiating Therapy • Make sure the patient has actually progressed − Repeat myeloma lab tests − Don’t compare results from different labs • Characterize the relapse − Asymptomatic biochemical (indolent) vs symptomatic clinical − Slow vs rapid − Early vs late 19 19 Selecting Treatment for RRMM: General Principles • Duration of initial response informs the biology of RRMM • Regimen: triplet* (eg, KRd) is preferred over doublet ‒ Include ≥1 agent from a new or non-refractory class ‒ Previously used agents may be effective in different combinations • When selecting therapy and optimal doses, consider ‒ Disease risk, ECOG PS, age, comorbidities ‒ Bone marrow biopsy at each relapse to reassess risk ‒ Prior and residual toxicities • Treat to maximum response and maintain on ≥1 agent until progression or intolerability *Two active classes plus dexamethasone. Laubach L, et al. Leukemia. 2016;30:1005-1017; NCCN Guidelines. Multiple myeloma. www.nccn.org/professionals/physician_gls/default.aspx. 20 Accessed Mar 23, 2020; Sonneveld P, Broijl A. Haematologica. 2016;101:396-406. 20 Establish the Goals of Treatment for the Patient • Balance treatment efficacy with Prior therapy Patient characteristics impact on QoL • Prior ASCT? • Goals of treatment • Prior IMiDs? PIs? • Age/frailty − May not need a regimen with a • Depth/DOR • Performance status high CR rate • Time to progression? • Lifestyle/mobility − Stable disease is an excellent • Toxicities • Comorbidities goal of therapy for many patients with RRMM Disease characteristics ‒ Little difference in clinical • Cytogenetics consequences between stable • CRAB present disease and CR • Extramedullary disease • Aggressive features • Short DOR 21 QoL = quality of life. 21 2020 PCE Spring Oncology Series 7

  19. New Treatment Paradigms in Relapsed/Refractory Multiple Myeloma: Integrating Novel Agents Into Clinical Practice Recent FDA Approved Agents and Combinations ≥2 Prior Courses ≥1 or 1 to 3 Prior Courses Daratumumab + pomalidomide + dexamethasone ≥1: Carfilzomib monotherapy (PX-171–003; FOCUS) Isatuximab + pomalidomide + dexamethsone 1-3: Carfilzomib + lenalidomide + dexamethasone (ASPIRE) Elotuzumab + pomalidomide + 1-3: Carfilzomib, dexamethasone (ENDEAVOR) dexamethasone (ELOQUENT-3) Pomalidomide + dexamethasone ≥1: Daratumumab + either lenalidomide or bortezomib + dexamethasone (POLLUX & CASTOR) Panobinostat + bortezomib + ≥1: Ixazomib + lenalidomide + dexamethasone (TOURMALINE-MM1) dexamethasone (PANORAMA-1) 1-3: Elotuzumab + lenalidomide + dexamethasone (ELOQUENT- 2) ≥3 or ≥4 Prior Courses ≥3: Daratumumab monotherapy (SIRIUS) ≥4: Selinexor + dexamethasone (STORM) Attal M, et al. Lancet. 2019;394:2096-2107; Chari A, et al. Blood. 2017;130:974-981; Chari A, et al. ASH 2018. Abstract 598; Dimopoulos MA, et al. Lancet Oncol. 2016;17:27-38; Dimopoulos MA, et al. N Engl J Med . 2016;375:1319-1331; Dimopoulos MA, et al. N Engl J Med 2018; 379:1811-1822; Hájek, et al. Leukemia . 2017;31:107-114; Lonial S, et al. Lancet. 2016;387:1551-1560; Lonial S, et al. N Engl J Med 2015; 373:621-631; Moreau P, et al. N Engl J Med. 2016; 374:1621-1634; Palumbo A, et al. N Engl J Med. 2016; 375:754-766; San-Miguel, et al. Lancet Haematol . 2016;3:e506-e515; Stewart K, et al. N Engl J Med. 2015; 372:142-152; Vij, et al. Br J Haematol . 2012;158:739–748. 22 22 Summary: mSMART Recommended Approaches After First Relapse On Maintenance* Off Therapy/Unmaintained* Triplet Preferred: Add ≥1 New Agent, or Next Generation Agent Indolent Relapse From Same Class Fit Patients or Frail Patients Indolent Relapse Fit Patients or Frail Patients • KRd • IRd If lenalidomide maintenance: If lenalidomide maintenance: • DaraRd • EloRd • KPomD • DaraVd • PomD • DaraVd • Id + cyclophosphamide If bortezomib maintenance: If bortezomib maintenance: • DaraRd • IRd • DaraRd *Consider salvage ASCT in eligible patients who have not had a previous ASCT. Consider second ASCT in eligible patients if response has been >18 months (unmaintained) or >36 months (maintained). DaraRd = daratumumab, lenalidomide, dexamethasone; DaraVd = daratumumab, bortezomib, dexamethasone; EloRd = elotuzumab, lenalidomide, dexamethasone; Id = isatuximab, dexamethasone; IRd = isatuximab, lenalidomide, dexamethasone; K/PomD = carfilzomib, pomalidomide, dexamethasone; PomD = pomalidomide, dexamethasone. 23 Dingli D, et al. Mayo Clin Proc. 2018;92:578-598. 23 Ranking of Treatments Based on Meta-analysis Results 24 Botta C, et al. Blood Adv. 2017;1:455-466. 24 2020 PCE Spring Oncology Series 8

  20. New Treatment Paradigms in Relapsed/Refractory Multiple Myeloma: Integrating Novel Agents Into Clinical Practice Case Study (cont’d) • Jean was retreated with VRd and achieved a partial response at 6 months; she presents now with complaints of persistent fatigue, shortness of breath, swelling of ankles, and bone pain in lower legs • Updated cytogenetics: unchanged—still high-risk del(17p) • Current laboratory measurements Finding At Diagnosis 6 Months Ago Today Serum M-protein 0.9 g/dL 0.6 g/dL 1.2 g/dL Serum creatinine 2.0 mg/dL 1.6 mg/dL 2.1 mg/dL Serum calcium — 10.2 mg/dL 11.6 mg/dL Hgb 11.0 g/dL 11.0 g/dL 10.2 g/dL Bone marrow — <10% plasma cells 16% plasma cells 25 25 Relapsed vs Refractory Disease • Relapsed/refractory MM: progression on therapy after achieving at least minor response or progression within 60 days of most recent therapy • Primary refractory MM: progression on therapy without achieving at least minor response • Relapsed MM: meets IMWG criteria for progressive disease but does not fit definition of RR or primary refractory 26 Nooka AK, et al. Blood . 2015;125:3085-3099. 26 Administration Considerations for PIs Bortezomib (V) Carfilzomib (K) Ixazomib (N, I) Route* SC** IV Oral Select AEs to assess PN Cardiac failure Thrombocytopenia Hypotension Renal insufficiency GI toxicity Cardiac toxicity Pulmonary toxicity, dyspnea Peripheral neuropathy Pulmonary toxicity Hypertension Rash GI toxicity Venous thrombosis Hepatotoxicity Thrombocytopenia Hemorrhage Neutropenia Thrombocytopenia Hepatic toxicity Rate of PN with PI + Rd Any grade: 35% Any grade: 11% Any grade: 28% Grade 3 or 4: 8% Grade ≥3: 2% Grade ≥3: 2% Management Monitor CBC; safe in renal failure, Monitor hydration, cardiopulmonary Reduce dose for hepatic/renal considerations herpes prophylaxis toxicities, herpes prophylaxis disease, herpes prophylaxis *Recommended dose and schedules vary depending on regimen and patient factors. Check prescribing information; **An IV formulation is available but is not recommended for use. AE = adverse event; CBC = complete blood count; Rd = lenalidomide/low-dose dexamethasone. Kyprolis [prescribing information]. Amgen; 2019; NCCN Guidelines. Multiple myeloma. www.nccn.org/professionals/physician_gls/default.aspx. 27 Accessed Mar 23, 2020; Ninlaro [prescribing information]. Takeda; 2020; Velcade [prescribing information]. Millennium Pharmaceuticals, Inc; 2019. 27 2020 PCE Spring Oncology Series 9

  21. New Treatment Paradigms in Relapsed/Refractory Multiple Myeloma: Integrating Novel Agents Into Clinical Practice Administration Considerations for mAbs Daratumumab (D, Dara) and Isatuximab (Isa) Elotuzumab (E, Elo) Route* IV IV AE prophylaxis Pre/post medication with corticosteroids, antipyretics, and 60 to 90 min before infusion, administer antihistamines; oral steroid may not be needed after infusion corticosteroids, H1 blocker, H2 blocker, if used in combinations that include dexamethasone acetaminophen ± Inhaled steroids for patients with COPD (Dara) Select AEs to assess Infusion reactions Infusion reactions Interference with cross-matching, red blood cell antibody Infection** screening, and determination of CR Second primary malignancy Infection** Hepatotoxicity Neutropenia, thrombocytopenia Interference with determination of CR Management For infusion reaction risk, pre/post medicate as directed; interrupt infusion if reaction occurs considerations Monitor CBC periodically during treatment with Dara and Isa; monitor during neutropenia for infection; dose delay with Dara or Isa may be required to allow neutrophil recovery Monitor patients during treatment for second primary malignancies, per IMWG guidelines (lsa, Elo) *Recommended dose and schedules vary depending on regimen and patient factors. Check prescribing information; **Patients should receive varicella zoster virus prophylaxis when receiving daratumumab or elotuzumab. Darzalex [prescribing information]. Janssen; 2019; Empliciti [prescribing information]. Bristol-Myers Squibb; 2019; Sarclisa [prescribing information]. Sanofi-aventis US; 2020. 28 28 Administration Considerations for XPO1 Inhibitor Selinexor Route and dosage Oral, 80 mg days 1 and 3 of each week when combined with dexamethasone Frequent AEs (>20%) Thrombocytopenia, fatigue, nausea, anemia, decreased appetite/weight, diarrhea, vomiting, hyponatremia, neutropenia, leukopenia, constipation, dyspnea, and URI Select AEs to assess Thrombocytopenia Neutropenia Considered highly emetogenic; GI adverse reactions, especially nausea Hyponatremia Infections Management Monitor patients for cytopenia, neutropenia, hyponatremia, infections considerations Provide antiemetic prophylaxis May cause dizziness or confusion; optimize hydration, blood counts, and concomitant medications to minimize risk Dose reductions (if needed for hematologic/non-hematologic toxicity) • First: 100 mg once weekly • Second: 80 mg once weekly • Third: 60 mg once weekly (discontinue after third reduction) URI = upper respiratory infection. 29 Xpovio [prescribing information]. Karyopharm Therapeutics; 2019. 29 Cardiotoxicity With PIs: Is This a Class Effect? • Patients with MM are at increased risk for CV complications due to disease factors and comorbidity • Cardiotoxicity increased with irreversible inhibition of ubiquitin-proteasome system ‒ Pre-existing uncontrolled hypertension or left ventricular hypertrophy increase risk for CVAE with carfilzomib • Note : PIs often are used in combination with other agents that also may affect CV function (eg, IMiDs) Bortezomib Carfilzomib Ixazomib • MoA: Reversible PI inhibition • MoA: Irreversible PI inhibition • MoA: Reversible PI inhibition Analysis of 8 myeloma studies (N = 3954), ENDEAVOR (phase 3, N = 929) TOURMALINE Grade ≥3 CVAE: Grade ≥3 with bortezomib: • Grade ≥3 hypertension • N = 361 IRd; 359 Rd patients • HF: 1.3% to 4.7% • 9% carfilzomib, 3% bortezomib • Arrhythmia: 6%; 4% • Arrhythmia: 0.6% to 4.1% • Any grade hypertension • Thromboembolism: <3%; <4% • Ischemic HD: 0.4% to 2.7% • 20.3% carfilzomib, 8.1% bortezomib • HF: 3%; 2% • Cardiac death: 0 to 1.4% • MI: <1%; <2% • No significant differences between bortezomib and placebo patients CV = cardiovascular; CVAE = cardiovascular adverse event (heart failure, hypertension, ischemia, arrhythmia); HD = heart disease; HF = heart failure; MI = myocardial infarction; MoA = mechanism of action; RCT = randomized controlled trial; RR = relative risk of CVAE for patients receiving carfilzomib compared with non–carfilzomib-receiving control patients. Bruno G, et al. Cancers (Basel). 2019;11:pii E622; Dimopoulos MA, et al. Lancet Oncol. 2016;17:27-38; Laubach JP, et al. Br J Haematol. 2017;178:547- 560; Li W, et al. JAMA Oncol. 2017;3:980-988; Moreau P, et al. N Engl J Med. 2016;374:1621-1634; Plummer C, et al. Blood Cancer J. 2019;9:26; 30 Waxman AJ, et al. JAMA Oncol. 2018;4:e174519. 30 2020 PCE Spring Oncology Series 10

  22. New Treatment Paradigms in Relapsed/Refractory Multiple Myeloma: Integrating Novel Agents Into Clinical Practice Assessing for Cardiotoxicity: Proactive Monitoring and Clinical Management of CV Events With Carfilzomib Strategy Suggestions Baseline CV risk • Assess risk, obtain ECG, and determine need for cardiology consultation assessment and • Control hypertension ongoing • Review prior history of anthracyclines or other cardiotoxic agents monitoring • Consider reduced fluid volume in cycle 1 if high CV risk, and adjust in subsequent cycles Intervention • Withhold carfilzomib for grade 3/4 CVAE until resolved or improved to baseline • Consider restarting carfilzomib therapy at 1 dose level reduction based on a benefit-risk assessment after consulting a cardiologist • When resuming therapy, consider follow-up echocardiograms and/or biomarkers (eg, BNP or NT-proBNP) based on cardiologist recommendations Patient education • Encourage recognition and prompt reporting of symptoms of CV decompensation • Recommend routine BP monitoring, keeping a daily record BNP = B-type natriuretic peptide; NT-proBNP = N-terminal pro hormone BNP. Jakubowiak AJ, et al. Hematology . 2017;22:585-591; Plummer C, et al. Blood Cancer J. 2019;9:26. 31 31 Factor Patient’s Treatment History and Comorbid Conditions Into Treatment Decisions • Most patients are older and have preexisting comorbid conditions: up to 69% have preexisting CV disease • Consider response and toxicity with previous lines of therapy • Consider disease factors that increase risk of CV complications, including renal impairment and anemia • Factor possible CV and other toxicities with recommended treatments into treatment decisions 32 Plummer C, et al. Blood Cancer J. 2019;9:26. 32 Case Study (cont’d) • Jean expresses a preference for oral treatment over repeated infusions ‒ You explain that ixazomib carries a small risk for grade 3 PN that carfilzomib does not have ‒ Jean still would prefer an all-oral regimen • She is prescribed ixazomib + PomD ‒ You recommend loperamide OTC to minimize diarrhea with treatment ‒ You and Jean create a dosing calendar to aid adherence with the dosing schedule of her different medications 33 33 2020 PCE Spring Oncology Series 11

  23. New Treatment Paradigms in Relapsed/Refractory Multiple Myeloma: Integrating Novel Agents Into Clinical Practice Example of Calendar for All-Oral Regimen 28-Day Cycle (4-Week Cycle) Week 1 Week 2 Week 3 Week 4 Treatment Day 1 Days 2-7 Day 8 Days 9-14 Day 15 Days 16-21 Day 22 Days 23-28 Yes ✓ Yes ✓ Yes ✓ Ixazomib No No No No No Yes ✓ Daily ✓ Yes ✓ Daily ✓ Yes ✓ Daily ✓ Pomalidomide No No Dexamethasone Yes ✓ No Yes ✓ No Yes ✓ No Yes ✓ No Ninlaro [prescribing information]. Takeda; 2020; Pomalyst [prescribing information]. Celgene; 2019. 34 34 Myelosuppression: Frequent With IMiDs and mAbs* • Expect cytopenia to occur and manage patient expectations • Increased risk of infection, poorer QoL, and treatment interruption • Use transfusions and growth factors as appropriate Criteria Lenalidomide Criteria Pomalidomide • Platelets <30K/mcL • Interrupt treatment; • Platelets <25K/mcL • Interrupt treatment; follow CBC weekly follow CBC weekly • Recovery ≥30K/mcL • Recovery >50K/mcL • Resume at next lower • Resume at 3 mg/day dose** • ANC <500/mcL or • Interrupt treatment; • ANC <1K/mcL • Interrupt treatment; febrile neutropenia follow CBC weekly follow CBC weekly • Recovery ≥1K/mcL • Recovery ≥500/mcL • Resume at 3 mg/day • Resume at 25 mg or • Subsequent drops in • Interrupt; with recovery starting dose** platelets or ANC resume at 1 mg less than • Subsequent drops in • Interrupt; with recovery previous dose platelets or ANC resume next lower dose *Dose modifications for myelosuppression are not indicated with mAbs; **Do not use dose <2.5 mg/day. Darzalex [prescribing information]. Janssen; 2019; Empliciti [prescribing information]. Bristol-Myers Squibb; 2019; Pomalyst [prescribing information]. Celgene; 2019; Revlimid 35 [prescribing information]. Celgene; 2019. 35 Toxicity Management Side Effect Clinical Management Cardiopulmonary • Assess risk at baseline • Provide patients/caregivers with contact info and guidelines for reportable signs/symptoms, along with prevention and treatment strategies Constipation • Hydration, diet, stool softeners/laxatives Diarrhea • Hydration, diet, antidiarrheal agents, dose modify if needed Fatigue • Counsel patients on exercise, sleep, stress reduction; assess and treat for depression, if indicated; review concurrent meds Rash • Treat symptoms with topical agents and antihistamines • Discontinue drug for rare severe drug reactions Peripheral neuropathy • Educate patients on early symptoms and reporting to medical staff • Modify bortezomib dose per prescribing information for peripheral neuropathy grade ≥2 Brigle K, et al. Clin J Oncol Nurs. 2017;21(5 Suppl):60-76; Catamero D, et al. Clin J Oncol Nurs. 2017;21(5 Suppl):7-18; Faiman B, et al. Clin J Oncol Nurs. 2017;21(5 Suppl):19-36; Kurtin SE, Bilotti E. J Adv Pract Oncol. 2013;4:307-321; Noonan K, et al. Clin J Oncol Nurs. 36 2017;21(5 Suppl):37-46; Velcade [prescribing information]. Millennium Pharmaceuticals; 2019. 36 2020 PCE Spring Oncology Series 12

  24. ̶ New Treatment Paradigms in Relapsed/Refractory Multiple Myeloma: Integrating Novel Agents Into Clinical Practice Toxicity Management (cont’d) Side Effect Clinical Management Thromboembolic events • Baseline risk assessment, including personal and family history Risk factors: • For patients receiving IMiDs: • Older age − Low risk (<2 risk factors): full-dose aspirin • History of thrombotic event − High risk (≥2 risk factors) or IMiD combined with high-dose dexamethasone: LMWH or full-dose warfarin (target INR 2-3) • Obese • Educate patients on preventive strategies and early detection • Immobilized • Can consider DOACs, although not well studied in this population • CV/renal disease • Diabetes Infusion reactions • Premedicate according to prescribing information • Ensure a hypersensitivity reaction protocol is in place DOAC = direct oral anticoagulants; INR = international normalized ratio; LMWH = low-molecular-weight heparin. Gleason C, et al. J Adv Pract Oncol. 2016;7(suppl 1):53-57; Kurtin SE, Bilotti E. J Adv Pract Oncol. 2013;4:307-321; NCCN Guidelines. Cancer-associated venous thromboembolic disease. www.nccn.org. Accessed Mar 24, 2020; NCCN Guidelines. Multiple myeloma. www.nccn.org/professionals/physician_gls/default.aspx. Accessed Mar 24, 2020; Noonan K, et al. Clin J Oncol Nurs. 2017;21(5 Suppl):37-46. 37 37 Treatment Considerations: Special Populations Patient Population Considerations Frail, elderly patients • Standard 3-drug regimens; use dose reductions to improve tolerability • Alternate: doublet therapy with Rd or use melphalan/bortezomib/prednisone Renal dysfunction • Bortezomib + IMiD: no dose adjustment needed with pomalidomide; adjust lenalidomide based on CrCl • Other options: bortezomib/daratumumab with high-dose dexamethasone or melphalan/bortezomib/prednisone Cardiac dysfunction • Avoid carfilzomib with preexisting uncontrolled hypertension or advanced HF • Use thromboprophylaxis with IMiD-based therapy Aggressive, high-risk • Consider induction with carfilzomib/Rd disease • Consider VTD-PACE and ASCT for extramedullary disease or PCL Peripheral neuropathy • Administer bortezomib SC using weekly dosing • Treatment with carfilzomib or ixazomib plus Rd CrCl = creatinine clearance; VTD-PACE = bortezomib, thalidomide, dexamethasone, cisplatin, doxorubicin, cyclophosphamide, and etoposide; PCL = plasma cell leukemia. NCCN Guidelines. Multiple myeloma. www.nccn.org/professionals/physician_gls/default.aspx. Accessed Mar 24, 2020; Richter J, et al. Hematol 38 Oncol. 2017;35:246-251. 38 Infection Prophylaxis • Keep current on appropriate vaccinations, including annual flu vaccine Inactivated vaccines are safe for use • Herpes prophylaxis when receiving PIs or mAbs: acyclovir, famciclovir, valacyclovir ‒ HSV: consider during active therapy, possibly longer ‒ Herpes zoster (VZV): at least 6 to 12 months after ASCT; safe to use inactivated vaccine (Shingrix) in patients with MM • PJP/herpes/antifungal prophylaxis if using high-dose dexamethasone • Pneumococcal vaccine: PCV13, then PPV23 1 year later • IVIG in setting of recurrent, life-threatening infections • Counsel patients to alert treating clinicians to potential infection symptoms, to reduce unnecessary antibiotics HSV = herpes simplex virus; IVIG = intravenous immunoglobulin; PCV = pneumococcal conjugate vaccine; PJP = Pneumocystis jiroveci pneumonia; PPV = pneumococcal polysaccharide vaccine; VZV = varicella zoster virus. Delforge M, et al. Blood . 2017;129:2359-2367; NCCN Guidelines. Multiple myeloma. www.nccn.org/professionals/physician_gls/default.aspx. Accessed 39 Mar 24, 2020; NCCN Guidelines. Infection prevention. www.nccn.org/professionals/physician_gls/default.aspx. Accessed Mar 24, 2020. 39 2020 PCE Spring Oncology Series 13

  25. New Treatment Paradigms in Relapsed/Refractory Multiple Myeloma: Integrating Novel Agents Into Clinical Practice Supportive Care for Bone Disease NCCN: All patients should receive bisphosphonates or denosumab • Bisphosphonates: pamidronate and zoledronic acid ‒ Similar efficacy, greater ONJ risk with zoledronic acid ‒ Monitor for renal impairment on bisphosphonates • SC denosumab preferred when renal disease is present ‒ May be given monthly; efficacy similar to zoledronic acid • Other supportive care ‒ Baseline dental exam and ONJ monitoring for all patients using a bone-modifying therapy ‒ Orthopedic consult if long-bone fracture present or imminent; consider vertebroplasty or kyphoplasty for vertebral compression fracture ONJ = osteonecrosis of the jaw. NCCN Guidelines. Multiple myeloma. www.nccn.org/professionals/physician_gls/default.aspx. Accessed Mar 23, 2020 40 40 Other Supportive Care Recommendations Condition Adjunctive Treatment Hypercalcemia • Hydration, bisphosphonates (zoledronic acid preferred), denosumab, steroids, and/or calcitonin Anemia • Perform type and screen before using daratumumab if transfusions indicated Liver function • Monitor for hepatotoxicity with PIs, IMiDs, daratumumab Renal • Monitor patients on carfilzomib for acute renal failure dysfunction • Monitor renal function in patients on bisphosphonates • Adequate hydration • Plasmapheresis (although not generally useful) • Avoid NSAIDs, intravenous contrast NSAIDs = nonsteroidal anti-inflammatory drugs. 41 NCCN Guidelines. Multiple myeloma. www.nccn.org/professionals/physician_gls/default.aspx. Accessed Mar 24, 2020 41 Assess Toxicity Risk and Implement Management Strategies • Evaluate patient for unresolved toxicities • Evaluate risk for new or progressive toxicities with continued treatment • Incorporate recommended prophylaxis – Low-dose aspirin for thromboprophylaxis with IMiDs – Herpes prophylaxis prior to PIs or mAbs • Manage and minimize the severity of toxicities as appropriate • Use supportive care for myeloma-related conditions • Educate patients and caregivers about how they can take an active role in managing potential toxicities Kurtin SE, Bilotti E. J Adv Pract Oncol. 2013;4:307-321; NCCN Guidelines. Multiple myeloma. 42 www.nccn.org/professionals/physician_gls/default.aspx. Accessed Mar 24, 2020; Trudel S, et al. OncoTargets Ther. 2019;12:5813-5822. 42 2020 PCE Spring Oncology Series 14

  26. New Treatment Paradigms in Relapsed/Refractory Multiple Myeloma: Integrating Novel Agents Into Clinical Practice At Each Step, Consider All Possible Treatment Strategies • Repeat previously effective drugs in new combinations and/or consider totally new combinations • Triple regimens preferred; consider doublets for frail patients • Include next-generation agent from same class or ≥1 new class ‒ Progression on a combination does not necessarily mean the individual drugs will be ineffective in combination with other agents ‒ Treatments that are ineffective alone are often effective when combined • Use drugs to which the patient has not been exposed • Refer patients for clinical trials where appropriate 43 43 Novel Approaches for RRMM Drug Description FDA Status Clinical Trials Results in RRMM Selinexor Oral nuclear Accelerated approval for Phase 2B trial (STORM): selinexor 80 mg plus dex export protein RRMM after ≥4 prior lines • N = 123 patients refractory to ≥3 prior therapies XPO1 inhibitor of therapy (incl. 2 PIs, 2 • ORR (≥PR) = 26% (including 2 stringent CR) IMiDs, and an anti-CD38 • AE: fatigue, nausea, grade 3-4 thrombocytopenia mAB) Venetoclax for BCL-2 inhibitor Approved in other Phase 3 RCT (BELLINI): venetoclax + Vd vs Vd t(11,14) cancers • N = 291; ≤3 prior therapies translocation • All patients: 61% ≥VGPR (vs 40%), MRD– :13% vs 1% • t(11,14)+ patients: 75% ≥VGPR (vs 27%); MRD– : 25% vs 0 • Grade ≥3 AEs: thrombocytopenia, anemia Isatuximab Anti-CD38 mAb Approved for patients with Phase 3 RCT (ICARIA-MM): Isatuximab + PomD vs PomD ≥2 prior lines of therapy, • N = 307; ≥2 prior therapies including lenalidomide • Improved PFS (primary end point): 11.5 months vs 6.5 months and a PI • Other phase 3 RCT with Kd and VRd ongoing ORR = overall response rate Attal M. et al. Lancet. 2019;394:2096-2107; Chari A, et al. N Engl J Med. 2019;381:727-738; Kumar S, et al. Blood. 2017;130:2401-2409; Mikhael J, et al. Blood. 2019;134:123-133; Moreau P, et al. ASH 2019: Abstract 653; Richardson PG, et al. Future Oncol. 2018;14:1035-1047; Sarclisa. 44 [prescribing information]. Sanofi-aventis US; 2020; Xpovio [prescribing information]. Karyopharm Therapeutics; 2019. 44 On the Horizon: BCMA-Targeted Agents in RRMM Drug Description FDA Status Current Research Results in RRMM Belantamab Immunoconjugate Investigational, Phase 2 (DREAMM-2): dose-ranging (2.5 & 3.4 mg), single agent mafodotin targeting BCMA granted priority review • N = 196; RRMM after ≥3 prior therapies; triple refractory Jan 2020 • Overall RR: 31% with 3.4 mg, 34% with 2.5 mg • Grade ≥3 AE: keratopathy, thrombocytopenia, anemia Phase 1 (DREAMM-1): ≥PR: 60%; median PFS = 12 mo T oxicities: Thrombocytopenia, corneal events: manage with supportive care Idecabtagene BCMA CAR T cell Investigational, Phase 2 (KarMMa): dose-ranging study vicleucel has breakthrough • N = 128; RRMM after ≥3 prior therapies; 84% triple-refractory (ide-cel) therapy designation • Overall RR (all patients) = 73.4% (31.3% CR); 81.5% at highest dose Nov 2017 • Grade ≥3 AEs: CRS (5.5%), neurotoxicity (3.1%) Phase 1: ORR = 85% (45% CR); median PFS = 11.8 mo T oxicities: • CRS: manage with antipyretics, hydration, tocilizumab +/- dex • ICANS: manage with seizure prophylaxis or treatment; monitor for severe symptom development BCMA = B cell maturation antigen; CAR = chimeric antigen receptor; CRS = cytokine release syndrome; ICANS = immune-effector cell neurotoxicity syndrome. Bristol-Myers Squibb. news.bms.com/press-release/corporatefinancial-news/bristol-myers-squibb-and-bluebird-bio-announce-positive-top-li. Accessed Mar 24, 2020; Lonial S, et al. Lancet Oncol. 2020;21:207-221; Mikhael J. Clin Lymphoma Myeloma Leuk. 2019;1:1-7; Raje N, et al. N Engl J Med. 2019;380:1726-1737; Trudel S, et al. Blood Cancer J. 2019;9:37; Wang BY , et al. ASH 2019: Abstract 579; Zhao WH, et al. 45 J Hematol Oncol. 2018;11:141. 45 2020 PCE Spring Oncology Series 15

  27. New Treatment Paradigms in Relapsed/Refractory Multiple Myeloma: Integrating Novel Agents Into Clinical Practice Relapsed/Refractory Multiple Myeloma: Summary • Relapse is still inevitable in MM • Current treatment strategies prolong DOR/PFS at each step of care ‒ Triplet therapies: PI + IMiD + Dex; combinations with PomD and/or mAbs ‒ ASCT for eligible patients, front-line or delayed ‒ Maintenance therapy after consolidation with lenalidomide or bortezomib • Longer survival underscores need to proactively manage disease- and treatment- related toxicities • For patients using oral agents, institute strategies to maintain adherence with sometimes complicated dosing schedules 46 46 PCE Action Plan  Confirm and characterize a relapse before changing or reinitiating therapy  Choose a regimen based on patient goals as well as balancing efficacy and safety  Consider previous history and be proactive in anticipating issues with subsequent lines of treatment  Evaluate toxicity risk and implement clinical management strategies  Consider all possible treatment strategies, using patient and disease factors to guide subsequent lines of treatment PCE Promotes Practice Change 47 47 2020 PCE Spring Oncology Series 16

  28. Triple-Negative Breast Cancer: Fitting New and Emerging Strategies Into Patient Care Triple-Negative Breast Cancer: Fitting New and Emerging Strategies Into Patient Care 1 Learning Objectives • Summarize the mechanisms of action of available and emerging therapies for TNBC within the context of the underlying tumor biology • Identify the role of new and emerging therapies in the treatment of TNBC • Formulate strategies for the identification and management of toxicities of novel therapies in TNBC 2 TNBC = triple-negative breast cancer. 2 Features of TNBC Common Features Risk Factors Lacks ER, PR, and HER2 Younger age Family history of breast cancer Subtypes include “basal-like” (>75% of TNBC), immunomodulatory, mesenchymal, mesenchymal stem-like, and African American and High BMI luminal androgen receptor Hispanic women More aggressive clinical course in metastatic setting Underlying BRCA1 Low levels of physical Tends to be higher grade vs other types of breast cancer mutation activity More responsive to chemotherapy vs other types of breast Higher parity Low socioeconomic cancer (≥3 children) conditions Rapid progression from onset of metastasis to death Most deaths occur in first 5 years ER = estrogen receptor; HER2 = human epidermal growth factor receptor 2; PR = progesterone receptor. Audeh MW. Pharmgenomics Pers Med. 2014;7:307-316; Brookes L. www.medscape.com/viewarticle/871606. Accessed Mar 23, 2020; Ismail-Khan R, Bui MM. Cancer Control. 2010;17:173-176; Mustacchi G, De Laurentiis M. Drug Des Devel Ther. 2015;9:4303-4318; 3 Phipps AI, et al. Cancer Epidemiol Biomarkers Prev. 2011;20:454-463; Phipps AI, et al. J Natl Cancer Inst. 2011;103:470-477. 3 2020 PCE Spring Oncology Series 1

  29. Triple-Negative Breast Cancer: Fitting New and Emerging Strategies Into Patient Care Case Study: Carol, 56 Years Old • Carol reported nodules in her right breast to her gynecologist ‒ No family history of breast or ovarian cancer ‒ Core biopsy: 2-cm high-grade infiltrating ductal carcinoma ‒ Immunohistochemistry: ER/PR/HER2-negative tumor • Carol is diagnosed with TNBC 4 4 BRCA Testing in Breast Cancer • Testing recommendations include: ‒ Individuals from families with a known BRCA1/2 mutation ‒ Patients with a personal history of breast cancer plus one or more of the following: • Diagnosed ≤45 years of age • Diagnosed between 46 and 50 years with: ‒ An unknown or limited family history • Diagnosed ≤60 years of age with TNBC • Diagnosed at any age with: ‒ An additional primary breast cancer ‒ ≥1 close blood relative with breast cancer ‒ ≥1 close blood relative with high-grade prostate cancer ‒ Male relative with breast cancer ‒ Ashkenazi Jewish ancestry • In metastatic breast cancer: ‒ Assess germline BRCA1/2 mutations to identify candidates for PARP inhibitor monotherapy NCCN.org. www.nccn.org/professionals/physician_gls/pdf/genetics_bop.pdf. Accessed Mar 23, 2020; NCCN Guidelines. Breast cancer. 5 www.nccn.org/professionals/physician_gls/pdf/breast.pdf. Accessed Mar 23, 2020 5 Case Study (cont’d) • Immunohistochemistry: ER/PR/HER2-negative tumor with BRCA1 mutation • Staging studies: right breast mass with possible lymph node involvement; no other areas of disease • After neoadjuvant dose dense AC-T chemotherapy, Carol underwent a lumpectomy and was found to have residual disease in her breast and one lymph node with malignant cells, RCB-II • She is treated with adjuvant capecitabine for 6 months • Two years later, Carol comes to see you complaining of intermittent right-upper quadrant pain, fatigue, and unexplained weight loss • A scan shows liver metastases; biopsy confirms mTNBC 6 AC-T = doxorubicin and cyclophosphamide followed by paclitaxel; mTNBC = metastatic triple-negative breast cancer; RCB = residual cancer burden. 6 2020 PCE Spring Oncology Series 2

  30. Triple-Negative Breast Cancer: Fitting New and Emerging Strategies Into Patient Care PD-L1 Biomarker Testing in TNBC • PD-L1 expression: status can currently help identify patients most likely to benefit from atezolizumab plus nab -paclitaxel ‒ PD-L1 expression occurs mainly on tumor-infiltrating immune cells • Can inhibit anticancer immune responses ‒ PD-L1 expression is defined as negative or positive Keytruda [prescribing information]. Merck & Co, Inc; 2020; NCCN Guidelines. Breast cancer. www.nccn.org/professionals/physician_gls/pdf/breast.pdf. Accessed Mar 23, 2020; Schmid P, et al. N Engl J Med . 2018;379:2108-2121; Tecentriq [prescribing information]. Genentech, Inc; 2019; Vennapusa B, et al. Appl Immunohistochem Mol Morphol . 2019;27:92-100. 7 7 PD-L1 Biomarker Testing: Available Assays • SP142 assay: only validated test to predict benefit with atezolizumab plus nab -paclitaxel ⎻ PD-L1 expression: <1% or ≥1% • 22C3 assay: used to select patients for therapy with pembrolizumab ⎻ PD-L1 expression: calculated using CPS • Other assays used for different cancers/immunotherapies CPS = combined positive score. Keytruda [prescribing information]. Merck & Co, Inc; 2020; NCCN Guidelines. Breast cancer. www.nccn.org/professionals/physician_gls/pdf/breast.pdf. Accessed Mar 23, 2020; Schmid P, et al. N Engl J Med . 2018;379:2108-2121; Tecentriq [prescribing information]. Genentech, Inc; 2019; Vennapusa B, 8 et al. Appl Immunohistochem Mol Morphol . 2019;27:92-100. 8 Overview: Chemotherapy Options for mTNBC • Stage I-III: HER2-Negative Neoadjuvant or Preferred regimens adjuvant Anthracyclines PARP inhibitors (for HER2-negative tumors Platinum (for triple-negative tumors • Doxorubicin, liposomal doxorubicin and germline BRCA1/2 mutation) and germline BRCA1/2 mutation) chemotherapy + Taxanes • Olaparib • Carboplatin surgery • Paclitaxel • Talazoparib • Cisplatin Antimetabolites Atezolizumab + albumin-bound • Stage IV: • Capecitabine, gemcitabine paclitaxel (for PD-L1-positive Microtubule inhibitors TNBC) chemotherapy • Vinorelbine, eribulin alone Other recommended regimens • Choice and order Cyclophosphamide Albumin-bound paclitaxel Epirubicin of chemotherapy Docetaxel Ixabepilone Useful in certain circumstances depends on Doxorubicin/cyclophosphamide Docetaxel/capecitabine Gemcitabine/carboplatin multiple factors Epirubicin/cyclophosphamide Gemcitabine/paclitaxel Paclitaxel/bevacizumab Cyclophosphamide/methotrexate/ Carboplatin/albumin-bound fluorouracil paclitaxel Carboplatin/paclitaxel Ehab M, Elbaz M. Breast Cancer (Dove Med Press). 2016;8:83-91; NCCN Guidelines. Breast cancer. www.nccn.org/ 9 professionals/physician_gls/pdf/breast.pdf. Accessed Mar 23, 2020; Schwartz KL, et al. Cancer. 2018;124:2104-2114. 9 2020 PCE Spring Oncology Series 3

  31. Triple-Negative Breast Cancer: Fitting New and Emerging Strategies Into Patient Care Paclitaxel vs Nab -Paclitaxel: Taxane Derivatives • Taxane therapy indicated in the adjuvant and metastatic setting • Paclitaxel is a poorly water soluble, potent microtubule inhibitor that is a taxane derivative • Nab -paclitaxel: nanoparticle, albumin-bound injectable version of paclitaxel ‒ Eliminates use of polyoxyethylated castor oil (Cremophor EL), a cause of toxicity in patients receiving taxane therapy ‒ Shorter infusion time ‒ Does not require premedication with corticosteroids for hypersensivity reactions ‒ Uses albumin transport mechanisms to form concentrations within the tumor Abraxane [prescribing information]. Celgene Corporation; 2018; Al-Hajeili M, et al. Oncol Targets Ther . 2014;7:187-192; Taxol [prescribing information]. Bristol-Myers Squibb Company; 2011; Waks AG. www.lbbc.org/learn/treatments-and-research/chemotherapy/types-chemotherapy/nab- paclitaxel. Accessed Mar 23, 2020. 10 10 Immune Checkpoint Inhibitors: Mechanism of Action • Compared with other subtypes, TNBC is associated with higher prevalence of tumor infiltrating lymphocytes and higher rates of PD-L1 positivity • Checkpoint pathways regulate the immune system and help prevent autoimmune responses ‒ Cancers may evade destruction by the immune system by co-opting the CTLA-4 and PD-1 immune checkpoint pathways • Immune checkpoint inhibitors: ‒ Target CTLA-4, PD-1, PD-L1 ‒ Block cancer cells from using the checkpoint pathway ‒ Allow re-establishment of the immune response Brahmer JR, et al. J Clin Oncol. 2018;36:1714-1768; Buchbinder EI, Desai A. Am J Clin Oncol. 2016;39:98-106; Dine J, et al . Asia Pac J Oncol 11 Nurs . 2017;4:127-135; Katz H, Alsharedi M. Med Oncol . 2017;35:13; Shimelis H, et al. J Natl Cancer Inst. 2018;110:855-862. 11 IMpassion130: Atezolizumab + Nab -Paclitaxel in PD-L1 + mTNBC 100 Median OS, mo Population HR (95% CI) 90 A + nab -P P + nab -P 80 PD-L1 IC+ 25.0 18.0 0.71 (0.54, 0.94) 70 PD-L1 IC− 19.6 19.6 0.99 (0.80, 1.23) 60 OS (%) 50 40 30 • Improved OS in A + nab -P (PD-L1+ n = 185) 20 P + nab -P (PD-L1+ n = 184) PD-L1–positive A + nab -P (PD-L1− n = 266) P + nab -P (PD-L1− n = 267) 10 patients 0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 Time (months) Clinical cutoff date: January 2, 2019. A = Atezolizumab; CI = confidence interval; IC = immune cell; HR = hazard ratio; ITT = intent to treat; nab -P = nab- paclitaxel; OS = overall survival; P = placebo. 12 Schmid P, et al. Lancet Oncol. 2020;21:44-59. 12 2020 PCE Spring Oncology Series 4

  32. Triple-Negative Breast Cancer: Fitting New and Emerging Strategies Into Patient Care IMpassion130: Progression-free Survival in PD-L1 + mTNBC 100 Median OS, mo A + nab -P (PD-L1+ n = 185) Population HR (95% CI) P + nab -P (PD-L1+ n = 184) 90 A + nab -P (PD-L1− n = 266) A + nab -P P + nab -P P + nab -P (PD-L1− n = 267) PD-L1+ (41%) 7.5 mo 5.3 mo 0.63 (0.50, 0.80) 80 PD-L1- (59%) 5.6 mo 5.6 mo 0.93 (0.77, 1.11) 70 60 PFS (%) 50 40 30 20 10 0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 Months PFS = progression-free survival. Schmid P, et al. Lancet Oncol. 2020;21:44-59. 13 13 Patient Counseling: Nab -Paclitaxel AEs Type of AE Advice to Patients Alopecia • Hair loss is common and may begin within a few days or weeks of treatment • Usually grows back once treatments are over and sometimes between treatments • Color and texture may change Hematologic effects • Low blood cell counts increase risk of severe and life-threatening infections • Wash hands often and avoid crowds and people who are sick • Report fever or evidence of infection to healthcare provider immediately Nervous system • Sensory neuropathy frequently occurs • Report numbness, tingling, pain, or weakness involving the extremities to healthcare provider • Should resolve slowly after end of treatment Pneumonitis • Indicated by sudden onset of dry persistent cough or shortness of breath • May overlap with atezolizumab-related pneumonitis when used in combination • Contact healthcare provider immediately Abraxane [prescribing information]. Celgene Corporation; 2018; BC Cancer. www.bccancer.bc.ca/drug-database-site/Drug%20Index/nab%20paclitaxel_ 14 handout.pdf. Accessed Mar 23, 2020; Schmid P, et al. N Engl J Med . 2018;379:2108-2121; Tecentriq [prescribing information]. Genentech, Inc; 2019. 14 Patient Counseling: Nab -Paclitaxel AEs (cont’d) Type of AE Advice to Patients Hypersensitivity • Could be severe and sometimes fatal • Contact healthcare provider for any signs of an allergic reaction that occur soon after treatment Common adverse reactions • Fatigue/asthenia and myalgia/arthralgia occur frequently with nab -paclitaxel • Contact healthcare provider for persistent nausea and vomiting, diarrhea or constipation, or signs of dehydration Embryo-fetal toxicity • Women should use effective contraception during treatment and for at least 6 months after the last dose • Males with female partners should use effective contraception during treatment and for 3 months after the last dose Abraxane [prescribing information]. Celgene Corporation; 2019; BC Cancer. www.bccancer.bc.ca/drug-database-site/Drug%20Index/nab%20 15 paclitaxel_handout.pdf. Accessed Mar 23, 2020. 15 2020 PCE Spring Oncology Series 5

  33. Triple-Negative Breast Cancer: Fitting New and Emerging Strategies Into Patient Care Select Ongoing Immunotherapy Trials in TNBC Setting Trial Name Regimen Neoadjuvant/ Carboplatin + paclitaxel + (anthracycline) + cyclophosphamide ± KEYNOTE-522 pembrolizumab ➔ pembrolizumab Adjuvant Doxorubicin + cyclophosphamide + paclitaxel + carboplatin ± atezolizumab NCT03281954 ➔ atezolizumab Doxorubicin + cyclophosphamide + nab -paclitaxel ± atezolizumab ➔ IMpassion031 atezolizumab NeoTRIPaPDL1 Atezolizumab + carboplatin + nab -paclitaxel Michelangelo Paclitaxel ➔ dose-dense doxorubicin/epirubicin + cyclophosphamide ± Adjuvant IMpassion030 atezolizumab Locally advanced KEYNOTE-355 or mTNBC Abraxane or paclitaxel or carboplatin/gemcitabine ± pembrolizumab IMpassion131 Paclitaxel ± atezolizumab ➔ = followed by. Marra A, et al. BMC Med. 2019;17:90; Gianni L, et al. 2019 San Antonio Breast Cancer Symposium; Abstract GS3-04. 16 16 KEYNOTE-522: Neoadjuvant Pembrolizumab Plus Chemotherapy in Early TNBC Pembrolizumab + Chemo Placebo + Chemo • Greater increase in pCR in patients with Δ 6.3 (95% CI, Δ 20.6 (95% CI, 100 lymph node-positive vs lymph node- -5.3 to 18.2) 8.9 to 31.9) 90 negative disease 64.9% 64.8 % 80 58.6% • Improvement in pCR rates occurred 70 pCR, % (95% CI) regardless of PD-L1 status 44.1 % 60 • In the preoperative TNBC setting with 50 pembrolizumab plus chemotherapy, 40 PD-L1 does not seem to be a predictive 30 biomarker 20 10 124/191 136/210 45/102 58/99 0 Negative Positive Nodal Status pCR = pathological complete response. 17 Schmid P, et al. N Engl J Med . 2020;382:810-821. 17 KEYNOTE-522: Event-free Survival Pembrolizumab-chemotherapy 100 91.3% 90 Patients Without an 80 Event or Death (%) 85.3% 70 Placebo-chemotherapy 60 50 40 30 20 10 0 0 3 6 9 12 15 18 21 24 27 Months No. at risk Pembrolizumab-chemotherapy 784 780 765 666 519 376 242 73 2 0 Placebo-chemotherapy 390 386 380 337 264 186 116 35 1 0 18 Schmid P, et al. N Engl J Med . 2020;382:810-821. 18 2020 PCE Spring Oncology Series 6

  34. Triple-Negative Breast Cancer: Fitting New and Emerging Strategies Into Patient Care NeoTRIPaPDL1 Michelangelo Study • Early, high-risk and locally advanced TNBC treated with: ‒ Atezolizumab plus carboplatin and nab -paclitaxel ‒ Compared with carboplatin and nab -paclitaxel • pCR rates did not improve in atezolizumab group • PD-L1 expression most significant factor for influencing pCR, regardless of treatment regimen • TRAEs similar for both regimens except: ‒ Significantly higher overall incidence of serious AEs and liver function test abnormalities with atezolizumab TRAEs = treatment-related adverse events. Gianni L, et al. 2019 San Antonio Breast Cancer Symposium; Abstract GS3-04. 19 19 KEYNOTE-355: First-line Pembrolizumab in PD-L1+ Patients With mTNBC • Phase 3 trial; chemotherapy ( nab -paclitaxel, paclitaxel, or gemcitabine/carboplatin) with or without pembrolizumab • Primary endpoint: PFS and OS in the overall population vs PD-L1-positive ‒ PD-L1 status defined by 22C3 assay with CPS • Interim analysis: in patients with PD-L1 CPS >10, first-line pembrolizumab + chemotherapy demonstrated statistically significant and clinically meaningful improvement in PFS compared with chemotherapy alone ‒ No new safety signals observed with pembrolizumab 20 Tucker N. www.targetedonc.com/news/keynote355-meets-a-coprimary-end-point-for-treatment-of-patients-with-mtnbc. Accessed Mar 23, 2020. 20 Case Study (cont’d) • After her second treatment with atezolizumab plus nab -paclitaxel, Carol returns to your office with a rash on her chest and back ‒ She says she is very uncomfortable ‒ She has tried to treat the rash with high-potency topical corticosteroids with no relief • You diagnose inflammatory dermatitis 21 21 2020 PCE Spring Oncology Series 7

  35. Triple-Negative Breast Cancer: Fitting New and Emerging Strategies Into Patient Care Potential irAEs With Immune Checkpoint Inhibitors System irAEs Ocular Uveitis, episcleritis Pulmonary Pneumonitis Hepatic Increased liver function enzymes Pancreatic Elevated lipase levels Infusion-related Infusion-related reaction or hypersensitivity Endocrine Hypothyroidism, hyperthyroidism, hypopituitarism, hypophysitis, adrenal insufficiency • Testing for TSH and FT4 every 4 to 6 weeks should be part of routine clinical monitoring on therapy Dermatologic Pruritus, rash, vitiligo, alopecia Gastrointestinal Diarrhea, colitis, nausea General Fatigue, headache, decreased appetite, arthralgia irAEs = immune-related adverse events; FT4 = free thyroxine 4; TSH = thyroid stimulating hormone. Brahmer JR, et al. J Clin Oncol . 2018;36:1714-1768; Cancer Council Victoria. www.cancervic.org.au/cancer-information/treatments/treatments- types/immunotherapy. Accessed Mar 23, 2020; Postow MA, et al. N Engl J Med . 2018;378:158-168. 22 22 Current Recommendations: Managing irAEs With Immune Checkpoint Inhibitors Toxicity Grade Recommendation Continue checkpoint inhibitors with close monitoring, with the exception of some neurologic, hematologic, Grade 1 and cardiac toxicities Hold for most grade 2 toxicities and consider resuming when symptoms and/or laboratory values return to grade 1 or less Grade 2 Corticosteroids (initial dose of 0.5-1 mg/kg/d of prednisone or equivalent) may be given • For pneumonitis, corticosteroids need to be tapered slowly over at least 4 weeks to prevent flare-up Hold checkpoint inhibitors; initiate high-dose corticosteroids (prednisone 1-2 mg/kg/d or methylprednisolone IV 1-2 mg/kg/d) • Taper corticosteroids over course of at least 4 to 6 weeks • If symptoms do not improve with 48 to 72 hours of high-dose corticosteroid, infliximab may be offered for Grade 3 some toxicities • Consider resuming checkpoint inhibitors when symptoms and/or laboratory values return to grade 1, after discussion of risk/benefits with patients Warrants permanent discontinuation of checkpoint inhibitors, with exception of endocrinopathies controlled by Grade 4 hormone replacement 23 Brahmer JR, et al. J Clin Oncol . 2018;36:1714-1768; Postow MA, et al. N Engl J Med . 2018;378:158-168. 23 Immune Checkpoint Inhibitors: Patient and Caregiver Education • Immunotherapy may take longer to work than other cancer treatments ‒ Disease may progress before patients experience improvement • Most irAEs occur within 2 to 3 treatment cycles, but can occur any time—even after therapy is discontinued ‒ Typically mild, but can be severe, irreversible, or life-threatening ‒ Do not occur in all patients for unknown reasons • Need for management of side effects throughout the continuum of cancer care Brahmer JR, et al. J Clin Oncol . 2018;36:1714-1768; Cancer Council Victoria. www.cancervic.org.au/cancer-information/treatments/treatments- 24 types/immunotherapy. Accessed Mar 23, 2020; Postow MA, et al. N Engl J Med . 2018;378:158-168. 24 2020 PCE Spring Oncology Series 8

  36. Triple-Negative Breast Cancer: Fitting New and Emerging Strategies Into Patient Care Case Study (cont’d) • 14 months after treatment with atezolizumab and nab -paclitaxel, Carol develops shortness of breath • A scan shows multiple bilateral pulmonary nodules ‒ Biopsy of one of the nodules showed it to be consistent with the primary cancer 25 25 PARP Inhibition in TNBC • PARP — enzymes that help maintain DNA integrity during replication • When cells lack BRCA1 or 2 —proteins involved in homologous-directed repairs of DNA—PARP inhibitors disrupt DNA damage repair mechanisms of tumor cells ‒ May lead to cell death and potentially reduction or stoppage of tumor growth ‒ May play a role in treatment of TNBC: BRCA mutations often associated with TNBC PARP BER Cell Survival DNA Damage Pathway DNA Repair Inactivated PARP NAD+ BER indicates base excision repair PARP Apoptosis Inhibition DNA Collapse BER = base excision repair; NAD = nicotinamide adenine dinucleotide. Benafif S, Hall M. Onco Targets Ther. 2015;8:519-528; Livraghi L, Garber JE. BMC Med . 2015;13:188; Okuma HS, Yonemori K. 26 Adv Exp Med Biol. 2017;1026:271-286. 26 OlympiAD: Olaparib Therapy Significantly Improved PFS • Olaparib vs chemotherapy evaluated in BRCA -mutated, high-risk, HER2-negative primary breast cancer previously treated with two lines of chemotherapy 100 90 80 Olaparib Chemotherapy TPC 70 (n = 205) (n = 97) PFS (%) 60 Events (%) 163 (79.5) 71 (73.2) 50 Olaparib Median PFS, months 7.0 4.2 40 30 Standard therapy 20 10 0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 Time From Randomization (months) TPC = treatment of physician’s choice. 27 Lynparza [prescribing information]. AstraZeneca Pharmaceuticals LP; 2019; Robson M, et al. N Engl J Med. 2017;377:523-533. 27 2020 PCE Spring Oncology Series 9

  37. Triple-Negative Breast Cancer: Fitting New and Emerging Strategies Into Patient Care OlympiAD: Overall Survival Analysis • No significant OS benefit at 64% data maturity: olaparib 19.3 vs TPC 17.1 months • Possible meaningful OS benefit among chemotherapy-naïve patients Overall population No prior chemotherapy Olaparib TPC 1.0 Olaparib TPC 1.0 Deaths, n (%) 130 (63) 62 (64) Deaths, n (%) 30 (50.8) 21 (75.0) 0.9 0.9 Median OS, mo 19.3 17.1 Median OS, mo 22.6 14.7 0.8 Probability of OS 0.8 Probability of OS 0.7 0.7 Olaparib 0.6 0.6 Olaparib 0.5 0.5 0.4 0.4 TPC 0.3 0.3 TPC 0.2 0.2 0.1 0.1 0.0 0.0 0 4 8 12 16 20 24 28 32 36 40 0 4 8 12 16 20 24 28 32 36 40 Time From Randomization (months) Time From Randomization (months) No. at risk No. at risk Olaparib 205 199 178 146 124 92 55 23 11 6 0 Olaparib 59 57 53 44 40 32 17 7 5 4 0 TPC 97 85 74 62 48 40 30 15 5 2 0 TPC 28 25 20 17 12 9 7 4 1 0 0 Robson ME, et al. Annals Oncol . 2019;30:558-566. 28 28 EMBRACA: Talazoparib Significantly Improved PFS • Talazoparib vs standard chemotherapy for Talazoparib Standard Therapy locally advanced or metastatic breast cancer (n = 287) (n = 144) with a germline BRCA1/2 mutation Events (%) 186 (65) 83 (58) Median, months (95% CI) 8.6 (7.2, 9.3) 5.6 (4.2, 6.7) 100 90 80 70 PFS (%) 60 50 40 30 T alazoparib 20 Standard therapy 10 0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 Months 29 Litton JK, et al. N Engl J Med. 2018;379:753-763; Talzenna [prescribing information]. Pfizer Inc.; 2019. 29 Talazoparib and the EMBRACA Trial: No Significant Improvement in OS* Talazoparib Standard Therapy (n = 287) (n = 144) 100 Events (%) 108 (38) 55 (38) 90 80 Median, months (95% CI) 22.3 (18.1-26.2) 19.5 (16.3-22.4) 70 OS (%) 60 50 40 Talazoparib 30 20 Standard therapy 10 0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 Months *These findings represent immature interim data. 30 Litton JK, et al. N Engl J Med. 2018;379:753-763. 30 2020 PCE Spring Oncology Series 10

  38. Triple-Negative Breast Cancer: Fitting New and Emerging Strategies Into Patient Care Management of Toxicities Associated With PARP Inhibitors • Majority of AEs typically occur during first cycles of treatment Toxicity Management Strategy Hematologic • Common class effect, particularly anemia • Monitor CBC with differential monthly in patients starting a PARP inhibitor or undergoing dose modification • Transfusions recommended for symptomatic anemia and for hemoglobin <7 g/dL Gastrointestinal • Common for all PARP inhibitors, especially nausea • Mostly based on expert opinion; similar to management of chemotherapy-induced GI toxicities Renal • Elevated serum creatinine might not reflect a true decline in GFR or kidney insufficiency • If GFR is appropriate, avoid dose reductions or interruptions Fatigue • Universal toxicity for all PARP inhibitors • Consider nonpharmacologic treatments: exercise, massage therapy, cognitive behavioral therapy • For more symptomatic patients, consider pharmacologic interventions with psychostimulants, such as methylphenidate and ginseng CBC = complete blood count; GFR = glomerular filtration rate. LaFargue CJ, et al. Lancet Oncol. 2019;20:e15-e28. 31 31 Management of Toxicities Associated With PARP Inhibitors (cont’d) Toxicity Management Strategy Laboratory • Increased cholesterol and serum aminotransferase common abnormalities • Manage persistent hypercholesterolemia with appropriate statin therapy, with careful attention to elevated liver enzymes Less Common Toxicities Neurologic • Headache, insomnia • Offer symptomatic therapies Respiratory • Most involve dyspnea, cough, nasopharyngitis, and upper respiratory tract infection • With new or worsening respiratory symptoms, hold PARP inhibitor and rule out cause Cutaneous • Mostly mild and consist of photosensitivity reactions, pruritus, rash, and peripheral edema • Counsel patients to use sun protection measures and skin moisturizers 32 LaFargue CJ, et al. Lancet Oncol. 2019;20:e15-e28. 32 Management of Nonhematologic AEs for PARP Inhibitors by Grade Grade Management Strategies • Continue PARP inhibitor 1 • Symptomatic treatment if necessary • Continue PARP inhibitor 2 • Consider dose interruption, reduction, or both, if toxicity remains uncontrolled despite symptomatic or prophylactic therapies • Withhold until resolution of AE: for olaparib, ≤grade 1 • Might continue treatment if AE is nausea, vomiting, or diarrhea, and controlled on 3 or 4 medication • If treatment was interrupted, consider dose reduction upon resumption (particularly if after second time withholding) 3 or 4 lasting more than 28 • Discontinue PARP inhibitor days with the lowest dose of PARP inhibitor 33 LaFargue CJ, et al. Lancet Oncol. 2019;20:e15-e28. 33 2020 PCE Spring Oncology Series 11

  39. Triple-Negative Breast Cancer: Fitting New and Emerging Strategies Into Patient Care Case Conclusion • Carol’s pulmonary nodules show minor response for 6 months, then progress • She is started on eribulin 34 34 Later-line Therapy • Options include carboplatin, gemcitabine, eribulin, vinorelbine • Best supportive care is also an option • Newly approved therapy: ‒ Sacituzumab govitecan-hziy; first-in-class ADC in mTNBC: • In third line or later therapy: response rate 33.3%; clinical benefit rate (including stable disease for at least 6 months), 45.4% • Phase 3 trial in mTNBC refractory or relapsing after at least 2 prior chemotherapies (including a taxane) compared with TPC currently under way ADC = antibody-drug conjugate. Bardia A, et al. N Engl J Med . 2019;380:741-751; ClinicalTrials.gov. clinicaltrials.gov/ct2/show/NCT02574455?term=eribulin&cond= 35 Triple+Negative+Breast+Cancer&phase=2&draw=2&rank=3. Accessed Mar 23, 2020. 35 PCE Action Plan  Test all patients with metastatic breast cancer for BRCA1/2 mutations  Test all patients with mTNBC for PD-L1  Consider rechallenge with checkpoint inhibitor therapy with caution in patients whose irAE symptoms and/or laboratory values revert to grade  1 after higher grade toxicity and drug holding  Initiate a discussion with patients and caregivers on how checkpoint inhibitor therapy differs from chemotherapy  Closely monitor patients for AEs during the first cycles of treatment with PARP inhibitors PCE Promotes Practice Change 36 36 2020 PCE Spring Oncology Series 12

  40. Key Updates in the Treatment of HER2-Positive Breast Cancer Key Updates in the Treatment of HER2-Positive Breast Cancer 1 Learning Objectives • Apply current evidence and guideline recommendations to identify the appropriate use of and optimally sequence HER2-targeted agents in the treatment of HER2- positive metastatic breast cancer • Evaluate emerging research, the mechanisms of action, and the role of novel HER2-targeted therapies in clinical investigation for patients with HER2-positive metastatic breast cancer • Implement best practices for the management of HER2-positive breast cancer brain metastases • Develop strategies to effectively manage adverse events associated with treatments for HER2-positive breast cancer 2 HER2 = human epidermal growth factor receptor 2. 2 Targeted Therapies for HER2+ Breast Cancer HER2-Targeted mAbs HER2-Targeted ADCs Pertuzumab T-DM1 Trastuzumab HER2 T-DXd HER3 HER2 HER2 HER2 P P hsp90 P Lapatinib P P MK-2206 inhibitor BKM120 HER2-Targeted Neratinib P13K Proteasome BEZ235 TKIs Tucatinib T-DM1 hsp90 AKT T-DXd Breakdown Everolimus mTOR of HER2 Temsirolimus P Endosome T-DM1 T-DXd ADC = antibody–drug conjugate; mAb = monoclonal antibody; TKI = tyrosine kinase inhibitor. 3 Gajria. Expert Rev Anticancer Ther. 2011;11:263. Pernas. Ther Adv Med Oncol. 2019;11:1758835919833519. 3 PCE 2020 Spring Oncology Series 1

  41. Key Updates in the Treatment of HER2-Positive Breast Cancer Guideline-Recommended Regimens for HER2-Positive Recurrent or Stage IV Breast Cancer Preferred regimens* Other Recommended Regimens* • Taxane + trastuzumab + pertuzumab (THP) † • Ado-trastuzumab emtansine (T-DM1) • Trastuzumab deruxtecan (T-DXd) • Trastuzumab + chemotherapy ‡§ • Trastuzumab + lapatinib (without cytotoxic therapy) • Trastuzumab + other agents § • Lapatinib + capecitabine • Neratinib + capecitabine • Trastuzumab + capecitabine + tucatinib *An FDA-approved biosimilar is an acceptable substitute for trastuzumab. † Docetaxel or paclitaxel. ‡ Paclitaxel ± carboplatin, docetaxel, vinorelbine, capecitabine. § Anthracyclines should be avoided due to significant cardiotoxicity. Wang. Signal Transduct Target Ther. 2019;4:34. Pernas. Ther Adv Med Oncol. 2019:11:1758835919833519. 4 4 CLEOPATRA: Standard First-line Treatment for HER2+ MBC With Docetaxel/Trastuzumab/Pertuzumab End of Study OS in ITT Population* 8 yrs Median OS, Mos 100 THP 57.1 80 TH + Pbo 40.8 OS (%) 60 Landmark OS: 37% Events: 235 (58.5%) 40 20 Landmark OS: 23% HR: 0.69 (95% CI: 0.58-0.82) Events: 280 (69.0%) 0 60 80 90 100 110 120 130 0 10 20 30 40 50 70 Mos Patients at Risk, n THP 402 371 318 269 228 188 165 150 137 120 71 20 0 0 TH + Pbo 406 350 289 230 181 149 115 96 88 75 44 11 1 0 *Crossover patients were analyzed in the placebo arm. H = trastuzumab; HR = hazard ratio; ITT = intention-to-treat; OS = overall survival; P = pertuzumab; Pbo = placebo; T = docetaxel. 5 Swain. ASCO 2019. Abstr 1020. 5 MARIANNE: First-line T-DM1 ± Pertuzumab versus Docetaxel/Trastuzumab in HER2+ MBC TH (n = 365) T-DM1 (n = 367) T-DM1 + P (n = 363) Median OS, mos 50.9 53.7 51.8 Events, n 169 175 168 100 Stratified HR vs HT (97.5% CI) -- 0.93 (0.73-1.20) 0.86 (0.67-1.11) Stratified HR vs T-DM1 (97.5% CI) -- -- 1.00 (0.78-1.28) 80 60 OS (%) 40 TH T-DM1 20 T-DM1 + P 0 Day 1 12 Mos 24 Mos 36 Mos 48 Mos 60 Mos 72 Mos Patients at Risk, n TH 365 303 251 197 155 28 T-DM1 367 322 264 216 176 37 T-DM1 + P 363 309 257 217 172 41 T-DM1 = trastuzumab emtansine. 6 Perez. Cancer. 2019;125:3974. 6 PCE 2020 Spring Oncology Series 2

  42. Key Updates in the Treatment of HER2-Positive Breast Cancer MARIANNE: Grade ≥ 3 AEs Trastuzumab + Taxane T-DM1 T-DM1 + Pertuzumab Grade ≥ 3 AE, % (n = 353) (n = 361) (n = 366) Any 55.8 47.1 48.6 Greater incidence Alopecia 60.1 7.2 9.0 with trastuzumab + CT 19.3 4.4 3.8 Neutropenia 6.5 0 0 Febrile neutropenia 4.2 0.3 2.7 Diarrhea 3.1 4.7 5.5 Greater incidence Hypertension with T-DM1 2.8 5.0 7.1 Anemia 0.8 4.4 6.0 ALT increase 0.3 6.9 3.3 AST increase 0.3 3.3 2.5 GGT increase 0 6.6 9.0 Thrombocytopenia AE = adverse event; ALT = alanine aminotransferase; AST = aspartate aminotransferase; CT = chemotherapy; GGT = gamma-glutamyl transferase. Perez. Cancer. 2019;125:3974. 7 7 EMILIA and TH3RESA: Standard Second-line Therapy for HER2+ MBC With T-DM1 After Progression on HER2-Targeted Agents EMILIA [1] : Randomized phase III study of T-DM1 vs lapatinib + TH3RESA [2] : Randomized phase III study of T-DM1 vs physician’s capecitabine for HER2+ MBC with progression on trastuzumab + choice for HER2+ MBC with progression on a taxane, lapatinib, and taxane (N = 991) ≥2 HER2-targeted regimens including trastuzumab (N = 602) Median OS, mos T-DM1 30.9 100 100 Median OS, mos 85.2% Lapatinib + Cape 25.1 T-DM1 22.7 80 80 Physician’s choice 15.8 78.4% 64.7% 60 OS (%) 60 OS (%) 51.8% 40 40 HR: 0.68 (95% CI: 0.55-0.85; P < .001) 20 20 HR: 0.68 (95% CI: 0.54-0.85; P = .0007) Efficacy stopping boundary: HR of 0.73 or P = .0037 0 0 38 40 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 Mos Mos Patients at Risk, n Patients at Risk, n (censored) Lapatinib + cape 496 471 453 435 403 368 297 240 204 159 133 110 86 63 45 27 17 7 4 Physician’s 198 (0) 150 (28) 122 (31) 107 (33) 80 (34) 66 (36) 59 (37) 39 (45) 16 (68) 1 (80) 0 choice T-DM1 495 485 474 457 439 418 349 293 242 197 164 136 111 86 62 38 28 13 5 T-DM1 404 (0) 368 (17) 321 (29) 280 (35) 226 (43) 192 (44) 167 (45) 132 (66) 54 (138) 12 (172) 0 Cape = capecitabine; MBC = metastatic breast cancer; T-DM1 = trastuzumab emtansine. 8 1. Verma. NEJM. 2012;367:1783. 2. Krop. Lancet Oncol. 2017;18:743. 8 What’s New in HER2-Targeted Agents? • HER2 TKIs ‒ Neratinib ‒ Tucatinib (FDA approved 4/2020) • HER2 ADCs ‒ Trastuzumab deruxtecan (T-DXd; approved 12/2019) ‒ Trastuzumab duocarmazine/trastuzumab-vc-seco-DUBA (SYD985) 9 ADC = antibody–drug conjugate; mAb = monoclonal antibody; TKI = tyrosine kinase inhibitor. 9 PCE 2020 Spring Oncology Series 3

  43. Key Updates in the Treatment of HER2-Positive Breast Cancer Case Study: Sonia • 49-yr-old woman presents with back pain and left breast mass (4 cm) ‒ She has no significant family history or past medical history ‒ Core biopsy of breast mass: invasive ductal carcinoma; ER: 0%, PgR: 0%, HER2: 3+ ‒ PET/CT: 3 liver lesions (largest 2 cm); several vertebral lesions in the thoracic and lower spine • She receives docetaxel/trastuzumab/pertuzumab (THP) and achieves PR in liver after 3 mos on therapy ‒ 18 mos later, progression is noted in liver (new 3-cm lesion, other lesions stable) • Receives T-DM1 and achieves PR in liver, with stable bone lesions ‒ 10 mos later, she complains of headache ‒ MRI of the brain: 3 lesions (1 cm) in the left frontal lobe with minimal edema ‒ PET/CT: liver lesions remain unchanged, no new liver lesions; bone lesions stable ER = estrogen receptor, PgR = progesterone receptor, PR = partial response; T-DM1 = trastuzumab emtansine. 10 10 Optimal Sequence of HER2-Targeted Agents for Patients With HER2-Positive MBC • Multiple treatment options are available for patients with HER2-positive MBC • Clinicians should reassess risks and benefits of additional lines of therapy based on patient’s fitness, comorbidities, and preferences at progression • If additional treatment is indicated, select therapy based on disease features as well as patient’s fitness, comorbidities, and preferences 11 11 In HER2+ MBC, CNS Disease Remains Incurable Despite Current Treatment Options • ≥ 50% of patients with HER2+ MBC will develop Risk of CNS Metastasis in HER2+ MBC by Subgroup [2] brain metastases [1] OR (95% CI) Ethnicity: Hispanic/Latino • Lapatinib + capecitabine approved in this No vs Yes 1.181 (0.718-1.943) Race setting but few patients respond Other vs black/African American 1.268 (0.580-2.769) ‒ In a pooled analysis, CNS ORR was 21.4%, White vs black/African American 1.619 (1.072-2.444) Age at MBC diagnosis median PFS was 4.1 mos, median OS was 50-69 vs ≥ 70 years 2.042 (1.248-3.341) 11.2 mos [1] < 50 vs ≥ 70 years 3.128 (1.852-5.284) ECOG PS • Neratinib + capecitabine approved in this 1 vs 0 1.192 (0.876-1.622) setting in Feb 2020 ≥ 2 vs 0 1.900 (1.125-3.201) • Trastuzumab + capecitabine + tucatinib MBC diagnosis type Recurrent vs de novo 1.650 (1.239-2.196) approved in this setting in April 2020 Hormone receptor status • T-DM1, trastuzumab, and pertuzumab do not Negative vs positive 1.841 (1.359-2.494) penetrate the CNS under normal conditions 0 1 4 2 3 5 Lower Risk of CNS Metastasis Higher Risk of CNS Metastasis CNS = central nervous system; ECOG = Eastern Cooperative Oncology Group; MBC = metastatic breast cancer; OR = odds ratio; PS = performance status; T-DM1 = trastuzumab emtansine. 12 1. Petrelli. Eur J Cancer. 2017;84:141. 2. Hurvitz. Clin Cancer Res. 2019;25:2433. 12 PCE 2020 Spring Oncology Series 4

  44. Key Updates in the Treatment of HER2-Positive Breast Cancer SystHERs Registry Analysis: PFS and OS by CNS Metastasis in HER2+ MBC CNS Mets CNS Mets CNS Mets CNS Mets No CNS Mets No CNS Mets PFS OS at Dx After Dx at Dx After Dx (n = 678) (n = 678) (n = 87) (n = 212) (n = 87) (n = 212) Median PFS, mos 19.1 9.2 9.9 Median OS, mos NE 30.2 38.3 2.49 2.52 2.86 1.94 HR (95% CI) HR(95% CI) -- -- (1.93-3.20) (2.13-2.99) (2.05-4.00) (1.52-2.49) vs no CNS mets vs no CNS mets P < .0001 P < .0001 P < .0001 P < .0001 1.0 1.0 Proportion With PFS 0.8 Proportion Surviving 0.8 0.6 0.6 0.4 0.4 0.2 0.2 0 0 0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 Mos on Study Since MBC Diagnosis Mos on Study Since MBC Diagnosis CNS = central nervous system; Dx = diagnosis; MBC = metastatic breast cancer; mets = metastases; NE = not estimable. 13 Hurvitz. Clin Cancer Res. 2019;25:2433. 13 CEREBEL: CNS Metastasis at First Relapse in HER2+ MBC With Lapatinib/Cape vs Trastuzumab/Cape 21-day • Randomized phase III study L + Cape T + Cape P cycle Endpoint (n = 251) (n = 250) Value Stratified by prior trastuzumab, lines of prior tx for MBC (0 vs ≥ 1) CNS as first 8 (3) 12 (5) .360 site of progression, n (%) Lapatinib 1250 mg/day + Patients with HER2+ MBC, Incidence of CNS 17 (7) 15 (6) .865 Capecitabine 2000 mg/m 2 /day any line of tx, including progression at any time, n (%) on Days 1-14 prior anthracyclines or Median time to first 5.7 4.4 NR taxanes; no CNS CNS progression, mos (range) (2-17) (2-27) metastasis Trastuzumab* 6 mg/kg Q3W + Median PFS, mos 6.6 8.1 .021 (N = 540) Capecitabine 2500 mg/m 2 /day • Trastuzumab naive 6.3 10.9 NR on Days 1-14 Median OS, mos 22.7 27.3 .095 *Loading dose of 8 mg/kg. ORR, % 27 32 NR • Trial closed early for futility in lapatinib • Primary endpoint: CNS as first site of relapse + capecitabine arm • Secondary endpoints: PFS, OS Cape = capecitabine; CNS = central nervous system; L = lapatinib; MBC = metastatic breast cancer; NR = not reported; T = trastuzumab; tx = therapy. 14 Pivot. JCO. 2015;33:1564. 14 Neratinib: Mechanism of Action • Pan-HER TKI HER1 (EGFR) HER2 HER3 HER4 Pertuzumab • Irreversible inhibition • Different MoA than trastuzumab and pertuzumab T-DM1 Trastuzumab Neratinib Lapatinib MoA = mechanism of action; T-DM1 = trastuzumab emtansine; TKI = tyrosine kinase inhibitor. 15 Baselga. Crit Rev Oncol Hematol. 2017;119:113. 15 PCE 2020 Spring Oncology Series 5

  45. ̶ Key Updates in the Treatment of HER2-Positive Breast Cancer NEfERT-T and TBCRC 022: Neratinib in HER2+ MBC TBCRC 022 Cohort 3 [2] : Single-arm 2-stage phase II study of NEfERT-T [1] : Randomized phase III study of neratinib/capecitabine in HER2+ MBC with CNS disease (n = 49) neratinib/paclitaxel vs trastuzumab/paclitaxel in previously untreated, HER2+ locally recurrent or MBC (N = 479) Best CNS Volumetric Response With Neratinib + Cape 1.0 100 in Lapatinib-Naive Patients (n = 37*) 0.8 80 Progression (%) Change From Baseline (%) 60 18 responses by volumetric criteria; No CNS 0.6 Neratinib + paclitaxel 40 CNS ORR: 49% (95% CI: 32-66) 0.4 Trastuzumab + paclitaxel 20 0 0.2 HR:0.449 (95% CI: 0.259-0.780; log-rank P = .0036) -20 0 CNS ORR with prior -40 0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 lapatinib: 33% (95% † Mos -60 CI: 10-65) †† Events Median Time to CNS Progression † †††† -80 *n = 6 who did not reach first reimaging assigned 0. N + P (n = 242) 20 NE -100 † CNS response by RANO-BM criteria. † T + P (n = 237) 41 NE Cape = capecitabine; CNS = central nervous system; MBC = metastatic breast cancer; N = neratinib; NE = not estimable; P = paclitaxel; RANO-BM = Response Assessment in Neuro-Oncology Brain Metastases criteria; T = trastuzumab. 1. Awada. JAMA Oncol. 2016;2:1557. 2. Freedman. JCO. 2019;13:1081. 16 16 NALA: Neratinib/Cape vs Lapatinib/Cape in HER2+ MBC With ≥ 2 Prior Lines of HER2-Targeted Agents • International, open-label, randomized phase III trial 21-day cycle Stratified by no. prior HER2-targeted therapies, disease location, hormone receptor status, geographic location Neratinib 240 mg/day PO continuously + Capecitabine * 1500 mg/m 2 PO on Days 1-14 † Patients with centrally confirmed (n = 307) Until PD HER2+ MBC; previously treated with ≥ 2 lines of HER2-targeted Survival Lapatinib 1250 mg/day PO continuously + agents for MBC; asymptomatic, follow-up Capecitabine * 2000 mg/m 2 PO on Days 1-14 stable brain metastases allowed (n = 314) (N = 621) *BID in 2 evenly divided doses. † Loperamide administered at 4 mg with first neratinib dose followed by 2 mg Q4H for first 3 days, followed by 2 mg every 6-8 hrs through end of cycle 1; as needed thereafter. • Secondary endpoints: PFS (locally determined), ORR, • Coprimary endpoints: OS, PFS (centrally confirmed) DoR, CBR, intervention for CNS metastases, safety, PRO Study positive if either endpoint statistically significant (OS, P < .04; PFS, P < .01) • No endocrine therapy permitted Cape = capecitabine; CBR = clinical benefit rate; CNS = central nervous system; DoR = duration of response; MBC = metastatic breast cancer; PD = progressive disease; PRO = patient-reported outcomes. 17 Saura. ASCO 2019. Abstr 1002. NCT01808573. 17 NALA: Baseline Characteristics Neratinib + Capecitabine Lapatinib + Capecitabine Characteristic, n (%) (n = 307) (n = 314) Age < 65 yrs 244 (79) 248 (79) Geographic region • Europe 121 (39) 123 (39) • North America 59 (19) 65 (21) • Rest of world 127 (41) 126 (40) Hormone receptor+ (ER+ and/or PgR+) 181 (59) 186 (59) Visceral disease at enrollment 247 (80) 253 (81) De novo metastatic disease 139 (45) 136 (43) No. prior HER2-targeted therapies for MBC • 2 215 (70) 215 (68) • ≥ 3 92 (30) 99 (32) Prior HER2-targeted therapies for MBC • Trastuzumab only 124 (40) 113 (36) • Trastuzumab + pertuzumab 24 (8) 23 (7) • Trastuzumab + T-DM1 58 (19) 64 (20) • Trastuzumab + pertuzumab + T-DM1 101 (33) 114 (36) MBC = metastatic breast cancer; T-DM1 = trastuzumab emtansine. 18 Saura. ASCO 2019. Abstr 1002. 18 PCE 2020 Spring Oncology Series 6

  46. Key Updates in the Treatment of HER2-Positive Breast Cancer NALA: Survival PFS (Prespecified Means Analysis) OS (Coprimary Endpoint) Mean OS, Mean PFS, Mos Mos Log-Rank Neratinib + capecitabine 8.8 P Value 1.0 Neratinib + capecitabine 24.0 HR (95% CI) 1.0 Lapatinib + capecitabine 6.6 0.88 (0.72-1.07) .2086 Lapatinib + capecitabine 22.2 0.8 0.8 Probability of OS Probability of PFS 0.6 0.6 Restriction: Restriction: 24 mos 0.4 0.4 48 mos Restricted mean analysis P = .0003 0.2 0.2 1.7 mos 2.2 mos 0 0 0 0 3 6 9 12 15 18 21 24 27 30 33 36 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 Patients Mos Since Randomization Mos Since Randomization Patients at Risk, n at Risk, n N + Cape 307 183 113 69 54 35 20 13 9 7 3 2 2 N + Cape 307 294 275 244 220 182 142 112 82 64 47 34 28 18 15 13 6 4 2 1 L + Cape 314 183 82 39 24 9 8 3 2 2 2 2 1 L + Cape 314 303 273 240 208 170 132 107 84 67 47 36 27 22 17 12 8 4 3 1 Cape = capecitabine; L = lapatinib; N = neratinib. Saura. ASCO 2019. Abstr 1002. 19 19 NALA: Time to Intervention for CNS Metastases 100 Neratinib + Capecitabine Lapatinib + Capecitabine (n = 55/307) (n = 75/314) Intervention, % 11 15 Radiation therapy 80 2 3 Surgery/procedure Cumulative incidence (%) 1 1 Anticancer medication 60 Neratinib + capecitabine Overall cumulative incidence (Gray’s test): 22.8% vs 29.2% ; P = .043 Lapatinib + capecitabine 40 20 0 0 6 12 18 24 30 36 42 48 54 60 Mos Since Randomization CNS = central nervous system. 20 Saura. ASCO 2019. Abstr 1002. 20 NALA: Safety Neratinib + Capecitabine (n = 303) Lapatinib + Capecitabine (n = 311) Treatment-Emergent AE, % All Grade Grade 3/4 All Grade Grade 3/4 Overall 100 61 99 60 • Diarrhea 83 24* 66 13* • Hand–foot syndrome 46 10 56 11 • Hypokalemia 12 5 14 6 • Nausea 53 4 42 3 • Vomiting 46 4 31 2 • Fatigue 34 3 31 3 • Neutropenia 7 3 5 2 • Asthenia 12 3 12 2 • Decreased appetite 35 3 22 2 • Dehydration 6 2 6 2 • Median duration of treatment numerically longer with • Discontinuation due to treatment-emergent AEs: neratinib vs lapatinib (5.7 vs 4.4 mos) neratinib arm, 10.9%; lapatinib arm, 14.5% *No grade 4 diarrhea observed. AE = adverse event. 21 Saura. ASCO 2019. Abstr 1002. 21 PCE 2020 Spring Oncology Series 7

  47. Key Updates in the Treatment of HER2-Positive Breast Cancer Phase II CONTROL Trial: Antidiarrheal Prophylaxis for Neratinib- Associated Diarrhea in Early HER2+ BC • Open-label phase II trial enrolled adults with stage I-IIIC HER2+ BC who completed trastuzumab- based adjuvant therapy* within 1 yr or who d/c due to AE (N = 501) All prophylaxis cohorts Neratinib 240 mg/day (13 cycles) Neratinib dose-escalation cohorts Neratinib 120 mg/day D1-7  160 mg/day D8-14 Loperamide (LPM) LPM 4 mg TID D1-14, then BID D15-56  240 mg/day (13 cycles) Budesonide 9 mg QD for 1 cycle LPM + Budesonide LPM as needed (16 mg/day max) LPM 4 mg TID D1-14, then BID D15-56 Colestipol 2 g BID for 1 cycle Neratinib 160 mg/day D1-14  200 mg/day D15-28 LPM + Colestipol  240 mg/day (13 cycles) LPM 4 mg TID D1-14, then BID D15-28 Colestipol 2 g BID for 1 cycle; Colestipol + LPM prn LPM as needed (16 mg/day max) LPM as needed (16 mg/day max) 0 1 2 3 4 5 6 7 8 9 10 11 12 13 0 1 2 3 4 5 6 7 8 9 10 11 12 13 *28-day cycles. Treatment-emergent diarrhea also managed with neratinib interruption/reduction, BSC. Data cutoff: August 26, 2019.; *Includes trastuzumab, trastuzumab + pertuzumab, and T-DM1. BC = breast cancer; AE = adverse event; d/c = discontinued; LPM = loperamide; tx = treatment. 22 Chan. SABCS 2019. Abstr P5-14-03. Chan. Lancet Oncol. 2016;17:367. Hurvitz. SABCS 2017. P3-14-01. 22 ExteNET vs CONTROL: Antidiarrheal Prophylaxis Reduces Incidence, Severity of Diarrhea With Neratinib ExteNET*: Adj Neratinib in CONTROL* Trastuzumab-Treated HER2+ EBC (N = 1408) Loperamide LPM + Budesonide LPM + Colestipol Neratinib Dose Escalation (n = 137) (n = 64) + LPM prn (n = 60) (n = 136) 5% 3% 14% 17% 15% 21% 20% 23% 31% 28% 40% 40% 25% 24% 28% 35% 42% 32% 25% 33% Discontinuation rate 20.4% 10.9% 3.7% 3.3% due to diarrhea: None Grade 1 Grade 2 Grade 3 • All preventive strategies in CONTROL reduced incidence of grade ≥ 3 diarrhea compared with phase III ExteNET trial as historical control (40%) *n = 1 grade 4 diarrhea on ExteNET, none on CONTROL. Adj = adjuvant; EBC = early breast cancer. 23 Chan. SABCS 2019. Abstr P5-14-03. Chan. Lancet Oncol. 2016;17:367. Hurvitz. SABCS 2017. P3-14-01. 23 Tucatinib: HER2-Selective TKI O NH N • Less EGFR-associated toxicity than other H N N N HER2-targeted TKIs N N O N • CNS penetration Phase Ib: Tucatinib + T-DM1 in HER2+ MBC Overall Response in Patients with Measurable Disease • Well tolerated and active in combinations (eg, with T-DM1, capecitabine, or trastuzumab) 60 diameter of target lesions (%) Max change in sum of 40 1 prior HER2 agent 20 ≥ 2 prior HER2 agents 0 Cellular Selectivity, IC 50 (nM) Agent HER2 EGFR -20 Tucatinib 8 4000 -40 Neratinib 7 8 -60 Lapatinib 49 31 -80 -100 CNS = central nervous system; MBC = metastatic breast cancer; T-DM1 = trastuzumab emtansine; TKI = tyrosine kinase inhibitor. 24 Borges. ASCO 2016. Abstr 513. Borges. JAMA Oncol. 2018;4:1214-1220. 24 PCE 2020 Spring Oncology Series 8

  48. ̶ Key Updates in the Treatment of HER2-Positive Breast Cancer Phase Ib Study: Tucatinib + Capecitabine/Trastuzumab in HER2+ MBC Tucatinib + Capecitabine/Trastuzumab (n = 23) Tucatinib at RP2D in Evaluable Patients With Measurable CNS Disease (n = 12) Max Change in Sum of Tumor Diameters (%) Max Change in Sum of Tumor Diameters (%) 40 P P No brain mets (n = 14) 40 Brain mets (n = 9) 20 P Prior pertuzumab (n = 18) 20 P P 0 0 P P -20 -20 P P P P P -40 -40 -60 P P Tucatinib + cape -60 P Tucatinib + Tz -80 P Tucatinib + cape + Tz Screening Post Cycle 6 -80 ORR: 61% (14/23) P -100 (Images selected to demonstrate mDoR: 10 mos (95% CI: 2.8-19.3) CNS ORR: 42% (5/12) -100 longest axis of lesions) P P n = 29 of 52 patients had brain mets at baseline, Bars represent change in measurable lesions, but some patients also have nonmeasurable lesions. n = 4 patients with 17 with nonmeasuarable lesions only nonmeasurable lesions only not included here. n = 1 patient did not have follow-up scan Cape = capecitabine; CNS = central nervous system; mDoR = median duration of response; MBC = metastatic breast cancer; mets = metastases; RP2D = recommended phase II dose; Tz = trastuzumab. Hamilton. SABCS 2016. Abstr P24-21-01. Murthy. Lancet Oncol. 2018;19:880. 25 25 HER2CLIMB: Phase II Study Design • Randomized, double-blind, placebo-controlled, active comparator phase II trial at 155 sites in 15 countries (February 2016 to May 2019); data cutoff: September 4, 2019; median f/u: 14.0 mos Stratified by brain mets (yes vs no), ECOG PS 21-day cycles (0 vs 1), and region (US or Canada vs rest of world) Tucatinib 300 mg PO BID + Patients with HER2+ MBC; Trastuzumab 6 mg/kg Q3W (loading dose: 8 mg/kg C1D1) + prior trastuzumab, pertuzumab, Capecitabine 1000 mg/m 2 PO BID on Days 1-14 and T-DM1; ECOG PS 0/1; (n = 410) brain mets allowed* (N = 612) Placebo PO BID + Trastuzumab 6 mg/kg Q3W (loading dose: 8 mg/kg C1D1) + *Including previously treated stable mets, untreated Capecitabine 1000 mg/m 2 PO BID on Days 1-14 mets not needing immediate local therapy, and (n = 202) previously treated progressing mets not needing immediate local tx. • Secondary endpoints (total population): OS, PFS in • Primary endpoint: PFS (RECIST v 1.1 by BICR) among patients with brain mets, ORR in patients with first 480 randomized patients measurable disease, safety in patients who received ≥ 90% power with 288 events at α = 5%, HR: 0.67 1 dose of study tx BICR = blinded independent central review; ECOG = Eastern Cooperative Oncology Group; f/u = follow-up; MBC = metastatic breast cancer; mets = metastases; RECIST = Response Evaluation Criteria in Solid Tumors; PS = performance status; T-DM1 = trastuzumab emtansine; tx = treatment. 26 Murthy. SABCS 2019. Abstr GS1-01. Murthy. NEJM. 2019;382:597. 26 HER2CLIMB: Baseline Characteristics (Total Population) Tucatinib + Trastuzumab/Capecitabine Placebo + Trastuzumab/Capecitabine Characteristic (n = 410) (n = 202) Female, n (%) 407 (99) 200 (99) Median age, yrs (range) 55.0 (22-80) 54.0 (25-82) ECOG PS 0/1, n (%) 204 (50)/206 (50) 94 (47)/108 (54) Stage IV at initial diagnosis, n (%) 143 (35) 77 (39) Hormone receptor status, n (%)  ER and/or PgR positive 243 (60) 127 (63)  ER and PgR negative 161 (40) 75 (37) Median prior lines of therapy, n (range)  Overall 4.0 (2-14) 4.0 (2-17)  Metastatic setting 3.0 (1-14) 3.0 (1-13) Presence or history of brain metastases, n (%) 198 (48) 93 (46)  Treated, stable 118 (59.6) 55 (59.1)  Untreated 44 (22.2) 22 (23.7)  Treated, progressing 36 (18.2) 16 (17.2) • Baseline characteristics balanced between endpoint populations and treatment arms ECOG = Eastern Cooperative Oncology Group; PS = performance status. 27 Murthy. SABCS 2019. Abstr GS1-01. Murthy. NEJM. 2019;382:597. 27 PCE 2020 Spring Oncology Series 9

  49. Key Updates in the Treatment of HER2-Positive Breast Cancer HER2CLIMB: PFS (Primary Endpoint Population) 100 Events, Median PFS, 1-Yr PFS, n/N Mos (95% CI) % (95% CI) Patients Alive and Free From Disease Progression (%) 7.8 (7.5-9.6) Tucatinib + Trastuzumab/Cape 178/320 33 (27-40) 80 5.6 (4.2-7.1) Placebo + Trastuzumab/Cape 97/160 12 (8-21) 62.9 HR: 0.54 (95% CI: 0.42-0.71; P < .00001) 60 46% reduction in risk of disease progression 46.3 40 33.1 20 12.3 0 0 3 6 9 12 15 18 21 24 27 30 33 36 Mos Since Randomization Patients at Risk, n Tucatinib arm 235 152 98 40 2 1 0 320 29 15 10 8 4 Placebo arm 160 94 45 27 6 4 2 1 1 0 0 0 0 Cape = capecitabine. Murthy. SABCS 2019. Abstr GS1-01. Murthy. NEJM. 2019;382:597. 28 28 HER2CLIMB: PFS in Patients With Brain Metastases (Total Population) 100 Events, Median PFS, 1-Yr PFS, n/N Mos (95% CI) % (95% CI) Patients Alive and Free From Disease Progression (%) Tucatinib + Trastuzumab/Cape 106/198 7.6 (6.2-9.5) 25 (17-34) 80 Placebo + Trastuzumab/Cape 51/93 5.4 (4.1-5.7) 0 60.4 60 HR: 0.48 (95% CI: 0.34-0.69; P < .00001) 52% reduction in risk of disease progression 40 24.9 33.9 20 0 0 0 3 6 9 12 15 18 21 24 27 30 33 36 Mos Since Randomization Patients at Risk, n Tucatinib arm 144 78 45 14 1 1 198 8 2 1 1 1 0 Placebo arm 93 49 12 4 0 0 0 0 0 0 0 0 0 Cape = capecitabine. 29 Murthy. SABCS 2019. Abstr GS1-01. Murthy. NEJM. 2019;382:597. 29 HER2CLIMB: OS (Total Population) 100 Events, Median OS, 2-Yr OS, n/N Mos (95% CI) % (95% CI) 75.5 Tucatinib + trastuzumab/cape 130/410 21.9 (18.3-31.0) 45 (37-53) 80 Placebo + trastuzumab/cape 85/202 17.4 (13.6-19.9) 27 (16-39) Patients Alive (%) 60 HR: 0.66 (95% CI: 0.50-0.88); P = .0048) 62.4 44.9 34% reduction in risk of death 40 26.6 20 0 0 3 6 9 12 15 18 21 24 27 30 33 36 Mos Since Randomization Patients at Risk, n Tucatinib Arm 410 388 322 245 178 123 80 51 34 20 10 4 0 160 119 77 2 1 0 Placebo Arm 202 191 48 32 19 7 5 Cape = capecitabine. 30 Murthy. SABCS 2019. Abstr GS1-01. Murthy. NEJM. 2019;382:597. 30 PCE 2020 Spring Oncology Series 10

  50. Key Updates in the Treatment of HER2-Positive Breast Cancer HER2CLIMB: OS Subgroup Analysis OS in Total Population Subgroup Event/N HR for Death (95% CI) Total 215/612 0.66 (0.50-0.88) Age ≥ 65 yrs 53/116 0.58 (0.32-1.06) 0.69 (0.50-0.95) < 65 yrs 162/496 Race 0.69 (0.50-0.96) White 160/444 0.51 (0.28-0.93) Nonwhite 55/168 Hormone receptor status 0.85 (0.59-1.23) Positive for ER, PgR, or both 128/370 0.50 (0.31-0.80) Negative for ER and PgR 87/242 Baseline brain metastasis 0.58 (0.40-0.85) Yes 114/291 0.72 (0.48-1.08) No 101/319 ECOG PS 0.51 (0.33-0.80) 0 81/298 1 134/314 0.84 (0.59-1.20) Geographic region United States and Canada 148/369 0.68 (0.48-0.95) Rest of world 67/243 0.63 (0.39-1.03) 0.1 1.0 10.0 Favors Tucatinib Arm Favors Placebo Arm ECOG = Eastern Cooperative Oncology Group; PS = performance status. 31 Murthy. SABCS 2019. Abstr GS1-01. Murthy. NEJM. 2019;382:597. 31 HER2CLIMB: Most Common Adverse Events (≥ 20% in Tucatinib Arm) 100 Grade Grade Grade 1 2 ≥ 3 80 Tucatinib + trastuzumab/cape Frequency (%) Placebo + trastuzumab/cape 60 40 20 0 ALT = alanine aminotransferase; AST = aspartate aminotransferase; Cape = capecitabine; PPE = palmar–plantar erythrodysesthesia. 32 Murthy. SABCS 2019. Abstr GS1-01. 32 Optimal Use of HER2-Targeted TKI for Patients With HER2- Positive MBC and Brain Metastases • HER2 TKIs known to have CNS penetration, data from clinical trials show systemic benefit as well as CNS benefit • Standard of care for patients with single or limited brain metastases continues to be radiotherapy of CNS lesions followed by continuation of current systemic therapy • For patients with progressive brain metastases despite initial radiotherapy, consider switching to systemic therapy with HER2 TKI • HER2 TKIs may also be an option for patients without brain lesions due to overall systemic benefit observed in clinical trials • On April 17, 2020, the FDA approved tucatinib in combination with trastuzumab/capecitabine for treatment of advanced, unresectable or metastatic HER2+ BC, including patients with brain metastases, who have received ≥ 1 previous HER2-targeted therapy in the metastatic setting 33 CNS = central nervous system; MBC = metastatic breast cancer; TKI = tyrosine kinase inhibitor. 33 PCE 2020 Spring Oncology Series 11

  51. Key Updates in the Treatment of HER2-Positive Breast Cancer Tucatinib Approval • On April 17, 2020, the FDA approved tucatinib in combination with trastuzumab/capecitabine for treatment of advanced, unresectable or metastatic HER2+ BC, including patients with brain metastases, who have received ≥ 1 previous HER2-targeted therapy in the metastatic setting ‒ Administration: 300 mg taken orally twice daily with or without food • Reduce dose to 200 mg orally twice daily for patients with severe hepatic impairment ‒ Tucatinib can cause severe diarrhea; administer antidiarrheal treatment as clinically indicated ‒ Tucatinib can cause severe hepatotoxicity; monitor ALT, AST, and bilirubin prior to starting tucatinib, every 3 weeks during treatment, and as clinically indicated ‒ Management of AEs may require temporary interruption, dose reduction, or discontinuation • Approval based on efficacy data from randomized phase II HER2CLIMB trial AEs = adverse events; ALT = alanine aminotransferase; AST = Aspartate transaminase; BC = breast cancer. Tucatinib PI. 34 34 Case Study: May • 60-yr-old woman presents with back pain and right breast mass (2 cm) ‒ She has no significant family history or past medical history ‒ Core biopsy of breast mass: invasive ductal carcinoma; ER: 0%, PgR: 0%, HER2: 2+; FISH ratio: 3.4 with copy number of 7 ‒ PET/CT: 3 liver lesions (largest 3 cm); several vertebral lesions in the thoracic and lumbar spine • She receives docetaxel/trastuzumab/pertuzumab (THP) and achieves PR in liver after 4 mos • 16 mos later, she experiences progression in liver (new 2.5-cm lesion, other lesions stable) • She receives T-DM1 and achieves PR in liver, with stable bone lesions • 12 mos later PET/CT shows increase in liver lesions to 3 cm, no new liver lesions, and bone lesions remain stable ‒ No brain lesions on MRI 35 RCB = residual cancer burden; T-DM1 = trastuzumab emtansine. 35 Optimal Sequence of HER2-Targeted Agents for Patients With HER2-Positive MBC • For patients who have received multiple lines of therapy including trastuzumab, pertuzumab, and T-DM1, consider treatment with next- generation ADC T-DXd ‒ T-DXd was granted accelerated FDA approval in Dec 2019 for treatment of unresectable or metastatic HER2-positive breast cancer after ≥ 2 previous lines of anti–HER2-based regimens for metastatic disease 36 ADC = antibody–drug conjugate; MBC = metastatic breast cancer; T-DM1 = trastuzumab emtansine; T-DXd = trastuzumab deruxtecan. 36 PCE 2020 Spring Oncology Series 12

  52. Key Updates in the Treatment of HER2-Positive Breast Cancer Structure of Antibody–Drug Conjugates Tumor antigen • Tumor antigen: abundant in tumors, Antigen- mAb that targets binding Site minimal in normal tissues; internalized tumor-specific or tumor-associated upon ADC binding antigens • Antibody: high affinity, avidity for antigen; optimal PK; internalized • Linker: stable in plasma; efficient release of cytotoxic agent inside tumor cells • Payload: drug cytotoxic to targeted Stable linker Potent tumor cells; not hydrophobic; must be releases cytotoxic payload only potent since limited number of payload in target cell molecules can be attached to antibody ADC = antibody–drug conjugate; mAb = monoclonal antibody; PK = pharmacokinetics. Thomas. Lancet Oncol. 2016;17:e254. 37 37 Mechanism of Action of HER2-Directed ADCs ADC = antibody–drug conjugate. Image from Rinnerthaler. Int J Mol Sci. 2019;20:1115. HER2 directed antibody-drug-conjugates beyond T-DM1 in 38 breast cancer. Licensed under Creative Commons Attribution 3.0 Unported License (CC BY 3.0). 38 Early- vs New-Generation Antibody–Drug Conjugates • Early generation New generation • ‒ Mouse antibodies; immunogenic — Chimeric or humanized antibodies; reduced immunogenicity ‒ Unstable in circulation — Stable in circulation ‒ Unable to release cytotoxic drug within tumor cell — Efficient linker technology able to ‒ Cytotoxic payload: chemotherapy drugs release cytotoxic drug within tumor cell such as doxorubicin, vinca alkaloids (eg, disulfide, dipeptide, or hydrazone (eg, vinblastine), or methotrexate linkage) — Cytotoxic payload: highly potent agents with subnanomolar IC 50 such as calicheamicin, maytansine derivative (eg, DM1, DM4), or auristatin (eg, MMAE, MMAF) 39 Thomas. Lancet Oncol. 2016;17:e254. 39 PCE 2020 Spring Oncology Series 13

  53. Key Updates in the Treatment of HER2-Positive Breast Cancer Structure of ado-Trastuzumab-Emtansine (T-DM1), a HER2-Targeted ADC • Tumor antigen: HER2 Thioether linker Trastuzumab • Antibody: monoclonal antibody (HER2-targeted mAb) trastuzumab • Linker: systemically stable thioether, not cleavable • Cytotoxic drug payload: Emtansine (DM1), a highly potent tubulin destabilizer Cytotoxic agent: DM1 ADC = antibody–drug conjugate. Lewis Phillips et al. Cancer Res. 2008;68:9280. 40 40 HER2-Targeted ADC: Trastuzumab Deruxtecan (DS-8201) Humanized anti-HER2 IgG1 mAb with same amino acid sequence as trastuzumab • High drug:antibody Tetrapeptide-based cleavable linker ratio: ~ 8 O O OH • Stable linker-payload O • Tumor-selectable N O O O O N H H cleavable linker H N Cys N N N N N N O H H H • High potency, O O O O F membrane-permeable payload with short O Cysteine residue HO NH systemic half-life Drug/linker O N • Bystander killing effect N F O OH O Topoisomerase I inhibitor (DXd) payload (exatecan derivative) ADC = antibody–drug conjugate; mAb = monoclonal antibody. 41 Nakada. Chem Pharm Bull (Tokyo). 2019;67:173. Trail. Pharmacol Ther. 2018;181:126. Ogitani. Cancer Sci. 2016;107:1039. 41 DESTINY-Breast01: Trastuzumab Deruxtecan (T-DXd) in Advanced HER2+ Breast Cancer • Open-label, multicenter, 2-part phase II study Part 1 Part 2 Pharmacokinetics (n = 65) Continuation (n = 134) Dose Finding* (n = 54) T-DXd 5.4 mg/kg T-DXd 5.4 mg/kg Adult patients with Newly T-DM1 (n = 22) (n = 28) T-DXd 5.4 mg/kg HER2+ unresectable enrolled R/R T-DXd 6.4 mg/kg T-DXd 6.4 mg/kg (n = 130) and/or metastatic patients (n = 249) (n = 22) (n = 26) BC; prior T-DM1; T-DXd 7.4 mg/kg ECOG PS 0/1; (n = 23) stable, treated brain T-DM1 *5.4 mg/kg confirmed as RP2D. metastases allowed; T-DXd 5.4 mg/kg Intolerant history of significant (n = 4) (n = 4) ILD excluded Total enrolled at 5.4 mg/kg: n = 184 • Primary endpoint: ORR by ICR (RECIST v1.1) • Data cutoff: August 1, 2019 • Secondary endpoints: investigator-assessed ORR, ‒ 79 (42%) continuing treatment DCR, DoR, CBR, PFS, OS, PK, safety ‒ 105 (57.1%) d/c (mostly for PD, 28.8%) CBR = clinical benefit rate; d/c = discontinuation; DCR = disease control rate; DoR = duration of response; ECOG = Eastern Cooperative Oncology Group; ICR = independent central review; ILD = interstitial lung disease; PD = progressive disease; PK = pharmacokinetics; PS = performance status; RP2D = recommended phase II dose; RECIST = Response Evaluation Criteria in Solid Tumors; R/R = resistant/refractory. 42 Krop. SABCS 2019. Abstr GS1-03. Modi. NEJM. 2020;382:610-621. 42 PCE 2020 Spring Oncology Series 14

  54. Key Updates in the Treatment of HER2-Positive Breast Cancer DESTINY-Breast01: Baseline Characteristics T-DXd 5.4 mg/kg T-DXd 5.4 mg/kg Characteristic Characteristic (N = 184) (N = 184) Median age, yrs (range) 55 (28-96) Median prior lines of treatment, n (range) 6 (2-27)  Trastuzumab, % 100 Female, % 100  T-DM1, % 100 Region, %  Pertuzumab, % 65.8  Asia 34.2  Other anti-HER2 therapy, % 54.3  North America 28.8  Hormone therapy, % 48.9  Europe 37.0  Other systemic therapy, % 99.5 ECOG PS, % Visceral disease, % 91.8  0/1 55.4/44.0 History of brain metastases, % 13.0  2 0.5 HER2 expression, % Hormone receptor status, %  IHC 3+ 83.7  Positive 52.7  Negative 45.1  IHC 2+, ISH+ 15.2  IHC 1+, ISH+ 1.1  Unknown 2.2 ECOG = Eastern Cooperative Oncology Group; PS = performance status; T-DM1 = trastuzumab emtansine; T-DXd = trastuzumab deruxtecan. Krop. SABCS 2019. Abstr GS1-03. Modi. NEJM. 2020;382:610. 43 43 DESTINY-Breast01: Response T-DXd 5.4 mg/kg Response (ITT) (N = 184) Best Change in Tumor Size 100 ORR* (by ICR; n = 112), % 60.9 (53.4-68.0) 80 (by ICR; n = 168) (95% CI) Best Percentage Change From Baseline in Sum of Diameters 60 • CR (n = 11) 6.0 40 • PR (n = 101) 54.9 20 • SD (n = 67) 36.4 • PD (n = 3) 1.6 0 • Not evaluable (n = 2) 1.1 -20 DCR, % (95% CI) 97.3 (93.8-99.1) -40 6-mo CBR, % (95% CI) 76.1 (69.3-82.1) -60 Median DoR, 14.8 (13.8-16.9) -80 mos (95% CI) Line at 20% indicates PD; line at −30% indicates PR. -100 Median time to response, 1.6 (1.4-2.6) Patients (N = 168) mos (95% CI) *Patients who received T-DXd 5.4 mg/kg. CBR = clinical benefit rate; DCR = disease control rate; DoR = duration of response; ICR = independent central review; ITT = intention-to-treat; PD = progressive disease; SD = stable disease; T-DXd = trastuzumab deruxtecan. 44 Krop. SABCS 2019. Abstr GS1-03. Modi. NEJM. 2020;382:610. 44 DESTINY-Breast01: ORR by Subgroup Subgroup Events/ Total Patients, n/N Objective Response, % (95% CI) All patients 112/184 61 (53-68) Previous pertuzumab use Yes 78/121 64 (55-73) No 34/63 54 (41-67) Hormone receptor Positive 56/97 58 (47-68) Negative 55/83 66 (55-76) No. of regimens excluding HT ≥ 3 99/167 59 (51-67) < 3 13/17 76 (50-93) Brain metastasis Yes 14/24 58 (37-78) No 98/160 61 (53-69) Presence of visceral disease Yes 102/169 60 (53-68) No 10/15 67 (38-88) Geographic region Asia 37/63 59 (46-71) North America 33/53 62 (48-75) Europe 42/68 62 (49-73) ECOG PS 0 67/102 66 (56-75) 1 45/81 56 (44-67) T-DXd tx immediately after T-DM1 Yes 36/56 64 (50-77) No 76/128 59 (50-68) HER2-positive tumor IHC 3+ 97/154 63 (55-71) IHC 1+ or 2+, ISH positive 13/28 46 (28-66) 0 10 20 30 40 50 60 70 80 90 100 ECOG = Eastern Cooperative Oncology group; HT = hormone therapy; PS = performance status; tx = therapy. 45 Modi. NEJM. 2020;382:610. 45 PCE 2020 Spring Oncology Series 15

  55. Key Updates in the Treatment of HER2-Positive Breast Cancer DESTINY-Breast01: Survival PFS OS mPFS: 16.4 mos (95% CI: 12.7-NR) mOS: NR 1.0 mPFS in 24 patients with brain mets: 1.0 18.1 mos (95% CI: 6.7-18.1) Probability of PFS 0.8 0.8 Probability of OS 0.6 0.6 0.4 0.4 0.2 Censored: 86.4% Censored: 68.5% 0.2 Events: 13.6% Events: 31.5% 0 0 0 1 2 3 4 5 6 7 8 9 10 11121314151617181920 0 1 2 3 4 5 6 7 8 9 1011121314151617181920 Mos Mos Patients Patients at Risk, 184 182 174 155 153 135 121 107 103 94 69 54 38 17 1 1 10 9 4 at Risk, 184 183 182 179 174 171 167 161 155 147 133 101 66 36 21 16 12 9 8 n 3 1 0 n 4 0 • Median follow-up: 11.1 mos (range: 0.7-19.9) Mets = metastases; mPFS = median PFS; NR = not reached; T-DXd = trastuzumab deruxtecan. 46 Modi. NEJM. 2020;382:610. 46 DESTINY-Breast01: AEs in Overall Population Nausea Fatigue Grade 1/2 Alopecia Grade ≥ 3 Vomiting Constipation Neutropenia Decreased appetite Anemia Diarrhea Decreased WBC count Thrombocytopenia Headache Cough 0 10 20 30 40 50 60 70 80 90 100 AE = adverse events; WBC = white blood cell count. 47 Krop. SABCS 2019. Abstr GS1-03. Modi. NEJM. 2020;382:610. 47 Case Study: May • After progressing on THP and T-DM1, she begins therapy with trastuzumab deruxtecan (T-DXd) 5.4 mg IV Q3W ‒ Treatment is generally tolerated well with minimal diarrhea and alopecia • At 3 months, PET/CT shows PR in liver, stable bone lesions • At 6 months, PET/CT shows continued PR but hazy infiltrates in upper lobes of both lungs ‒ She has no apparent symptoms and reports no shortness of breath or dyspnea on exertion 48 T-DM1 = trastuzumab emtansine; THP = docetaxel/trastuzumab/pertuzumab, Q3W = every 3 weeks. 48 PCE 2020 Spring Oncology Series 16

  56. Key Updates in the Treatment of HER2-Positive Breast Cancer DESTINY-Breast01: Interstitial Lung Disease T-DXd 5.4 mg/kg (N = 184) AE, n (%) Grade 1 Grade 2 Grade 3 Grade 4 Grade 5 Any Grade ILD 5 (2.7) 15 (8.2) 1 (0.5) 0 4 (2.2) 25 (13.6) • Among the 25 ILD events: ‒ Median time to investigator-reported onset: 193 days (range: 42-535) ‒ 17/20 patients with grade ≥ 2 ILD received glucocorticoids ‒ 7 patients recovered, 2 were recovering, 12 were unknown/not followed to ILD resolution, 4 had died • For 4 fatal cases, onset was from 63-148 days and death 9-60 days after ILD diagnosis (3 received steroids) • Recommendation: monitor for symptoms; hold T-DXd and re-image for grade 1 ILD; discontinue T- DXd and start steroids immediately upon suspecting grade 2 or greater ILD AE = adverse events; ILD = interstitial lung disease; T-DXd = trastuzumab deruxtecan. Krop. SABCS 2019. Abstr GS1-03. 49 49 Strategies to Manage ILD Associated with T-DXd Therapy in HER2-Positive MBC • Monitor for ILD and promptly investigate signs and symptoms including cough, dyspnea, fever, and other new or worsening respiratory symptoms ‒ Evaluate with imaging and consider pulmonology consult • For patients with asymptomatic ILD, hold T-DXd and re-image in 4 wks ‒ Consider corticosteroid treatment, if necessary ‒ If resolved, restart T-DXd with dose reduction • For patients with symptomatic ILD, discontinue T-DXd and initiate steroids ‒ Consider pulmonary consult 50 ILD = interstitial lung disease; MBC = metastatic breast cancer; T-DXd = trastuzumab deruxtecan. 50 Guidelines for the Management of Trastuzumab Deruxtecan–Induced Interstitial Lung Disease Grade 1 Grade 2 Grade 3/4 • Hospitalization required • Monitor with close follow-up in 2-7 days for • Immediately begin systemic steroids (≥ 1 onset of clinical symptoms, pulse oximetry mg/kg/day prednisone or equivalent) until • Immediately begin empiric high-dose clinical improvement, followed by gradual methylprednisolone IV (500-1000 mg/day for • Consider follow-up imaging in 1-2 wks (or as taper over at least 4 wks 3 days), followed by ≥ 1 mg/kg/day of clinically indicated) prednisone (or equivalent) until clinical • Monitor symptoms closely • Consider initiating systemic steroids (≥ 0.5 improvement, followed by gradual taper over mg/kg/day prednisone or equivalent) until • Re-image as clinically indicated at least 4 wks improvement, followed by gradual taper over • Re-image as clinically indicated • For worsening symptoms or no improvement at least 4 wks within 5 days: • For no improvement within 3-5 days: • If ILD worsens despite initiation of ⎻ Consider increasing dose of steroids to ⎻ Reconsider additional workup for corticosteroids, follow grade 2 guidelines 2 mg/kg/day prednisone or equivalent alternative etiologies as described above and/or switch to IV administration with • Restart T-DXd if ILD resolves within 28 days ⎻ Consider other immunosuppressants methylprednisolone after onset and/or treat per local practice ⎻ Reconsider additional workup for • Restart T-DXd at reduced dose if ILD resolves alternative etiologies as described above > 28 days after onset ⎻ Escalate care as clinically indicated • Permanently discontinue T-DXd if grade 1 ILD occurs beyond cycle Day 22 and has not • Permanently discontinue T-DXd • Permanently discontinue T-DXd resolved within 49 days from last infusion ILD = interstitial lung disease; T-DXd = trastuzumab deruxtecan. 51 Krop. SABCS 2019. Abstr GS1-03. 51 PCE 2020 Spring Oncology Series 17

  57. Key Updates in the Treatment of HER2-Positive Breast Cancer Trastuzumab Deruxtecan Approval • On December 20, 2019, the FDA approved fam-trastuzumab deruxtecan-nxki for treatment of patients with unresectable or metastatic HER2+ BC who have received ≥ 2 previous HER2-targeted therapies in the metastatic setting ‒ Administration/dose: IV 5.4 mg/kg QW3 ‒ Monitor CBC prior to each administration; assess LVEF prior to initiation and at regular intervals during treatment as clinically indicated; monitor for ILD and pneumonitis during treatment ‒ Management of AEs may require temporary interruption, dose reduction, or discontinuation • Based on ORR and DoR data from randomized phase II DESTINY-Breast01 trial AE = adverse event; BC = breast cancer; CBC = complete blood count; DoR = duration of response; ILD = interstitial lung disease; LVEF = left ventricle ejection fraction. Trastuzumab deruxtecan PI. 52 52 Future Directions in HER2+ MBC 53 HER2CLIMB-02: Tucatinib or Placebo + T-DM1 in Unresectable HER2-Positive Breast Cancer • Randomized, double-blind, phase III trial Patients with HER2+ unresectable LA Tucatinib 300 mg PO BID + or metastatic BC; previous treatment T-DM1 3.6 mg/kg IV Q3W with trastuzumab and a taxane; previous pertuzumab permitted but not required; untreated brain mets not requiring immediate therapy or Placebo 300 mg PO BID + Placebo 300 mg PO BID + previously treated and stable brain T-DM1 3.6 mg/kg IV Q3W T-DM1 3.6 mg/kg IV Q3W mets permitted (planned N = 460) • Primary endpoint: PFS (RECIST v 1.1 by investigator assessment) • Secondary endpoints: OS, PFS (BICR), ORR, DoR, CBR, rate of AEs AE = adverse event; BC = breast cancer; BICR = blinded independent central review; CBR = clinical benefit rate; DoR = duration of response; LA = locally advanced; mets = metastases; RECIST = Response Evaluation Criteria in Solid Tumors; T-DM1 = trastuzumab emtansine. 54 NCT03975647 . 54 PCE 2020 Spring Oncology Series 18

  58. Key Updates in the Treatment of HER2-Positive Breast Cancer DESTINY-Breast02: T-DXd vs Trastuzumab/Cape or Lapatinib/Cape in HER2+ MBC With Prior T-DM1 • Randomized, open-label, active-controlled phase III trial Stratified by hormone receptor status, prior pertuzumab, history of visceral disease Trastuzumab Deruxtecan 5.4 mg/kg IV Q3W Patients with HER2+, unresectable and/or metastatic BC; at least third (planned n = 400) line; progression on prior HER2- targeted agents including T-DM1; no prior capecitabine; Investigator’s Choice of Trastuzumab/Cape no CNS metastases or Lapatinib/Cape (planned N = 600) (planned n = 200) • Primary endpoint: PFS (RECIST v 1.1 by BICR) • Secondary endpoints: OS, PFS by investigator assessment, ORR, DoR, CBR BC = breast cancer; BICR = blinded independent central review; Cape = capecitabine; CBR = clinical benefit rate; CNS = central nervous system; DoR = duration of response; MBC = metastatic breast cancer; RECIST = Response Evaluation Criteria in Solid Tumors; T-DM1 = trastuzumab emtansine. NCT03523585. 55 55 DESTINY-Breast03: Second-line T-DXd vs T-DM1 in HER2+ MBC After Progression on Trastuzumab/Taxane • Randomized, open-label phase III trial at ~160 sites in North America and Europe Stratified by hormone receptor status, prior pertuzumab, history of visceral disease Patients with HER2+, Trastuzumab Deruxtecan 5.4 mg/kg IV Q3W unresectable and/or metastatic (Planned n = 250) BC; previous treatment with trastuzumab and a taxane; no prior HER2-targeted ADC; CNS T-DM1 3.6 mg/kg IV Q3W metastases allowed (Planned n = 250) (planned N = 500) • Primary endpoint: PFS (RECIST v 1.1 by BICR) • Secondary endpoints: OS, ORR, DoR, CBR, PFS (investigator assessment) ADC = antibody–drug conjugate; BC = breast cancer; BICR = blinded independent central review; CBR = clinical benefit rate; CNS = central nervous system; DoR = duration of response; MBC = metastatic breast cancer; RECIST = Response Evaluation Criteria in Solid Tumors; T-DM1 = trastuzumab emtansine; T-DXd = trastuzumab deruxtecan. 56 NCT03529110. 56 Efficacy of Trastuzumab Deruxtecan in HER2-Low MBC 100 % Change in Tumor Size by Best % Change in Tumor Size by 80 HER2 IHC Status 80 HER2 IHC Status 60 60 n = 48 Change in Tumor Size From BL (%) Tumor Size From BL IHC 2+ Best % Change in 40 40 IHC 1+ 20 20 * 0 * * * * * * x 0 * -20 * -20 -40 IHC 2+ -40 * * -60 -60 IHC 1+ -80 -80 -100 *Hormone receptor negative -100 10 20 30 40 50 60 70 80 90 100 110 120 Line at 20% indicates PD; line at -30% indicates PR. Time (weeks) Efficacy in HER2-Low MBC Confirmed ORR, % Median DoR, Mos Median PFS, Mos All (N = 54) 37.0 10.4 11.1 IHC 2+ (n = 26) 38.5 -- -- IHC 1+ (n = 28) 35.7 -- -- HR+ (n = 47) 40.4 -- -- Prior CDK4/6 inhibitor (n = 16) 43.8 -- -- BL = baseline; DoR = duration of response; ILD = interstitial lung disease; MBC = metastatic breast cancer; NR = not reported; PD = progressive disease. 57 Modi. JCO. 2020: JCO1902318. 57 PCE 2020 Spring Oncology Series 19

  59. Key Updates in the Treatment of HER2-Positive Breast Cancer DESTINY-Breast04: T-DXd vs Chemotherapy in Unresectable HER2- Low Breast Cancer • Randomized, open-label, active-controlled phase III trial Stratified by HER2 IHC status, no. of prior lines of CT, HR status (HR+ without previous CDK4/6i vs HR+ with previous CDKi vs HR-) Patients with HER2-low (IHC1+ or Trastuzumab Deruxtecan 5.4 mg/kg IV Q3W IHC2+/ISH-), unresectable and/or (planned n = 360) metastatic BC; previous treatment with trastuzumab and a taxane; progression on endocrine therapy; Physician’s Choice of CT: no prior HER2 positivity Capecitabine, Eribulin, Gemcitabine, Paclitaxel or nab -Paclitaxel (planned N = 540) (planned n = 180) • Primary endpoint: PFS (RECIST v 1.1 by BICR) • Secondary endpoints: OS, PFS (investigator assessment), ORR, DoR BC = breast cancer; BICR = blinded independent central review; CT = chemotherapy; DoR = duration of response; HR = hormone receptor; RECIST = Response Evaluation Criteria in Solid Tumors; T-DM1 = trastuzumab emtansine; T-DXd = trastuzumab deruxtecan. NCT03734029. 58 58 HER2-Targeted ADC: Trastuzumab Duocarmazine (SYD985) • HER2 antibody with same amino Trastuzumab-vc-seco-duocarmycin-hydroxybenzamide-azaindole acid sequence as trastuzumab Antibody Linker Prodrug • Proteolytic cleavage of linker in Trastuzumab Maleimide Protease- Self- Seco-duocarmycin linker cleavable elimination progrug tumor microenvironment leads to linker spacers activation of prodrug payload Valine PABC Cyclization • Active toxin (DUBA) alkylates Citrulline spacer DNA, kills dividing and O NH 2 nondividing cells HN CI O O • Bystander killing effect H H N S N O N N O O N H OH H O N N O O N O N O O SYD985 N O O OH O ~2.8 ADC = antibody–drug conjugate. 59 Dokter. Mol Cancer Ther. 2014;13:2618. Elgersma. Mol Pharm. 2015;12:1813. 59 Phase I Study: Trastuzumab Duocarmazine in Locally Advanced or Metastatic HER2+ Breast Cancer Dose-Expansion Cohorts (n = 146) 100 Drug-Related AE, n (%) Best % Change in Tumor Size in HER2+ Cohort Grade 1/2 Grade 3 80 Tumor Size From BL (%) Fatigue 43 (29) 5 (3) 60 Best Change in 40 ORR: 33% (95% CI: 20.4-48.4) Conjunctivitis 41 (28) 4 (3) 20 Dry eye 44 (30) 1 (1) 0 * * * * * Increased lacrimation 29 (20) 0 -20 Dry skin 26 (18) 0 -40 Decreased appetite 27 (18) 2 (1) -60 -80 Alopecia 26 (18) 0 -100 Nausea 27 (18) 0 *Dose-expansion phase. n = 5 patients with 0% best percentage change. Stomatitis 24 (16) 0 • Most drug-related TEAEs mild to moderate Neutropenia 14 (10) 9 (6) ⎻ Ocular toxicity reported in 2/3 of patients; most Vomiting 17 (12) 0 common reason for treatment discontinuation Anemia 13 (9) 2 (1) ⎻ Ocular toxicity, neutropenia most common reason Pyrexia 9 (6) 0 for dose modifications AE = adverse event; BL = baseline; TEAE = treatment-emergent adverse event. 60 Banerji. Lancet Oncol. 2019;20:1124. 60 PCE 2020 Spring Oncology Series 20

  60. Key Updates in the Treatment of HER2-Positive Breast Cancer TULIP: Trastuzumab Duocarmazine vs Physician’s Choice of Tx in Locally Advanced or Metastatic Breast Cancer • Randomized, active-controlled phase III trial Patients with HER2+, Trastuzumab Duocarmazine Q3W Until PD, unresectable, locally (planned n = 230) toxicity, or advanced and/or metastatic withdrawal BC; progression on or after ≥ 2 HER2-targeted regimens or Survival f/u Physician’s Choice: Lapatinib/Capecitabine, after T-DM1; Q3M ECOG PS 0-2 Trastuzumab/Capecitabine, Trastuzumab/Vinorelbine, Trastuzumab/Eribulin (planned N = 345) (planned n = 115) Tumor evaluation Q6W • Primary endpoint: PFS (RECIST v 1.1) • Secondary endpoints: OS, PFS (investigator assessment), ORR, PROs/QoL BC = breast cancer; ECOG = Eastern Cooperative Oncology Group; f/u = follow-up; PD = progressive disease; PRO = patient-reported outcomes; PS = performance status; QoL = quality of life; RECIST = Response Evaluation Criteria in Solid Tumors; T-DM1 = trastuzumab emtansine. NCT03262935. 61 61 Margetuximab: Novel HER2-Targeted Monoclonal Antibody Increased CD16A Affinity: Enhance Innate Immunity/More Potent ADCC Stimulation • Margetuximab has the same specificity, NK affinity to HER2 as trastuzumab with similar Cell Perforins Cancer Cell ability to disrupt signaling Destruction HER2 • However, via Fc engineering with intent to CD16A HER2+ Cancer activate immune responses, margetuximab Cell Granzymes has altered Fc receptor affinity ‒ Trastuzumab: WT IgG1 effector domains; Decreased CD32B Affinity: binds and activates immune cells Enhance Adaptive Immunity/Increase Immune Activation ‒ Margetuximab: Increased affinity for HER2-specific Lymphocyte activating Fcγ RIIIA (CD16A) and Proliferation decreased affinity for inhibitory Fcγ RIIB CD32B T-cell (CD32B) APC TAA ADCC = Antibody-dependent cellular cytotoxicity; APC, antigen presenting cell; WT = wildtype. Nordstrom. Breast Cancer Res. 2011;13:R123. Stavenhagen. Cancer Res. 2007;67:8882. 62 Nordstrom. ASCO 2019. Abstr 1030. Clynes. Nat Med. 2000;6:443. 62 SOPHIA: Margetuximab vs Trastuzumab in HER2+ Advanced Breast Cancer After ≥ 2 HER2 Therapies • Randomized, open-label phase III trial (data cutoff: September 30, 2019) Stratified by CT, no. of prior lines of tx (> 2 vs ≤ 2), no. of metastatic sites (> 2 vs ≤ 2) Margetuximab 15 mg/kg Q3W + CT* Patients with HER2+ advanced BC with in 3 wk cycles ≥ 2 previous anti-HER2 therapies, (n = 266) including pertuzumab; 1-3 prior lines of tx for metastatic disease; prior brain metastasis allowed if Trastuzumab 8 mg/kg loading  6 mg/kg Q3W + treated/stable CT* in 3-wk cycles (N = 536) (n = 270) *Investigators choice of CT: capecitabine, eribulin, gemcitabine, or vinorelbine. • Sequential primary endpoint: PFS, OS • Secondary endpoints: ORR by central blinded analysis, investigator-assessed PFS • Tertiary and exploratory endpoints: investigator-assessed CBR, DoR, safety, and effect of CD16A, CD32A, and CD32B alleles on margetuximab efficacy BC = breast cancer; CBR = clinical benefit rate; CT = chemotherapy; DoR = duration of response; tx = treatment. 63 Rugo. SABCS 2019. Abstr GS1-02. 63 PCE 2020 Spring Oncology Series 21

  61. Key Updates in the Treatment of HER2-Positive Breast Cancer SOPHIA: Investigator-Assessed PFS Investigator-Assessed PFS (Oct 2018 Cutoff) Investigator-Assessed PFS (Sep 2019 Cutoff) + Events, Median PFS, 100 + + Events, Median PFS, 100 + + + + + + n Mos (95% CI) + n Mos (95% CI) + + + + 5.7 (5.22-6.97) + + + + Margetuximab + CT (n = 266) 208 + Margetuximab + CT (n = 266) 160 5.6 (5.06-6.67) + + + + 80 + 80 + + + + Trastuzumab + CT (n = 270) 222 4.4 (4.14-5.45) Trastuzumab + CT (n = 270) 177 4.2 (3.98-5.39) + + + + + + + + + + + + + + + + + + + + + + + HR: 0.70 (95% CI: 0.56-0.87; P = .001) + HR: 0.71 (95% CI: 0.58-0.86; P = .0006) + + + + 60 60 ++ PFS (%) + PFS (%) + 29% reduction in risk of disease progression + + 30% reduction in risk of disease progression + + + + + + + + + + + + + + + 40 + + + 40 + + + + + + + + + + + + + + + + + 20 + + 20 ++ + ++ + + + + + + ++ + + + + + + + + + + ++ + + + + + + ++ + + + + + + + + + 0 0 0 10 20 30 0 5 10 15 20 25 Mos From Randomization Mos From Randomization 266 206 155 112 72 61 33 32 16 13 8 7 3 2 2 0 0 0 Margetuximab + CT 266 210 137 100 62 36 6 5 3 2 2 0 Margetuximab + CT 25 14 11 Trastuzumab + CT 270 184 130 87 59 45 25 21 10 5 4 3 1 1 1 1 1 0 Trastuzumab + CT 270 192 108 72 42 20 8 4 3 2 2 1 0 CT = chemotherapy. Rugo. SABCS 2019. Abstr GS1-02. 64 64 SOPHIA: Interim OS Analyses (ITT) First Interim OS Analysis (Oct 2018 Cutoff) Second Interim OS Analysis (Sep 2019 Cutoff) Events, Median OS, Events, Median OS, n Mos (95% CI) n Mos (95% CI) Margetuximab + CT (n = 266) 78 18.9 (16.16-25.07) + + + + + + + 100 + ++ + + + ++ 100 131 21.6 (18.86-24.05) + + + + Trastuzumab + CT (n = 270) 80 17.2 (15.80-33.31) Margetuximab + CT (n = 266) + ++ + + + + + + + + + + + + + ++ ++ + + + + Trastuzumab + CT (n = 270) 139 19.8 (17.54-22.28) + + + + + + + + ++ + + HR: 0.95 (95% CI: 0.69-1.31; P = .758) + + + + + ++ + HR: 0.89 (95% CI: 0.69-1.13; P = .326) 80 + + + + 80 ++ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + 60 + + + + + 60 + + + ++ + + + OS (%) + + OS (%) + + + + + + + ++ + + ++ ++ + + + + + ++ + + + + + + + + + + + + + + + + + + + + + ++ + + + + + + + + + + + 40 40 + + + + + + + + + + + + + + + + + + + Median difference: 1.8 mos + + + + + ++ + + + + + + ++ + + + + + + ++ Median difference: 1.7 mos 20 20 + + Median follow-up: 9.2 mos Median follow-up: 15.6 mos 0 0 0 10 20 30 0 10 20 30 40 Mos From Randomization Mos From Randomization Margetuximab + CT 266 241 209 174 125 85 57 42 29 17 8 3 2 0 0 Margetuximab + CT 266 259 249 239 230 214 186 159 131 107 80 64 47 35 31 22 14 9 3 2 2 0 Trastuzumab + CT 270 237 194 163 122 92 63 37 24 14 6 3 2 1 0 Trastuzumab + CT 270 260 246 235 218 205 183 160 126 102 74 57 43 30 22 16 10 6 2 2 2 1 0 CT = chemotherapy; ITT = intention-to-treat. 65 Rugo. SABCS 2019. Abstr GS1-02. 65 SOPHIA: Prespecified Exploratory OS in CD16A-158F Carriers 100 + + + + + + Events, Median OS, + + + + + n Mos (95% CI) 80 + + Margetuximab + CT (n = 221) 103 23.7 (18.89-28.32) + ++ + Trastuzumab + CT (n = 216) 114 19.4 (16.85-22.28) + + + + + + + + ++ + + + + 60 +++ + + + + + + + + HR: 0.79 (95% CI: 0.61-1.04; P = .087) + + + OS (%) + + + + + + + + + + + + + + Median follow-up: 15.6 mos + + + ++ +++ + + + + + + + + 40 + + + + + + ++ + + + + + + + + + + + + + + + + + Median difference: 4.3 mos 20 + + 0 0 10 20 30 40 Mos From Randomization Margetuximab + CT 221 219 212 204 196 181 157 135 111 91 68 55 42 31 27 19 13 8 2 1 1 0 Trastuzumab + CT 216 210 201 192 176 165 145 123 98 81 57 43 30 21 16 11 9 6 2 2 2 1 0 • CD16A-158F carriers (FF or FV): 437/506 (86%) of genotyped patients CT = chemotherapy. Data Cutoff: September 2019. 66 Rugo. SABCS 2019. Abstr GS1-02. 66 PCE 2020 Spring Oncology Series 22

  62. Key Updates in the Treatment of HER2-Positive Breast Cancer SOPHIA: Safety Margetuximab + CT Trastuzumab + CT AEs, n (%) (n = 264) (n = 265) Any grade 260 (98.5) 261 (98.1) Any margetuximab- or trastuzumab-related AE 160 (60.6) 132 (49.6) Grade ≥ 3 AE 142 (53.8) 140 (52.6) Grade ≥ 3 margetuximab- or trastuzumab-related AE 34 (12.9) 22 (8.3) Any serious AE 43 (16.3) 49 (18.4) Any margetuximab- or trastuzumab-related serious AE 5 (1.9) 4 (1.5) AE leading to treatment discontinuation 8 (3.0) 7 (2.6) AE resulting in death* 3 (1.1) 2 (0.8) AEs of special interest All Grade Grade ≥ 3 All Grade Grade ≥ 3 • IRR 35 (13.3) 4 (1.5) 9 (3.4) 0 2 (0.6) 0 0 0 • Discontinuation due to IRR 4 (1.5) 0 6 (2.3) 0 • LV dysfunction resulting in delayed dosing or discontinuation *Deaths due to pneumonia (n = 2), pneumonia aspiration (n = 1) in margetuximab arm; pneumonia (n = 1), acute kidney injury (n =1) in trastuzumab arm. None related to study treatments. Data cutoff: April 2019. AE = adverse event; CT = chemotherapy; IRR = infusion-related reaction; LV = left ventricle. Rugo. SABCS 2019. Abstr GS1-02. 67 67 Implications for Practice • HER2-targeted TKIs are a reasonable therapy for HER2+ MBC in the third-line setting and beyond ‒ Tucatinib data are particularly strong and may be a good option for patients with progressive brain metastases • Trastuzumab deruxtecan is a major new therapy approved for HER2+ MBC in the third-line setting, likely to move to earlier settings ‒ Post neoadjuvant therapy ‒ Second-line T-DXd vs T-DM1 (DESTINY-Breast03) ‒ Also being looked at for HER2-low disease (DESTINY-Breast04) • Margetuximab is of unclear benefit (perhaps in CD16A-F allele carriers?) 68 MBC = metastatic breast cancer; T-DM1 = trastuzumab emtansine; T-DXd = trastuzumab deruxtecan; TKI = tyrosine kinase inhibitor. 68 PCE Action Plan  Clinicians should reassess risks and benefits of additional lines of therapy based on patient’s fitness, comorbidities, and preferences at progression  If additional treatment is indicated, select therapy based on disease features as well as patient’s fitness, comorbidities, and preferences  For patients with brain metastases, consider treatment with HER2 TKI-based therapy  After ≥ 2 previous lines of anti–HER2-based therapy, consider T-DXd for eligible patients  For patients receiving T-DXd, monitor for signs of interstitial lung disease and manage ILD using recommended guidelines PCE Promotes Practice Change 69 ILD = interstitial lung disease; T-DXd = trastuzumab deruxtecan; TKI = tyrosine kinase inhibitor. 69 PCE 2020 Spring Oncology Series 23

  63. Raising the Bar for the Standard of Care: Advances in the Management of Advanced Renal Cell Carcinoma Raising the Bar for the Standard of Care: Advances in the Management of Advanced Renal Cell Carcinoma 1 Learning Objectives • Formulate treatment strategies for advanced renal cell carcinoma (RCC) based on current evidence and patient/disease factors • Identify potential immune-related adverse events (AEs) and their onset during and after therapy • Implement strategies to recognize and appropriately manage side effects associated with tyrosine kinase inhibitors (TKIs) for advanced RCC 2 2 Overview of RCC • More than 50% of patients with RCC have no symptoms ‒ Diagnosis is through incidental imaging of the abdomen or chest ordered for unrelated symptoms • Hematuria serves as a warning sign: necessitates further evaluation and imaging leading to a diagnosis and treatment plan • Solid tumors are managed by size ‒ 20% of tumors >3 cm discovered incidentally will be benign ‒ Tumors ≥ 4 cm have metastatic potential • Treatment options include active surveillance, ablation, nephron-sparing tumor excision, nephrectomy, and systemic treatment • Predictors of a poor prognosis include poor functional status and metastasis 3 Gray RE, Harris GT. Am Fam Physician. 2019;99:179-184. 3 2020 PCE Spring Oncology Series 1

  64. Raising the Bar for the Standard of Care: Advances in the Management of Advanced Renal Cell Carcinoma RCC Statistics 8th most common cancer – more common in men than women – representing 4.2% of all new cancers in the US • • In 2019, there were ~73,820 new cases of kidney and renal pelvis cancer and ~14,770 deaths from this disease Percent of Cases by Stage 5-Year Relative Survival 3% 100% 92.5% 16% Localized (Confined to Primary Site) 80% 69.6% Percent Surviving Regional (Spread to 60% Regional Lymph 41.9% Nodes) 40% Distant (Cancer Has Metastasized) 17% 20% 12.0% Unknown (Unstaged) 65% 0% Stage Localized Regional Distant Unknown National Cancer Institute Surveillance, Epidemiology, and End Results Program. seer.cancer.gov/statfacts/html/kidrp.html; Accessed Mar 26, 2020. 4 4 Risk Factors for RCC • Hereditary factors include familial syndromes, including: ‒ von Hippel-Lindau syndrome ‒ Hereditary type 1 papillary renal carcinoma ‒ Familial renal oncocytoma ‒ Birt-Hogg-Dube syndrome • Few risk factors for RCC have been established ‒ Nonhereditary risk factors that possibly contribute to RCC include: • Cigarette smoking (increases in a dose-dependent fashion) • Obesity, particularly in women (as weight increases, risk of RCC increases) • Older age (median age at diagnosis: 64 years) Chow WH, et al. Nat Rev Urol. 2010;7:245-257; Sachdeva K, et al. emedicine.medscape.com/article/281340-overview#showall. 5 Accessed Mar 26, 2020. 5 Histology of RCC • Clear-cell RCC is the most common variety: 70% to 90% • Non − clear-cell RCC includes: ‒ Papillary: 10% to 15% ‒ Chromophobe: 3% to 5% ‒ Collecting duct: 1% to 2% ‒ Unclassified: 4% to 6% • In one study of 254 patients with advanced RCC, 16.1% harbored pathogenic germline mutations ‒ More than 20% of patients with non − clear-cell RCC had germline mutations • Sarcomatoid or rhabdoid features can be associated with any histology ‒ Harbinger of a poor prognosis in the VEGF TKI era VEGF = vascular endothelial growth factor. Carlo MI, et al. JAMA Oncol. 2018;4:1228-1235; Muglia VF, Prando A. Radiol Bras. 2015;48:166-174; Warren AY , Harrison D. World J Urol. 6 2018;36:1913-1926. 6 2020 PCE Spring Oncology Series 2

  65. Raising the Bar for the Standard of Care: Advances in the Management of Advanced Renal Cell Carcinoma Patient Factors to Consider When Selecting Therapy • Comorbidities, especially conditions that affect a patient’s immune status • Symptoms of disease • Sites of disease • ECOG PS • Histology • Risk stratification • Medication history, including use of steroids ECOG PS = Eastern Cooperative Oncology Group performance status. Heng DY , et al. J Clin Oncol. 2009;27:5794-5799; Heng DY , et al. Lancet Oncol. 2013;14:141-148; van der Zanden LF, et al. Urol Oncol. 2017;35:e9-e16. 7 7 Risk Stratification: Laboratory and Clinical IMDC Criteria Risk Factors Yes (1)/ Risk Group by Number of Risk Factors No (0) KPS <80% 1/0 Favorable 0 Time from diagnosis <12 months 1/0 Intermediate 1-2 Hemoglobin <LLN 1/0 Neutrophil count >ULN 1/0 Poor 3-6 Platelet count >ULN 1/0 Corrected serum calcium >ULN 1/0 • Current FDA indications restrict certain treatments based on these risk categories KPS = Karnofsky Performance Status; LLN = lower limit of normal; ULN = upper limit of normal. IMDC, International Metastatic RCC Database Consortium. 8 Heng DY , et al. J Clin Oncol. 2009;27:5794-5799; Heng DY , et al. Lancet Oncol. 2013;14:141-148. 8 Goals of Treatment • Goal of therapy is different for each patient ‒ May be curative vs improvement in length and/or quality of life, depending on staging • For active sites of disease ‒ Medical treatments aim to shrink and destroy the cancer ‒ Surgical treatment aims to remove the cancer ‒ Ablative treatments (eg, radiation or thermal) aim to destroy local disease • For patients with multiple sites of disease, the mainstay treatment has been medical/systemic therapy Choueiri TK, et al. J Urol. 2011;185:60-66; NCCN Guidelines. Kidney cancer. www.nccn.org/professionals/physician_gls/pdf/kidney.pdf. 9 Accessed Mar 26, 2020. 9 2020 PCE Spring Oncology Series 3

  66. Raising the Bar for the Standard of Care: Advances in the Management of Advanced Renal Cell Carcinoma Changing Treatment Landscape for Metastatic RCC • In the last 15 years, the landscape of treatment for clear-cell mRCC has changed immensely Nivolumab + Sorafenib Temsirolimus Axitinib Ipilimumab Targeted Therapy Era Immunotherapy Combination Era 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 2019 Pembrolizumab Bevacizumab + IFN- ⍺ Nivolumab +Axitinib Sunitinib Everolimus Cabozantinib Avelumab Pazopanib Everolimus + Levatinib + Axitinib mRCC = metastatic renal cell carcinoma. Klaassen Z. www.urotoday.com/conference-highlights/asco-2019-annual-meeting/asco-2019-kidney-cancer/113076-asco-2019-evolving-front-line- therapy-in-metastatic-renal-cell-carcinoma.html. Accessed Mar 26, 2020. 10 10 Immunotherapy Mechanism of Action • T-cell activation is required for effective antitumor response • PD-1 and CTLA-4 expressed on Activated T cell T cell T cells act as “off” switches to down- CTLA-4 regulate the immune response PD-1 • Tumor cells can masquerade as Anti-PD-1 CD28 TCR normal cells by expressing PD-L1 PD-L1 Anti- Tumor cell TCR CTLA-4 death MHC • Blockade of PD-1 and PD-L1 MHC B7 and CTLA-4 ultimately allow up-regulation of immune responses Antigen-presenting Renal cancer cell targeting the tumor cell CTLA-4 = cytotoxic T-lymphocyte antigen 4; PD-1 = programmed cell death protein; PD-L1 = programmed death-ligand 1. Buchbinder EI, Desai A. Am J Clin Oncol . 2016;39:98-106; Institute for Clinical Immuno-Oncology. www.accc-cancer.org/docs/immuno- 11 oncology/iclio-webinar-new-mechanisms-of-action-v3-final. Accessed Mar 26, 2020; Tarhini A, et al. Cancer Biother Radiopharm . 2010;25:601-613. 11 Targeted Therapy Plus Immunotherapy in Advanced RCC Anticancer Immunity • Boosts the RCC armamentarium • VEGF inhibitors infiltrate T cells into tumors and enhance antitumor CD4 CD3 immunity • Adding PD-1 inhibitors may augment Anti-VEGF Myeloid VEGF TKI these effects CD3 DCs • Standard of care has shifted to VEGF/R Anti-PD-1 immunotherapy-based combination CD3 Treg APC regimens in the 1st-line setting PD-1 MDSCs Anti-PD-L1 Macrophage Tumor PD-L1 (M2 phenotype) 12 Garje R, et al. Cancers (Basel). 2020;12:143. 12 2020 PCE Spring Oncology Series 4

  67. Raising the Bar for the Standard of Care: Advances in the Management of Advanced Renal Cell Carcinoma Case Study 1: Oliver • 63-year-old African American man presented for evaluation of hematuria and urinary obstruction • Medical history notable for hypertension and ongoing smoking • CT scan showed a left renal mass: 13.3 x 12.3 x 10 cm • Imaging revealed multiple lung nodules measuring up to 1.5 cm, consistent with metastatic disease • Oliver underwent biopsy of a lung nodule ‒ Pathology revealed metastatic clear-cell RCC with no sarcomatoid features • Oliver has a good PS and no additional IMDC risk factors other than needing systemic therapy within a year of diagnosis PS = performance status. 13 13 Guidelines for Recurrent or Advanced Clear-Cell RCC: First-line Therapy Risk Status First-line Therapy • Axitinib + pembrolizumab Favorable risk • Pazopanib • Sunitinib Preferred regimens Poor/intermediate • Axitinib + pembrolizumab risk • Ipilimumab + nivolumab • Cabozantinib • Ipilimumab + nivolumab Favorable risk • Cabozantinib Other recommended regimens • Axitinib + avelumab Poor/intermediate • Pazopanib risk • Sunitinib • Axitinib + avelumab 14 NCCN Guidelines. Kidney cancer. www.nccn.org/professionals/physician_gls/pdf/kidney.pdf. Accessed Mar 26, 2020. 14 KEYNOTE-426: Pembrolizumab + Axitinib in Treatment-naïve Advanced RCC OS in ITT Population • Pembrolizumab is an anti–PD-1 antibody that 100 has shown antitumor activity 90 Pembrolizumab + axitinib • Axitinib is a highly potent VEGFR-TKI Patients Who Were Alive (%) approved in the 2nd-line setting and has 80 shown antitumor activity in the 1st-line setting 70 • Combination pembrolizumab + axitinib Sunitinib 60 demonstrated high PFS, ORR, and OS vs sunitinib 50 ‒ OS in the ITT population at 12 months: 40 89.9% vs 78.3% 30 • Benefit observed in all IMDC subgroups 20 and PD-L1 expression categories Hazard ratio for death, 0.53 (95% CI, 0.38-0.74) 10 ‒ PFS: 15.1 vs 11.1 months P <0.0001 0 ‒ ORR: 59.3% vs 35.7% (CR: 5.8% vs 1.9%) 0 4 8 12 16 18 24 CR = complete response; ITT = intent to treat; ORR = overall response rate; Months OS = overall survival; PFS = progression-free survival; VEGFR = vascular endothelial growth factor receptor. 15 Rini BI, et al. N Engl J Med . 2019;380:1116-1127 . 15 2020 PCE Spring Oncology Series 5

  68. Raising the Bar for the Standard of Care: Advances in the Management of Advanced Renal Cell Carcinoma JAVELIN Renal 101: Avelumab + Axitinib vs Sunitinib as First-line Treatment PFS in Patients With PD-L1-Positive Tumors • PD-L1 inhibitor avelumab was studied in 100 combination with axitinib (VEGFR-TKI) vs 90 sunitinib 80 • Patients stratified by ECOG PS and geographic region 70 • Improvements seen in patients with PD-L1– PFS (%) 60 positive tumors Avelumab + axitinib 50 ‒ Median PFS: 13.8 vs 7.2 months 40 ‒ ORR: 55.2% vs 25.5% 30 Sunitinib ‒ Median OS: 11.6 vs 10.7 months (NS); 20 longer follow-up needed 10 • PFS benefit maintained in overall population as well, regardless of PD-L1 status 0 0 2 4 6 8 10 12 14 16 18 20 22 24 Months Motzer RJ, et al. N Engl J Med . 2019;380:1103-1115. 16 16 CheckMate 214: Nivolumab + Ipilimumab vs Sunitinib as First-line Treatment • Combination of checkpoint inhibitors OS in Intermediate-/Poor-Risk Disease 1.0 nivolumab + ipilimumab was studied in 0.9 patients with intermediate- or poor-risk 74% 0.8 advanced RCC Nivolumab + ipilimumab 0.7 • Extended follow-up (minimum 42 OS (probability) v 60% months) showed superiority of nivolumab 0.6 52% 60% + ipilimumab vs sunitinib: 0.5 47% ‒ OS: 47.0 vs 26.6 months 0.4 39% ‒ ORR: 42% vs 29% (CR: 12% vs 1%) 0.3 Sunitinib • In ITT patients, nivolumab + ipilimumab 0.2 showed improved efficacy compared with 0.1 sunitinib 0.0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 No. at risk Months 17 Tannir NM, et al. 2020 ASCO GU; Abstract 609. 17 Case Study (cont’d): Oliver • Oliver agrees to begin axitinib and pembrolizumab for his advanced RCC • Both Oliver and his family are educated on the treatment plan, mechanisms of action of the drugs, and potential adverse effects of therapy • He is instructed to take daily BP assessments at home and to call the office if he develops hypertension, defined for this patient as 150/90 mm Hg • He is to call the oncology provider if he develops any new symptoms 18 18 2020 PCE Spring Oncology Series 6

  69. Raising the Bar for the Standard of Care: Advances in the Management of Advanced Renal Cell Carcinoma irAEs and Their Toxicity Spectrum irAEs Can Affect Any Organ System • Checkpoint inhibitors stimulate the immune Encephalitis Aseptic meningitis Uveitis environment and can cause irAEs Hypophysitis • irAEs differ from AEs with chemotherapy and Thyroiditis Dry mouth Hypothyroidism Mucositis targeted therapy Hyperthyroidism ‒ Many occur within 2 to 3 treatment cycles, Pneumonitis Myocarditis but can occur any time—even after therapy is discontinued Hepatitis ‒ Typically mild, but can be severe, irreversible, Autoimmune Colitis Diabetes or life-threatening Enteritis Pancreatitis Thrombocytopenia • irAEs do not occur in all patients Rash Anemia Vitiligo Vasculitis ‒ Reasons are unknown Neuropathy Arthralgia 19 Brahmer JR, et al. J Clin Oncol. 2018;36:1714-1768; Cancer Council Victoria. www.cancervic.org.au/cancer-information/treatments/treatments- types/immunotherapy. Accessed March 30, 2020; Postow MA, et al. N Engl J Med . 2018;378:158-168. 19 19 Most Common AEs ( ≥ 20%) Associated With Pembrolizumab + Axitinib Combination Treatment (n = 429) AE, % Any Grade (n = 429) Grade 3, 4, or 5 (n = 425) AEs of any cause 98.4 75.8 Diarrhea 54.3 9.1 Hypertension 44.5 22.1 Fatigue 38.5 2.8 Hypothyroidism 35.4 0.2 Decreased appetite 29.6 2.8 Hand-foot-skin reaction 28.0 5.1 Nausea 27.7 0.9 ALT increased 26.8 13.3 AST increased 26.1 7.0 Dysphonia 25.4 0.2 Cough 21.2 0.2 Constipation 20.7 0 ALT = alanine aminotransferase; AST = aspartate transaminase. 20 Rini BI, et al. N Engl J Med . 2019;380:1116-1127. 20 Combination Therapy Patient Education • Before starting treatment: ⎻ Educate patients about mechanisms of action and reasons for using combination treatment ⎻ Record all medications, including supplements and OTC medications ⎻ Provide patients with a wallet card outlining the type of treatments they are receiving, potential AEs, and their care team contact numbers ⎻ Educate patients/caregivers about potential toxicity profiles, presenting symptoms, and timing of their treatments ⎻ Inform patients of educational resources • Tell patients to notify the oncology healthcare team: ⎻ If any new signs or symptoms develop • Monitor symptoms for at least 2 years after treatment has concluded ‒ When admitted to the hospital ‒ If any new medications are prescribed or prior to receiving any immunizations/vaccines NCCN Guidelines. Management of immunotherapy-related toxicities. www.nccn.org/professionals/physician_gls/pdf/immunotherapy.pdf. 21 Accessed Mar 26, 2020. 21 2020 PCE Spring Oncology Series 7

  70. Raising the Bar for the Standard of Care: Advances in the Management of Advanced Renal Cell Carcinoma Case Study (cont’d): Oliver • Front-line treatment with pembrolizumab 200 mg IV every 3 weeks and axitinib 5 mg twice a day was initiated, and a follow-up call 2 days later revealed no adverse effects • 8 days after initiation of cycle 3 of axitinib and pembrolizumab, Oliver called with complaints of increasing fatigue, loss of appetite, difficulty with fluid intake, and 5 loose stools in the past 24 hours (grade 2) despite maximum dosing of loperamide 22 22 Managing Diarrhea Associated With Axitinib + Pembrolizumab • Diarrhea is one of the most common side effects of axitinib ‒ For most cases, supportive care and use of antidiarrheals can control this toxicity ‒ For grade 3 or 4 diarrhea, reduce the axitinib dose or interrupt therapy until diarrhea improves to grade 1 • When diarrhea occurs when axitinib is given in combination with pembrolizumab and can be attributed to either drug, stop axitinib for a few days as an initial step ‒ Axitinib-induced toxicity should improve significantly with cessation of therapy due to its short half-life ‒ Pembrolizumab-induced toxicity would not improve after stopping axitinib • If diarrhea does not resolve with axitinib cessation and an irAE is suspected, follow the appropriate guidelines Greene HR. www.practiceupdate.com/content/management-of-diarrhea-associated-with-targeted-rcc-therapy/27360. Accessed Mar 26, 2020; Wood 23 LS, Ornstein MC. JCO Oncology Practice. 2020;16(2 suppl):15s-19s. 23 Guidelines for Managing irAEs Toxicity Grade Recommendation Continue checkpoint inhibitors with close monitoring, with exception of some neurologic, hematologic, and cardiac Grade 1 toxicities Hold for most grade 2 toxicities and consider resuming when symptoms and/or laboratory values return to Grade 2 grade 1 or less Corticosteroids (initial dose of 0.5 to 1 mg/kg/d of prednisone or equivalent) may be given Hold checkpoint inhibitors for grade 3 AEs and initiate high-dose corticosteroids (prednisone 1 to 2 mg/kg/d or methylprednisolone IV 1 to 2 mg/kg/d) Grade 3 • Taper corticosteroids over course of at least 4 to 6 weeks • If symptoms do not improve with 48 to 72 hours of high-dose corticosteroid, infliximab may be offered for some toxicities Warrants permanent discontinuation of checkpoint inhibitors, with exception of endocrinopathies controlled by Grade 4 hormone replacement • When symptoms and/or lab values revert to grade 1 or less, rechallenging with checkpoint inhibitors may be offered. Use caution when administering to patients with early-onset irAEs, and dose adjustments are not recommended. 24 Brahmer JR, et al. J Clin Oncol . 2018;36:1714-1768; Postow MA, et al. N Engl J Med. 2018;378:158-168. 24 2020 PCE Spring Oncology Series 8

  71. Raising the Bar for the Standard of Care: Advances in the Management of Advanced Renal Cell Carcinoma Monitoring Patients on Drugs With Different Mechanisms of Action • Dealing with two different mechanisms of action with two sets of AE profiles is challenging • Classical AEs of VEGF TKIs are fatigue, hypertension, diarrhea, oral pain, and hand-foot-skin reaction • Classical AEs of immunotherapy involve organ inflammation • Notable crossover AEs: fatigue, diarrhea, hypothyroidism, LFT elevations LFT = liver function test. Rini BI, et al. N Engl J Med. 2019;380:1116-1127. 25 25 Case Conclusion: Oliver • Oliver’s TSH increased from 3.4 at baseline to 13.0, and he was put on levothyroxine • Otherwise, he tolerated the combination of axitinib and pembrolizumab with no other AEs except occasional diarrhea • Imaging 3 months after start of treatment demonstrated regression of all lung nodules and shrinkage of the primary renal mass • The plan is to continue treatment for up to 2 years and take a break 26 TSH = thyroid stimulating hormone. 26 Case Study 2: Margaret • 72-year-old woman diagnosed with advanced clear-cell RCC and lung and liver metastases • She was treated 1st-line with axitinib + pembrolizumab • After 3 months on treatment, her first follow-up scan showed marked progression in her lung and local recurrence • Her KPS was 70 and her risk score was 2 (intermediate) 27 27 2020 PCE Spring Oncology Series 9

  72. Raising the Bar for the Standard of Care: Advances in the Management of Advanced Renal Cell Carcinoma Tyrosine Kinase Inhibitors Mechanism of Action of Multi-TKIs • The novel multitargeted TKIs cabozantinib and lenvatinib (combined with everolimus) Growth factor Growth factor signals to make signals for the have shown favorable data in advanced RCC blood vessels cell to divide ‒ Cabozantinib is an inhibitor of multiple Receptor receptor tyrosine kinases, including Receptor Multi TKI VEGFR, MET, the TAM kinases, KIT, FLT3, blocks the signal TRKB, and TIE2 ‒ Lenvatinib is an inhibitor of VEGFR1–3, TKI going into cell FGFR1–4, PDGFRa, KIT, and RET • Inhibiting these signaling molecules contributes to the antitumor immunomodulatory effect of these drugs Bergerot P, et al. Mol Cancer Ther. 2019;18:2185-2193; De Lisi D, et al. Expert Opin Drug Metab Toxicol. 2018;14:461-467. 28 28 Guidelines for Recurrent or Advanced Clear-Cell RCC: Subsequent Lines Subsequent Therapy • Cabozantinib (category 1) Preferred regimens • Nivolumab (category 1) • Ipilimumab + nivolumab • Axitinib (category 1) • Lenvatinib + everolimus (category 1) Other recommended • Axitinib + pembrolizumab regimens • Everolimus • Pazopanib • Sunitinib • Axitinib + avelumab (category 3) 29 NCCN Guidelines. Kidney cancer. www.nccn.org/professionals/physician_gls/pdf/kidney.pdf. Accessed Mar 26, 2020. 29 Lenvatinib + Everolimus • Multitargeted TKI lenvatinib was PFS by Treatment Group 100 approved in 2016 as combination therapy with the mTOR inhibitor 80 everolimus for 2nd-line treatment of Progression-free Survival(%) Levatinib + everolimus Single-agent lenvatinib advanced RCC Single-agent everolimus 60 • Small randomized phase 2 study with ~50 patients in each of 3 arms 40 • Median PFS vs everolimus monotherapy: 14.6 vs 5.5 months 20 • Median OS vs everolimus: 25.5 vs 15.4 months 0 0 3 6 9 12 15 18 21 24 Time (months) mTOR = mammalian target of rapamycin. 30 Lenvima [prescribing information]. Eisai Inc; 2020; Motzer RJ, et al. Lancet Oncol. 2015;16:1473-1482. 30 2020 PCE Spring Oncology Series 10

  73. Raising the Bar for the Standard of Care: Advances in the Management of Advanced Renal Cell Carcinoma Cabozantinib • Multitargeted TKI approved in 2017 for front-line use in previously untreated RCC in patients with intermediate/poor risk ‒ Approval based on results from the phase 2 CABOSUN trial ‒ Compared with sunitinib, cabozantinib reduced risk of progression or death by 52% ‒ Median PFS: 8.6 months vs 5.3 months with sunitinib • Now approved for both 1st- and 2nd-line treatment of advanced RCC • Toxicity profile of cabozantinib similar to other VEGFR TKIs for the treatment of advanced RCC ‒ Most common grade 3 or 4 side effects were hypertension, diarrhea, and fatigue Cabometyx [prescribing information]. Exelixis, Inc; 2020; Choueiri TK, et al. 2017 ESMO Congress. LBA38; Choueiri TK, et al. J Clin Oncol. 2017;35:591-597; Martinez Chanza N, et al. Lancet Oncol . 2019;20:581-590; US Food and Drug Administration. www.fda.gov/drugs/informationondrugs/approveddrugs/ucm589842.htm. Accessed Mar 26, 2020 31 31 Case Study (cont’d): Margaret • After 2 months of treatment with combination lenvatinib and everolimus, Margaret begins to experience extreme fatigue 32 32 Toxicity Profile of Lenvatinib + Everolimus Lenvanitib + • Most common grade 1-2 TEAEs Everolimus AE, % Lenvanitib Everolimus reported in lenvatinib + everolimus Diarrhea 65 60 32 group Decreased appetite 45 54 18 ‒ Diarrhea, decreased appetite, fatigue Fatigue 45 42 36 • Most common TEAEs of grade ≥3 in the lenvatinib + everolimus group ‒ Constipation, diarrhea, fatigue • For toxicities thought to be related to everolimus alone, such as stomatitis and noninfectious pneumonitis, the drug should be discontinued, interrupted, or used on alternate days, according to the label • For toxicities considered to be related to both lenvatinib and everolimus, the lenvatinib dose should be reduced first TEAEs = treatment-emergent adverse events. Afinitor [prescribing information]. Novartis Pharmaceuticals Corporation; 2020; Motzer RJ, et al. Lancet Oncol. 2015;16:1473-1482; Stenger M. 33 ascopost.com/issues/june-10-2016/lenvatinib-in-combination-with-everolimus-in-advanced-renal-cell-carcinoma/. Accessed Mar 26, 2020. 33 2020 PCE Spring Oncology Series 11

  74. Raising the Bar for the Standard of Care: Advances in the Management of Advanced Renal Cell Carcinoma Case Conclusion • Eight months later, Margaret complained of fatigue, abdominal discomfort, and weight loss; she subsequently developed back pain • CT scan of abdomen and chest showed new liver lesions and progression of previously identified lesions • MRI of the spine showed multiple metastatic lesions of the thoracic and lumbar vertebrae, with no evidence of cord compression • She was switched to cabozantinib 60 mg and her symptoms subsided within 4 weeks • She was maintained on cabozantinib for approximately 13 months until the disease progressed • Margaret is being considered for enrollment into a clinical trial MRI = magnetic resonance imaging. 34 34 PCE Action Plan  Be aware of patient factors that help determine the most appropriate therapy options  Provide patients with resource materials, reminders, and other tools (eg, wallet cards) to reinforce details about toxicities related to combination therapy  Consider rechallenge with checkpoint inhibitor therapy with caution in patients whose irAE symptoms and/or laboratory values revert to grade ≤ 1  It is important to discern causative therapy, since management of AEs is dependent on differentiation PCE Promotes Practice Change 35 35 2020 PCE Spring Oncology Series 12

  75. Evolving Options in Metastatic Prostate Cancer Evolving Options in Metastatic Prostate Cancer 1 Learning Objectives • Implement guideline-recommended treatment strategies for patients with nonmetastatic castrate-resistant prostate cancer (CRPC) • Formulate personalized management strategies for patients with metastatic CRPC based on patient preferences and efficacy and safety of novel agents • Apply strategies to identify and manage AEs associated with novel therapies for CRPC 2 AE = adverse event. 2 Prostate Cancer in 2020 • Estimated for 2020 ‒ 191,930 new cases ‒ 33,330 deaths ‒ Incidence and mortality rates have declined ‒ 10-year overall survival (OS): 98% • Risk factors ‒ Advancing age ‒ African ancestry Image: Histology slide showing prostate cancer. Courtesy of the National Cancer Institute. ‒ Family history Photographer: Otis Brawley, ‒ Genetic mutations American Cancer Society. www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and- 3 figures/2020/cancer-facts-and-figures-2020.pdf. Accessed Mar 24, 2020. 3 2020 PCE Spring Oncology Series 1

  76. Evolving Options in Metastatic Prostate Cancer Advances in Treatment Approvals Apalutamide (next- generation ARSI) Enzalutamide (next- Darolutamide Docetaxel for nmCRPC Cabazitaxel generation ARSI) (next-generation ARSI) (taxane) Radium-223 (novel taxane) postdocetaxel for nmCRPC (radiopharmaceutical) 2004 2010 2011 2012 2013 2014 2018 2019 Sipuleucel-T Abiraterone (next- Abiraterone Enzalutamide Enzalutamide (immunotherapy) generation ARSI) predocetaxel predocetaxel Enzalutamide for mHSPC postdocetaxel for nmCRPC mHSPC = metastatic hormone-sensitive prostate cancer; nmCRPC = nonmetastatic castrate-resistant prostate cancer. Komura K, et al. Int J Urol . 2018;25:220-231; US Food and Drug Administration. www.fda.gov/newsevents/newsroom/pressannouncements/ucm596768.htm. Accessed Mar 24, 2020; US Food and Drug Administration. www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=210951. Accessed Mar 24, 2020. US Food and Drug Administration. www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-darolutamide-non-metastatic-castration-resistant-prostate-cancer. Accessed Mar 24, 2020; US Food and Drug Administration. www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-enzalutamide- metastatic-castration-sensitive-prostate-cancer. Accessed Mar 24, 2020. 4 4 CHAARTED: ADT + Docetaxel in mHSPC All Patients OS Benefit by Volume of Disease 100 • High volume: 17 months • Low volume: no benefit 80 OS (%) 60 ADT + docetaxel: (median OS, 57.6 months) 40 ADT alone (n = 393): Death with ADT + docetaxel (n = 397): 20 (median OS, 44.0 months) HR, 0.61 (95% CI, 0.47-0.80) P <.001 0 12 24 36 48 60 72 0 84 Number at Risk ADT + docetaxel 397 333 189 89 46 5 2 0 ADT alone 393 318 168 71 27 3 1 0 Median follow-up: 28.9 months ADT = androgen deprivation therapy; CI = confidence interval; HR = hazard ratio; PSA = prostate-specific antigen. 5 Sweeney CJ, et al. N Engl J Med . 2015;373:737-746. 5 STAMPEDE, Arm C: ADT and Docetaxel in HSPC Median OS (Months) 5-Year Survival (%) 70% 60% Median OS Metastatic 45 Months 63% 50% 60 Months 50% 40% 55% 30% Median OS 71 Months 39% 20% 81 Months 10% 0 10 20 30 40 50 60 70 80 90 0% 5-Year Survival (Metastatic) 5-Year Survival ADT Alone ADT + Docetaxel ADT Alone ADT + Docetaxel ADT alone: n = 1184 ADT + docetaxel: n = 592 Median follow-up: 43 months 6 James ND, et al. Lancet . 2016;387:1163-1177. 6 2020 PCE Spring Oncology Series 2

  77. Evolving Options in Metastatic Prostate Cancer Phase 3 Trials of ADT + Abiraterone in mHSPC LATITUDE STAMPEDE, Arm G N = 1199: ADT + abiraterone + prednisone vs ADT + placebo N = 960: ADT + abiraterone + prednisolone vs ADT alone 100 80 100 ADT + abiraterone 80 60 rPFS (%) PFS (%) 60 Abiraterone 40 40 ADT Placebo HR, 0.47 (95% CI, 0.39-0.55) 20 20 P <.001 HR, 0.29 (95% CI, 0.25-0.34) 0 P <.001 0 8 16 24 32 40 0 0 6 12 18 24 30 36 42 48 54 Months Months PFS = progression-free survival; rPFS = radiographic progression-free survival. Fizazi K, et al. N Engl J Med. 2017;377:352-360; James ND, et al. N Engl J Med . 2017;377:338-351. 7 7 Some Agents Used in Advanced Settings Are Now Being Used in Earlier Disease rPFS: significant TITAN Phase 3 ADT + apalutamide vs improvement in both low- Study ADT + placebo in and high-volume disease (N >1050) mHSPC ( P <.001) with apalutamide PFS: significant ARCHES Phase 3 ADT + enzalutamide vs improvement in both low- Study ADT + placebo in and high-volume disease (N = 1150) mHSPC ( P <.001) with enzalutamide Armstrong AJ, et al. J Clin Oncol. 2019;37(7 suppl):Abstract 687; Chi KN et al. J Clin Oncol . 2019;37(15 suppl):Abstract 5003; US Food and Drug Administration. www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-enzalutamide-metastatic-castration-sensitive-prostate- 8 cancer. Accessed Mar 24, 2020. 8 2019 NCCN Guidelines for mHSPC • Based on results of clinical trials, for patients with mHSPC, consider adding to ADT: ‒ Docetaxel 75 mg/m 2 every 3 weeks for 6 cycles • Patients with high-volume disease derive greater benefit ‒ Abiraterone acetate + steroid ‒ Apalutamide ‒ Enzalutamide NCCN = National Comprehensive Cancer Network. 9 NCCN Guidelines. Prostate cancer. www.nccn.org/professionals/physician_gls/pdf/prostate.pdf. Accessed Mar 24, 2020. 9 2020 PCE Spring Oncology Series 3

  78. Evolving Options in Metastatic Prostate Cancer Castrate-Resistant Prostate Cancer • Disease progression despite castrate levels of testosterone (<50 ng/mL) • Heterogeneous—can be symptomatic or asymptomatic, with or without metastases • Affects 10% to 20% of men with prostate cancer within 5 years of diagnosis ‒ Before recent therapeutic advances, ≥50% of these patients would have died within 3 years • Natural history can involve progressive decline in health-related QoL • Metastasis-free survival (MFS) is a new, reasonable endpoint for both clinical trials and clinical discussions with patients QoL = quality of life. Anantharaman A, et al. Expert Rev Anticancer Ther . 2017;17:625-633; Beaver JA, et al. N Engl J Med . 2018;378:2458-2460; Nussbaum N, et al. Prostate Cancer Prostatic Dis . 2016;19:111-121. 10 10 Typical Progression of CRPC Rising PSA mHSPC despite castrate Criterion 1: levels of Rising Identification of testosterone PSA metastases Both criteria met Localized/locally Biochemical Start Definitive mCRPC advanced recurrence ADT therapy prostate cancer Criterion 2: Rising PSA Identification of despite castrate metastases levels of testosterone nmCRPC 11 Adapted with permission from Anantharaman A, et al. Expert Rev Anticancer Ther . 2017;17:625-633. 11 Nonmetastatic CRPC • CRPC with no clinical or radiologic evidence of metastases • Newer imaging techniques have greater sensitivity (eg, 18 F-fluorocholine or PSMA-targeted PET) ‒ May reveal metastases earlier • PSA testing every 4 to 6 months is advised • Treatment is recommended for men with PSADT ≤10 months • Until recently, no approved drugs were available for nmCRPC Image from Singh A, et al. PET Clin . 2017;12:193-203. PET = positron emission tomography; PSADT = prostate-specific antigen doubling time; PSMA = prostate-specific membrane antigen. Anantaraman A, et al. Expert Rev Anticancer Ther . 2017;17:625-633; Virgo KS, et al. J Clin Oncol . 2017;35:1952-1964; Zimmerman ME, et al. 12 Clin Adv Hematol Oncol . 2019;17:455-463. 12 2020 PCE Spring Oncology Series 4

  79. Evolving Options in Metastatic Prostate Cancer Case Study 1: Earl, 69 Years Old • Earl has mild COPD and occasional arrhythmias ‒ No family history of cancer • He underwent radiotherapy for localized prostate cancer 4 years ago • Earl experienced biochemical recurrence as evidenced by increasing PSA • Because of previous radiotherapy, he was not considered a candidate for surgery • He was started on ADT 1 year ago 13 13 Case Study (cont’d): Earl’s Test Results • PSA increased from 6 ng/mL to 14 ng/mL, with PSADT of 8 months ‒ Testosterone level: 23 ng/dL ‒ No evidence of metastases on CT or bone scan, no bone pain ‒ No lymph node masses detected • Now diagnosed with nmCRPC 14 14 Factors to Consider When Selecting Therapies Patient Disease Treatment • Preferences • Metastatic? • Toxicity profile • Medical history, – To bone? • Possible drug-drug comorbidities, medications interactions – Visceral? • Treatment and response • Effects on pain, QoL • Disease volume history – Low or high? • Practitioner experience • Symptoms and preference • Risk level/aggressiveness • Overall condition and performance status Basch E, et al. J Clin Oncol . 2014;32:3436-3448; Crawford ED, et al. J Urol . 2015;194:1537-1547; Nussbaum N, et al. Prostate Cancer Prostatic 15 Dis . 2016;19:111-121; Zarrabi K, et al. J Hematol Oncol . 2019;12:89. 15 2020 PCE Spring Oncology Series 5

  80. Evolving Options in Metastatic Prostate Cancer Shared Decision-Making • Especially important for complex diseases such as CRPC • Endorsed by all major guidelines • Patients and clinicians collaborate on treatment selection • May enhance adherence to therapies • May improve outcomes: Greater adherence → better treatment responses Fennimore LA, Ginex PK. Nurs Clin North Am . 2017;52:115-131; Makarov DV, et al. www.auanet.org/guidelines/shared-decision-making. Accessed Mar 24, 2020. 16 16 SPARTAN and PROSPER: Grade ≥3 AEs Occurring in >1% of Patients SPARTAN PROSPER AE Apalutamide + ADT Placebo + ADT Enzalutamide + ADT Placebo + ADT Any grade ≥3 AE 362 (45.1%) 136 (34.2%) 292 (31%) 109 (23%) Hypertension 115 (14.3%) 47 (11.8%) 43 (5%) 10 (2%) Rash 42 (5.2%) 1 (0.3%) NR NR Fracture 22 (2.7%) 3 (0.8%) NR NR Falls 14 (1.7%) 3 (0.8%) 12 (1%) 3 (1%) Fatigue 7 (0.9%) 1 (0.3%) 27 (3%) 3 (1%) Hematuria NR NR 16 (2%) 13 (3%) NR = not reported. 17 Hussain M, et al. N Engl J Med . 2018;378:2465-2474; Smith MR, et al. N Engl J Med . 2018;378:1408-1418. 17 ARAMIS: Darolutamide in nmCRPC Phase 3, placebo-controlled trial; N = 1509 (PSADT ≤10 months) AEs (≥5% or grade ≥3) were similar 1.0 HR, 0.41 (95% CI, 0.34-0.50) between groups and included: P <.001 Probability of Survival 0.8 Without Metastasis • Fatigue Darolutamide: 40.4 months (median) 0.6 • Back pain 0.4 • Arthralgia Placebo: 18.4 months (median) 0.2 • Diarrhea • Hypertension 0.0 0 4 8 12 16 20 24 28 32 36 40 44 48 • Constipation Months Median follow-up time at primary analysis: 17.9 months Risk of metastasis or death from any cause was reduced by 59% 18 Fizazi K, et al. N Engl J Med . 2019;380:1235-1246. 18 2020 PCE Spring Oncology Series 6

  81. Evolving Options in Metastatic Prostate Cancer 2019 NCCN Guidelines for nmCRPC • In addition to continuing ADT to maintain castrate serum levels of testosterone (<50 ng/dL): ‒ For men whose PSADT is ≤10 months: apalutamide, darolutamide, enzalutamide, or other secondary hormone therapy ‒ For men whose PSADT is >10 months: observation or other secondary hormone therapy NCCN Guidelines. Prostate cancer. www.nccn.org/professionals/physician_gls/pdf/prostate.pdf. Accessed Mar 24, 2020. 19 19 Case Conclusion • Earl is taking apalutamide 240 mg/day and continuing ADT • Bone health is being monitored closely • Disease progression has plateaued ‒ PSA = 3.5 ng/mL • Will continue serial PSA monitoring • Will undergo imaging only if new symptoms develop or PSA level increases 20 20 Metastatic Prostate Cancer • 72% increase from 2004 to 2013, even as incidence of low-risk prostate cancer declined ‒ Trend started before USPSTF recommendation for reduced routine early screening so is not associated solely with that reduction • 5-year survival rate: ~30% vs nearly 100% for nonmetastatic disease • Approximately 90% of men with mCRPC have bone metastases • Treatment evolving rapidly ‒ Novel therapies improve outcomes but increase treatment complexity USPSTF = United States Preventive Services Task Force. American Cancer Society. www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and- figures/2020/cancer-facts-and-figures-2020.pdf. Accessed Mar 24, 2020; NCCN Guidelines. Prostate cancer. www.nccn.org/professionals/physician_gls/default.aspx. Accessed Mar 24, 2020; Weiner AB, et al. Prostate Cancer Prostatic Dis . 2016;19:395-397; 21 Vogelzang NJ et al. Clin Genitourin Cancer . 2017;15:42-52. 21 2020 PCE Spring Oncology Series 7

  82. Evolving Options in Metastatic Prostate Cancer Case Study 2: Eli, 72 Years Old • Eli has prehypertension and well-controlled diabetes ‒ Family history: mother had breast cancer • Diagnosed 6 years ago with de novo metastatic prostate cancer, with a PSA level of 45 ng/mL • Has high-volume disease: metastasis to multiple bone sites and to lymph nodes 22 22 Case Study (cont’d): Eli’s Initial Treatment • Started on ADT and received 6 cycles of docetaxel ‒ His PSA level became undetectable but began to increase 2 years after he started treatment • Presents with asymptomatic mCRPC ‒ Reports no pain ‒ Imaging unchanged since completion of chemotherapy 23 23 Treatment Options: Immunotherapy Sipuleucel-T Day 1 Days 2-3 Days 3-4 Leukapheresis Sipuleucel-T is manufactured Patient receives infusion • First FDA-approved immunotherapy for prostate cancer • Shows OS benefit, even without PSA response Apheresis Center Central Processing Clinician’s Office • Most beneficial in less advanced disease → thus, early use recommended COMPLETE COURSE OF THERAPY Weeks 0, 2, 4 24 Gupta S et al. Onco Targets Ther . 2011;4:79-96; Hu R et al. Ther Adv Urol . 2016;8:272-278; Kantoff PW et al. N Engl J Med . 2010;363:411-422. 24 2020 PCE Spring Oncology Series 8

  83. Evolving Options in Metastatic Prostate Cancer Sipuleucel-T: Randomized Phase 3 IMPACT Trial • AEs more frequent (≥20%) than Sipuleucel-T: Survival Benefit in Phase 3 Trial with placebo: chills, fatigue, pyrexia, nausea 100 P = .032 (Cox model) Probability of Survival (%) HR, 0.78 (95% CI, 0.61 – 0.98) • Explain to patients that Median survival benefit = 4.1 months 75 benefits may not manifest as typical signs of improvement Sipuleucel-T (n = 341) 50 (eg, changes in PSA) Median survival: 25.8 months 25 Placebo (n = 171) Median survival: 21.7 months 0 0 6 12 18 24 30 36 42 48 54 60 66 Months Since Randomization Kantoff PW et al. N Engl J Med . 2010;363:411-422; Pieczonka CM et al. Rev Urol . 2015;17:203-210. 25 25 Case Study (cont’d) • Eli undergoes 3 sessions of sipuleucel-T infusion over 4 weeks • At interim assessment a few months later, his cancer has progressed, with additional bone lesions revealed on scanning, but lymph node disease is stable • He reports back pain that is not debilitating, but he now requires intermittent opioids 26 26 Treatment Options for mCRPC: Newer ARSIs • Both drugs are approved for use with or without prior docetaxel Abiraterone Enzalutamide • Inhibits CYP17, enzyme needed • Androgen receptor (AR) for androgen synthesis antagonist; binds competitively to ligand-binding domain of AR • Administered with steroids • Concomitant steroids not required CYP = cytochrome. Beer TM, et al. N Engl J Med . 2014;371:424-433; de Bono JS, et al. N Engl J Med. 2011;364:1995-2005; Gomez L, et al. Steroids . 2015;95:80-86; 27 Ryan CJ, et al. N Engl J Med . 2013;368:138-148; Scher HI, et al. N Engl J Med ; 2012;367:1187-1197. 27 2020 PCE Spring Oncology Series 9

  84. Evolving Options in Metastatic Prostate Cancer COU-AA-301: Phase 3 Trial of Second-line Abiraterone in mCRPC • Abiraterone vs placebo: 100 HR, 0.65 (95% CI, 0.54-0.77) P <.001 1195 patients with mCRPC progressing after docetaxel 80 Abiraterone Acetate Median survival: 14.8 months • 2 prior chemo OS: 14.0 months (95% Cl, 14.1-15.4) abiraterone vs 10.3 months placebo Survival (%) 60 • 1 prior chemo OS: 15.4 months abiraterone vs 11.5 months placebo 40 Placebo Median survival: 10.9 months • Most common AEs, grade ≥3: (95% Cl, 10.2-12.0) 20 ‒ Fatigue (<9% vs 10%) ‒ Anemia (7% vs 8%) 0 0 3 6 9 12 15 18 21 ‒ Back pain (<7% vs <10%) Months de Bono JS, et al. N Engl J Med . 2011;364:1995-2005. 28 28 AFFIRM: Phase 3 Trial of Second-line Enzalutamide in mCRPC Enzalutamide vs placebo for 1199 men with mCRPC after chemotherapy 100 100 HR, 0.40 (95% CI, 0.35-0.47) 80 80 P <.001 Enzalutamide 60 60 OS (%) rPFS (%) 40 40 Placebo Enzalutamide 20 HR, 0.63 (95% CI, 0.53-0.75) 20 P <.001 Placebo 0 0 0 6 12 18 24 0 6 12 18 24 Months Months Most common grade ≥3 AEs: fatigue (6% vs 7%), diarrhea (1% vs <1%), cardiac disorder (1% vs 2%) 29 Scher HI, et al. N Engl J Med . 2012;367:1187-1197. 29 Phase 3 Trials in Chemotherapy-naïve mCRPC COU-302: Abiraterone + Prednisone PREVAIL: Enzalutamide 100 100 Enzalutamide 80 80 Abiraterone + prednisone OS (%) OS (%) Placebo 60 60 Placebo + prednisone 40 40 Men with mild or no HR, 0.71 (95% CI, 0.60-0.84) 20 HR, 0.81 (95% CI, 0.70-0.93) 20 symptoms P <.001 P = .0033 0 0 0 6 12 13 24 30 36 42 43 54 60 0 3 6 9 12 15 18 21 24 27 30 33 Primary endpoints: OS (Months) OS, rPFS OS (Months) 100 100 HR, 0.19 (95% CI, 0.15-0.23) HR, 0.53 (95% CI, 0.45-0.93) No prior P = .0033 P <.001 80 80 ketoconazole Enzalutamide PFS (%) Abiraterone + prednisone PFS (%) 60 60 Men with liver 40 40 metastases eligible in Placebo Placebo + prednisone 20 20 PREVAIL 0 0 0 3 6 9 12 15 18 21 24 27 30 0 3 6 9 12 15 18 PFS (Months) PFS (Months) 30 Beer TM, et al. N Engl J Med . 2014;371:424-433; Ryan CJ, et al. Lancet Oncol. 2015;16:152-160; Ryan CJ, et al. N Engl J Med . 2013;368:138-148. 30 2020 PCE Spring Oncology Series 10

  85. Evolving Options in Metastatic Prostate Cancer Abiraterone and Enzalutamide: Drug Characteristics and Toxicities Abiraterone Enzalutamide Dosage 1000 mg/day orally 160 mg/day orally Empty stomach required Yes No Prednisone required Yes No Drug interactions (CYP) Yes Yes Hypokalemia Yes No Lowers seizure threshold No Yes Potential liver toxicity Yes Less likely Hypertension Yes* Yes Fatigue Yes More likely Cardiac toxicity More likely Yes *Risk of hypertension is increased by required coadministration of prednisone. Beer TM, et al. N Engl J Med . 2014;371:424-433; Mayo Clinic. www.mayoclinic.org/steroids/art-20045692. Accessed Mar 24, 2020; Moreira RB, et al. Oncotarget . 2017;8:84572-84578; Ryan CJ, et al. Lancet Oncol. 2015;16:152-160; Ryan CJ, et al. N Engl J Med . 2013;368:138-148; Tonyali S, et al. Curr Urol . 2017;10:169-173; Zytiga [prescribing information]. Janssen Biotech; 2018. 31 31 Treatment Options: Radiopharmaceuticals ─ Radium-223 • Unlike beta-emitting radioisotopes (eg, samarium-153), radium-223, an alpha-emitting isotope, delivers less radiation to bone marrow, resulting in fewer effects of marrow suppression ALSYMPCA: randomized, placebo-controlled study of symptomatic mCRPC with bone metastases Time to First Symptomatic Skeletal Event Overall Survival 100 100 HR, 0.70 (95% Cl, 0.58-0.83) HR, 0.66 (95% Cl, 0.52-0.83) Patients Without Symptomatic P <.001 P <.001 80 80 Skeletal Event (%) Radium-223 Survival (%) (median time to first symptomatic Radium-223 60 60 skeletal event, 15.6 months) (median OS, 14.9 months) 40 40 Placebo (median time to first symptomatic Placebo skeletal event, 9.8 months) 20 20 (median OS, 11.3 months) 0 0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 0 3 6 9 12 15 18 21 24 27 30 Months Since Randomization Months Since Randomization Most common AEs: bone pain, nausea, anemia; no clinically meaningful between-group differences Anderson M, Vogelzang N. pcri.org/insights-blog/2017/3/17/targeted-radiation-administered-by-injection. Accessed Mar 24, 2020; Parker C, et al. N 32 Engl J Med . 2013;369:213-223; Parker C, et al. Prostate Cancer Prostatic Dis . 2018;21:37-47. 32 Case Study (cont’d) • Eli is treated with enzalutamide, which was chosen because of the extent of his disease and to avoid steroids, which are necessary with abiraterone but are contraindicated for patients with diabetes • Subsequently treated with radium-223 • After an initial decrease in PSA, his mCRPC progresses, with a PSA increase to 38 ng/mL, and his use of opioids for pain has become more regular 33 33 2020 PCE Spring Oncology Series 11

  86. Evolving Options in Metastatic Prostate Cancer Role of Genetic Testing • Germline mutations have raised the issue of inheritable cancer risk • No validated biomarkers available; several are being investigated • Every patient with prostate cancer should be considered for genetic testing and possible genetic counseling • Patients should be counseled before genetic testing Connors LM. Clin J Oncol Nurs . 2019;23:32-35; NCCN Guidelines. Prostate cancer. www.nccn.org/professionals/physician_gls/pdf/prostate.pdf. Accessed Mar 24, 2020. 34 34 Biomarkers: Examples of Potential Utility • PTEN loss may indicate increased risk of disease progression Imaging • AR-V7 leads to loss of binding in the AR ‒ May indicate resistance to ARSIs but Serum not to taxanes • DNA repair gene mutations Tissue (biopsy) ‒ Seen in approximately ¼ of patients with mCRPC Urine ‒ Promising: BRCA1/BRCA2 AR-V7 = androgen receptor variant 7; PTEN = phosphatase and tensin homolog. Connors LM. Clin J Oncol Nurs . 2019;23:32-35; NCCN Guidelines. Prostate cancer. www.nccn.org/professionals/physician_gls/default.aspx. 35 Accessed Mar 24, 2020. 35 Treatment Options: Chemotherapy • Docetaxel (first-generation taxane) ‒ Until 2010, only approved drug to improve OS for mCRPC Cabazitaxel 2010 ‒ Appropriate for castrate-sensitive disease in select Docetaxel 2004 patients Mitoxantrone • Cabazitaxel (next-generation taxane) 1996 ‒ Improves OS among docetaxel-pretreated patients Cyclophosphamide with mCRPC 1993 ‒ Improves QoL; reduces pain through 5-FU 10 treatment cycles 1991 ‒ Approved at lower dosage (20 mg/m 2 ) in 2017 for patients with mCRPC previously treated with docetaxel ‒ Likely to move up in sequencing Bahl A, et al. BJU Int . 2015;116:880-887; de Wit R, et al. N Engl J Med . 2019;381:2506-2518; Eisenberger M, et al. J Clin Oncol. 2017;35:3198- 36 3206; Parimi S, et al. Int J Urol . 2016;23:726-733. 36 2020 PCE Spring Oncology Series 12

  87. Evolving Options in Metastatic Prostate Cancer CARD Trial: Randomized, Open-label Study of Cabazitaxel vs Abiraterone or Enzalutamide in mCRPC N = 255 men with mCRPC that progressed ≤12 months on prior alternative ARSI (before or after docetaxel) rPFS OS rPFS, months (95% CI) Median OS, months (95% CI) 100 Cabazitaxel: 8.0 (5.7-9.2) Cabazitaxel: 13.6 (11.5-17.5) Patients Who Were Alive (%) 100 ARSI: 3.7 (2.8-5.1) ARSI: 11.0 (9.2-12.9) 90 Patients With PFS (%) 90 80 80 HR for progression or death, 0.54 HR for death, 0.64 (95% CI, 0.46-0.89) 70 70 (95% CI, 0.40-0.73) P = .001 P = . 008 60 60 50 50 40 40 Cabazitaxel 30 30 Cabazitaxel ARSI 20 ARSI 20 10 10 0 0 0 3 6 9 12 18 24 30 0 3 6 9 12 18 24 30 Months Months de Wit R, et al. N Engl J Med . 2019;381:2506-2518. 37 37 Example of Therapy Sequencing for mCRPC • Optimal sequencing not First Line* Second Line* Third Line* established (sample Sipuleucel-T Abiraterone Docetaxel Asymptomatic shown) (chemonaïve) or or Enzalutamide Cabazitaxel • Treatment pathway is unique for each patient Abiraterone Docetaxel Cabazitaxel Symptomatic • Cross-resistance between or or or abiraterone and Enzalutamide Radium-223 Radium-223 or (bone (bone enzalutamide Docetaxel metastases) metastases) • Need to identify molecular Treatment Exhaustion mCRPC Patient subtypes for more rational sequencing Clinical Trials (eg, PARP inhibitors, immunotherapy) *All treatment options should include ADT (surgical/medical orchiectomy). PARP = poly (ADP-ribose) polymerase. Li Y , et al. Am J Hematol Oncol. 2017;13:26-31; Lorente D, et al. Lancet Oncol . 2015;16:e279-92; Parente P, et al. Asia Pac J Clin Oncol . 2014;10:205-215; Sartor O. Clin Adv Hematol Oncol . 2015;13:570-572; Sartor O, et al. N Engl J Med . 2018;378:645-657; Terada N, et al. Int J Urol. 38 2017;24:441-448. 38 Several Novel Agents Are Under Study PARP INHIBITORS IMMUNE CHECKPOINT INHIBITORS Olaparib: Phase 3 study in mCRPC with homologous recombination repair (HRR) mutation Pembrolizumab: Tissue-agnostic granted FDA priority review approval (for MSI-H) Has shown promise in prostate Niraparib : Phase 2 study for cancer studies BRCA1/BRCA2 gene-mutated mCRPC  breakthrough therapy designation Talazoparib: Promising interim results from phase 2 Ipilimumab: Being studied in phase 1, 2, TALAPRO-1 study and 3 trials in prostate cancer Rucaparib: Priority review for supplemental NDA granted from FDA based on phase 3 TRITON3 trial MSI-H = microsatellite instability-high. ASCO Post Staff. ascopost.com/news/february-2020/talazoparib-for-pretreated-patients-with-metastatic-castration-resistant-prostate-cancer/. Accessed March 24, 2020; Boettcher AN et al. Front Oncol . 2019;9:884; Clarke N, et al. Lancet. 2018;19:975-986; Hansen AR, et al. Ann Oncol . 2018;29:1807- 1813; Hussain M, et al. ESMO 2019 Congress. Abstract LBA12_PR; Smith MR, et al. Ann Oncol. 2019;30(suppl 5):v884-v885; Zhu J. www.urotoday.com/conference-highlights/asco-2018/asco-2018-prostate-cancer/104947-asco-2018-keynote-199-pembrolizumab-for-docetaxel- 39 refractory-metastatic-castration-resistant-prostate-cancer-mcrpc.html. Accessed Mar 24, 2020. Clinicaltrials.gov. NCT02975934. Accessed April 9, 2020. 39 2020 PCE Spring Oncology Series 13

  88. Evolving Options in Metastatic Prostate Cancer PROfound Trial: Phase 3 Study of Olaparib vs Enzalutamide or Abiraterone for mCRPC With HRR Gene Alterations Olaparib 300 mg bid Cohort A: n = 162 Endpoints BRCA1, BRCA2, or Key Eligibility ATM Criteria Physician’s Choice N = 245 Primary: n = 83 - rPFS in Cohort A mCRPC with disease progression on prior 2:1 Randomization Upon BICR progression, physician’s choice Secondary: NHA, eg, abiraterone or enzalutamide patients were allowed to cross over to olaparib - rPFS in Cohorts Open Label A & B Alterations in ≥1 of Olaparib 300 mg bid - ORR in Cohort A any qualifying gene n = 94 - TTPP in Cohort B: with a direct or Cohort A Other alterations indirect role in HRR - OS in Cohort A N = 142 Physician’s Choice n = 48 ATM = ataxia-telangiectasia mutated gene product; BICR = blinded independent central radiology; NHA = new hormonal agent; ORR = objective response rate; TTPP = time to PSA progression. Hussain M, et al. ESMO 2019 Congress. Abstract LBA12_PR. 40 40 PROfound Trial: Results • Patients with mCRPC + HRR Cohort A: rPFS by BICR Among Patients With Alterations in alterations who progressed on BRCA1, BRCA2, or A TM prior abiraterone + prednisone 6-month rate and/or enzalutamide had 1.0 59.76% significantly improved rPFS and Probability of rPFS 0.8 22.63 12-month rate ORR vs physician’s choice of Physician’s Olaparib 28.11% choice either enzalutamide or 0.6 9.40% Events (%) 106 (65.4) 68 (81.9) abiraterone + prednisone Median PFS (months) 7.39 3.55 0.4 • Favorable trend for OS was HR (95% Cl) 0.34 (0.25-0.47) observed despite crossover by a 0.2 P <.0001 large proportion of patients initially treated with physician’s 0.0 0 1 3 5 7 9 11 13 15 17 19 21 choice hormonal therapy Time From Randomization (months) Prespecified sensitivity analysis based on investigator assessment: HR, 0.24% (95% Cl, 0.17-0.34); P <.0001 41 Hussain M, et al. ESMO 2019 Congress. Abstract LBA12_PR. 41 Phase 2 GALAHAD Study: Breakthrough Therapy Designation for Niraparib for Treatment of mCRPC Oral PARP inhibitor for BRCA 1/2 gene-mutated mCRPC (prior taxane chemo and AR-targeted therapy) BRCA1/2 (n = 46) Non-BRCA (n = 35) Response n (%) (95% CI) n (%) (95% CI) ORR 12/29 (41) (23.5-61.1) 2/22 (9) (1.1-29.2) ≥50% Decline in PSA 23/46 (50) (34.9-65.1) 1/35 (3) (0.1-14.9) Circulating Tumor Cells Conversion 18/38 (47) (31.0-64.2) 5/24 (21) (7.1-42.2) Composite Response Rate 29/46 (63) (47.6-76.8) 6/35 (17) (6.6-33.7) Months (95% CI) Months (95% CI) Median rPFS, months (95% CI) 8.2 (5.2-11.1) 5.3 (1.9-5.7) Median OS, months (95% CI) 12.6 (9.2-15.7) 14.0 (5.3-20.1) Smith M, et al. oncologypro.esmo.org/Meeting-Resources/ESMO-2019-Congress/Pre-specified-interim-analysis-of-GALAHAD-A-phase-2-study-of- niraparib-in-patients-pts-with-metastatic-castration-resistant-prostate-cancer-mCRPC-and-biallelic-DNA-repair-gene-defects-DRD. Accessed Mar 42 24, 2020. 42 2020 PCE Spring Oncology Series 14

  89. Evolving Options in Metastatic Prostate Cancer Case Conclusion • Eli receives 20 mg/m 2 of cabazitaxel every 3 weeks • His blood pressure and neutrophil count are monitored regularly • At the end of first treatment cycle: ‒ PSA has decreased to 7 ng/mL ‒ He reports decreased pain ‒ Bone scans show stable lesions and no new lesions ‒ Blood pressure has not increased 43 43 Overcoming Barriers to Effective Treatment • Patient and clinician perceptions of AEs may differ: Communication is key • Monitor and manage AEs to optimize adherence and treatment benefit • High costs of some treatments may make them unattainable for some patients and/or affect adherence ‒ Investigate financial assistance programs Bultijnck R, et al. Eur Urol Focus. 2016;2:514-521; Buonerba C, et al. J Cancer . 2017;8:2663-2668; Pollard ME, et al. Asian J Urol . 2017;4:37-43; 44 Sartor O, et al. N Engl J Med . 2018;378:645-657. 44 Evidence-based Strategies to Reduce AEs of ADT and Other Treatments • Skeletal: resistance exercise; bone-protective agents • Metabolic: exercise (aerobic and resistance); diet; treatment for dyslipidemia, hypertension; monitoring/treatment for diabetes • Fatigue: exercise (aerobic and resistance) • Hot flushes: medroxyprogesterone, venlafaxine, gabapentin • Gynecomastia: prophylactic radiation, tamoxifen Bultijnck R, et al. Eur Urol Focus. 2016;2:514-521; Buonerba C, et al. J Cancer . 2017;8:2663-2668; Pollard ME, et al. Asian J Urol . 2017;4:37-43; 45 Sartor O, et al. N Engl J Med . 2018;378:645-657. 45 2020 PCE Spring Oncology Series 15

  90. Evolving Options in Metastatic Prostate Cancer PCE Action Plan  For patients with mHSPC, consider adding docetaxel (± prednisone), abiraterone + steroid, apalutamide, or enzalutamide to ADT  Implement shared decision-making to optimize treatment outcomes  Consider early use of approved agents for nmCRPC to improve MFS  Consider genetic testing and possible genetic counseling for all patients with prostate cancer PCE Promotes Practice Change 46 46 2020 PCE Spring Oncology Series 16

  91. Advances in Chronic Lymphocytic Leukemia: Key Elements for Today’s Clinic Advances in CLL: Key Elements for Today’s Clinics 1 Learning Objectives • Analyze the efficacy and safety of treatment options as well as molecular features of CLL and patient characteristics/preferences to aid in the successful delivery of individualized therapy to patients with newly diagnosed and relapsed/refractory CLL • Consider the optimal treatment for patients with newly diagnosed and relapsed/refractory CLL based on available clinical data, guidelines, and expert recommendations • Develop team-based strategies to address challenges to optimal treatment, including the identification and management of AEs, to ensure treatment compliance as well as improved clinical outcomes and quality of life 2 AE = adverse event; CLL = chronic lymphocytic leukemia. 2 CLL/SLL: Background • More than 21,000 estimated new cases in 2020 in the United States alone [1] ‒ Most common type of leukemia in adults (37%) • Median age at diagnosis: 70 years [2] • SLL and CLL considered the same B-cell malignancy [3] ‒ CLL: > 5000 clonal B cells in peripheral blood ‒ SLL: presence of lymphadenopathy and/or splenomegaly and < 5000 clonal B cells in peripheral blood • Historical 5-year survival: 66% (range: few mos to normal life span) [4] ‒ Current (2009-2015) 5-year survival: 85% [2] SLL = small lymphocytic lymphoma. 3 1. Siegel. CA Cancer J Clin. 2020;70:7. 2. SEER Cancer Stat Facts. Chronic lymphocytic leukemia. 3 3. American Cancer Society. Chronic lymphocytic leukemia. 4. Nabhan. JAMA. 2014;312:2265. 3 2020 PCE Spring Oncology Series 1

  92. Advances in Chronic Lymphocytic Leukemia: Key Elements for Today’s Clinic CLL: Prognostic Value of FISH Probability of OS From Diagnosis, by Genetic Aberration FISH Abnormalities Present in 268/325 Patients (82%) 100 17p deletion 11q deletion Lesion % Median OS, Mos 12q trisomy del(13q) 55 133 Normal 80 del(11q) 18 79 13q deletion as Patients Surviving (%) sole abnormality Trisomy 12 16 114 60 del(17p) 7 32 del(6q) 6 N/A Normal 18 111 40 FISH Patients With Abnormality (%) Lesion Dohner et al Oscier et al Jarosova et Dewald et Sindelarava 20 1997 1999 al 2001 al 2003 et al 2005 del(13q) 45 36 18 47 54 Trisomy 12 15 15 13 25 16 0 del(17p) 10 8 11 8 16 Months del(11q) 20 17 11 15 12 Dohner. NEJM. 2000;343:1910. Dohner. Leukemia. 1997;11(suppl 2):S19. Oscier. Haematologica. 1999;84(suppl EHA-4):88. Jarosova. Onkologie. 2001;24:60. Dewald. Br J Haematol. 2003;121:287. Sindelárová. Cancer Genet Cytogenet. 2005;160:27. 4 4 CLL: Impact of TP53 Mutations and TP53 Deletion on OS (N = 1148) • OS effect of TP53 wild type: ‒ vs TP53 mut only: P = .013 ‒ vs TP53 del only: P = .006 ‒ vs TP53 mut + del: P < .001 9 Relation to Total Size of Each Cohort 100 100 Frequency of TP53 Alterations in TP53 mut only TP53 wt 8 TP53 del only TP53 wt TP53 mut + del 80 80 7 6 60 60 TP53 mut only 5 OS (%) OS (%) (%) 4 40 TP53 alteration 40 TP53 del only 3 2 20 20 TP53 mut + del 1 P < .001 0 0 0 CLL 0 1 2 3 4 5 6 7 8 9 10 0 1 2 3 4 5 6 7 8 9 10 Years Years • Analysis based on cases referred to the Munich Leukemia Laboratory between August 2005 and May 2013 5 Stengel. Leukemia. 2017;31:705. 5 Survival in CLL According to IGHV Mutational Status All Patients (n = 84) Binet Stage A Patients (n = 62) 100 100 80 80 Mutated Surviving (%) Surviving (%) Mutated 60 60 40 40 Unmutated 20 Unmutated 20 P = .001 P = .0008 0 0 0 50 100 150 200 250 300 0 50 100 150 200 250 300 Months Months 6 Hamblin. Blood. 1999;94:1848. 6 2020 PCE Spring Oncology Series 2

  93. Advances in Chronic Lymphocytic Leukemia: Key Elements for Today’s Clinic Previously Untreated CLL 7 Case Study 1: An Elderly Patient With del(17p) and a TP53 Mutation • 75-year-old female patient who presented in 2013 with WBC 13K, ALC 9, Hgb 13, PLTs 160K • Flow: typical CLL pattern • FISH: no mutations • She was observed for 5 years • In 2018, progressive weight loss, splenomegaly, bulky lymphadenopathy, WBC 310K, Hgb 9 ‒ IGHV unmutated, TP53 mutation ‒ FISH: del(17p) 8 8 Phase III RESONATE-2: Ibrutinib vs Chlorambucil in Patients 65 Years of Age or Older With Untreated CLL/SLL • An international, randomized phase III trial Ibrutinib 420 mg/day until PD or unacceptable toxicity Patients 65 years of age (n = 136) Crossover or older with treatment- upon PD (n = 43) naive CLL/SLL; no Chlorambucil del(17p); no warfarin use 0.5 mg/kg (up to maximum of 0.8 mg/kg) (N = 269) on Days 1, 15 of 28-day cycle for up to 12 cycles (n = 133) • Primary endpoint: PFS • Secondary endpoints: OS, ORR, EFS, rate of hematologic improvement, and safety 9 9 Burger. NEJM. 2015;373:2425. 9 2020 PCE Spring Oncology Series 3

  94. Advances in Chronic Lymphocytic Leukemia: Key Elements for Today’s Clinic RESONATE-2: 5-Year Follow-up Results 100 100 Ibrutinib 80 80 Ibrutinib 60 Chlorambucil Ibrutinib Chlorambucil 60 OS (%) PFS (%) (n = 136) (n = 133) mPFS, mos NE 15 HR (95% CI) 0.146 (0.098-0.218) 40 40 Ibrutinib Chlorambucil 5-year PFS rate, % 70 12 mOS, mos NE NE HR (95% CI) 0.450 (0.266-0.761) Chlorambucil 20 20 5-year OS rate, % 83 68 0 0 0 3 6 9 12 1518 2124 2730 3336 3942 45 48 5154 57 606366 69 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60 63 66 69 Months Months • Ibrutinib was generally well tolerated with no new safety signals reported with long-term follow-up (many AEs decreased over time) • More than one half (58%) of patients remained on ibrutinib at the 5-year follow-up Burger. Leukemia. 2020;34:787. 10 10 Phase III E1912 Trial of Ibrutinib + Rituximab vs FCR in Patients ≤ 70 Years of Age With Previously Untreated CLL • Primary analysis of randomized, open-label phase III trial (data cutoff: October 24, 2018) Stratified by age (< vs ≥ 60 yrs), ECOG PS (0/1 vs 2), stage (III-IV vs I-II), del(11q22.3) vs other Ibrutinib 420 mg PO daily for cycles 1-7 + Rituximab 50 mg/m 2 IV on Day 1, cycle 2, then 325 mg/mg 2 on Patients with previously untreated CLL Ibrutinib maintenance Day 2, cycle 2, then 500 mg/m 2 on Day 1, cycles 3-7 until PD requiring treatment per IWCLL 2008, ≤ (n = 354) 70 years of age, ECOG PS 0-2, CrCl > 40 mL/min, ability to tolerate FCR, no Fludarabine 25 mg/m 2 IV on Days 1-3 for cycles 1-6 + del(17p) by FISH Cyclophosphamide 250 mg/m 2 IV on Days 1-3 for cycles 1-6 + (N = 529) Rituximab 50 mg/m 2 IV on Day 1, cycle 1, then 325 mg/mg 2 on Day 2, cycle 1, then 500 mg/m 2 on Day 1, cycles 2-6 (n = 175) 28-day cycles • Primary endpoint: PFS ⎻ Study has 80% power to detect PFS HR for IR vs FCR of 0.67 using stratified log-rank test, with prespecified boundary of 2.87 for first PFS interim analysis corresponding to 1-sided P = .0025 • Secondary endpoints: OS, safety 11 11 Shanafelt. NEJM. 2019;381:432. Shanafelt. ASH 2019. Abstr 33. 11 E1912: PFS (Primary Endpoint) Median follow-up: 48 months 1.0 Ibrutinib + rituximab (58 events/354 cases) 0.8 FCR (52 events/175 cases) Probability 0.6 0.4 0.2 HR: 0.39 (95% CI: 0.26-0.57) P < .0001 3-year rates: 89%, 71% 0 0 1 2 3 4 5 Years Number at risk FCR 175 145 123 82 31 0 Ibrutinib + R 354 338 321 280 121 8 12 Shanafelt. ASH 2019. Abstr 33. 12 2020 PCE Spring Oncology Series 4

  95. Advances in Chronic Lymphocytic Leukemia: Key Elements for Today’s Clinic E1912: PFS by IGHV Status Median follow-up: 48 months IGHV Unmutated IGHV Mutated 1.0 1.0 Ibrutinib + rituximab (10 events/70 cases) 0.8 0.8 Ibrutinib + rituximab FCR (8 events/44 cases) (36 events/210 cases) FCR (29 events/71 cases) Probability 0.6 Probability 0.6 0.4 0.4 0.2 0.2 HR: 0.28 (95% CI: 0.17-0.48) HR: 0.42 (95% CI: 0.16-1.16) P = .086 P < .0001 3-year rates: 89%, 65% 3-year rates: 88%, 82% 0 0 0 1 2 4 3 5 0 1 2 3 4 5 Years Years Number at risk Number at risk FCR 71 63 50 31 8 0 FCR 44 38 34 25 11 0 Ibrutinib + R 210 202 193 165 72 7 Ibrut + R 70 67 64 54 20 1 Shanafelt. ASH 2019. Abstr 33. 13 13 E1912: OS Median follow-up: 48 months Ibrutinib + rituximab (11 events/354 cases) 1.0 FCR (12 events/175 cases) 0.8 Probability 0.6 0.4 0.2 HR: 0.34 (95% CI: 0.15-0.79) P = .009 3-year rates: 99%, 93% 0 0 1 2 3 4 5 Years Number at risk FCR 175 155 143 131 69 9 Ibrutinib + R 354 347 343 355 193 37 14 Shanafelt. ASH 2019. Abstr 33. 14 First-line Ibrutinib vs Ibrutinib + Rituximab vs Bendamustine + Rituximab in CLL/SLL (A041202): Study Design • Multicenter, randomized, double-blind phase III study (data cutoff: October 4, 2018) Stratified by Rai stage (high vs intermediate risk), del(11q22.3) or del(17p13.1) (presence vs absence), ZAP-70 methylation (< vs ≥ 20%) Ibrutinib 420 mg daily Until PD (n = 182) Untreated patients with CLL meeting IWCLL 2008 criteria for tx initiation; ≥ 65 years of age; ECOG Ibrutinib 420 mg daily + PS 0-2; ANC ≥ 1000 unless due to Rituximab 375 mg/m 2 weekly x 4 weeks starting cycle 2 Day 1; cycles 3-6 Day 1* Ibrutinib until PD BM involvement; PLT ≥ 30; (n = 182) CrCl CG ≥ 40; AST/ALT ≤ 2.5 x ULN; no heparin or warfarin Crossover to Bendamustine 90 mg/m 2 on Days 1, 2 + (N = 547) ibrutinib within Rituximab 375 mg/m 2 on cycle 1 Day 1; 500 mg/m 2 on cycles 2-6 Day 1* 1 year of PD (n = 183) allowed *28-day cycles. • Primary endpoint: PFS ‒ 2 primary comparisons of ibrutinib vs BR and ibrutinib + R vs BR with 90% power to detect HR of 0.586 (estimated 2-yr PFS rates: ibrutinib, 75%; BR, 61%) and overall 1-sided α = 0.025 for each comparison ‒ If both primary comparisons significant, third planned comparison of ibrutinib + R vs ibrutinib 15 Woyach. NEJM. 2018;379:2517. 15 2020 PCE Spring Oncology Series 5

  96. Advances in Chronic Lymphocytic Leukemia: Key Elements for Today’s Clinic A041202: PFS of Eligible Patients* (Primary Endpoint) • PFS significantly improved with 100 ibrutinib vs BR and ibrutinib + R 80 vs BR (both 1-sided P < .001) PFS (%) 60 ‒ HR for ibrutinib vs BR: 0.39 (95% CI: 0.26-0.58) Events, Median PFS, 2-Yr PFS, 40 n/N Mos (95% CI) % (95% CI) ‒ HR for ibrutinib + R vs BR: 0.38 Ibrutinib 34/178 NR 87 (81-92) 20 Ibrutinib + R 32/170 NR 88 (81-92) (95% CI: 0.25-0.59) BR 68/176 43 (38-NR) 74 (66-80) 0 • No significant difference for ibrutinib + 0 6 12 18 24 30 36 42 48 R vs ibrutinib only (1-sided P = .49) Months Number at risk ‒ HR: 1.00 (95% CI: 0.62-1.62) Ibrutinib 178 165 154 147 136 120 78 45 22 0 170 159 145 138 132 115 74 40 20 0 Ibrutinib + R BR 176 140 129 122 103 88 57 26 11 0 *524 of 547 randomized patients. Woyach. NEJM. 2018;379:2517. 16 16 A041202: PFS by del(17p) and del(11q) Status del(17p) del(11q) Neither del(17p) or del(11q) 1.0 1.0 1.0 PFS Probability 0.8 0.8 0.8 0.6 0.6 0.6 0.4 0.4 0.4 0.2 0.2 0.2 0 0 0 0 12 18 0 6 12 18 24 30 36 42 48 52 0 6 12 18 24 30 36 42 48 52 6 24 30 36 42 48 52 Months Months Months Events, Median PFS, Events, Median PFS, Events, Median PFS, n/N Mos (95% CI) n/N Mos (95% CI) n/N Mos (95% CI) Ibrutinib 2/9 NE Ibrutinib 4/35 NE Ibrutinib 27/137 NE Ibrutinib + R 3/11 NE Ibrutinib + R 7/37 NE Ibrutinib + R 25/132 NE BR 10/14 7 (4-23) BR 15/33 41 (36-NE) BR 45/134 51 (43-NE) • PFS benefit with ibrutinib-containing regimens vs BR observed in all cytogenetic factor–related subgroups, with del(17p13.1) being most pronounced 17 Woyach. NEJM. 2018;379:2517. 17 A041202: PFS by IGHV Mutation Status Unmutated IGHV Mutated IGHV 1.0 1.0 0.8 0.8 PFS Probability PFS Probability 0.6 0.6 0.4 0.4 Events, Median PFS, Events, Median PFS, n/N Mos (95% CI) n/N Mos (95% CI) Ibrutinib 7/45 NE 0.2 Ibrutinib 16/77 NE 0.2 Ibrutinib + R 6/45 NE Ibrutinib + R 20/70 NE (48-NE) BR 12/52 51 (51-NE) BR 31/71 39 (32-NE) 0 0 0 6 12 18 24 30 36 42 48 52 0 6 12 18 24 30 36 42 48 52 Months Months • No significant interaction between IGHV mutation status and PFS benefit by regimen ‒ Increased PFS among patients with mutated vs unmutated IGHV disease (HR: 0.51; 95% CI: 0.32-0.81) 18 Woyach. NEJM. 2018;379:2517. 18 2020 PCE Spring Oncology Series 6

  97. Advances in Chronic Lymphocytic Leukemia: Key Elements for Today’s Clinic A041202: Safety Ibrutinib Ibrutinib + R BR Grade 3-5 AEs During Treatment or Follow-up,* n (%) P Value (n = 180) (n = 181) (n = 176) Any hematologic 74 (41) 70 (38) 107 (61) < .001 • Anemia 21 (12) 11 (6) 22 (13) .09 • Neutropenia 27 (15) 39 (22) 71 (40) < .001 • Thrombocytopenia 12 (7) 9 (5) 26 (15) .008 Any nonhematologic 133 (74) 134 (74) 111 (63) .04 • Bleeding 3 (2) 5 (3) 0 .46 • Infections 37 (21) 37 (20) 26 (15) .62 • Febrile neutropenia 3 (2) 1 (1) 13 (7) < .001 • Atrial fibrillation 17 (9) 10 (6) 5 (3) .05 • Hypertension 53 (29) 61 (34) 25 (14) < .001 Death • Unexplained/unwitnessed 7 (4) 4 (2) 2 (1) .24 • During active treatment + 30 days 13 (7) 13 (7) 2 (1) -- • During active treatment + 30 days, up to 6 cycles 3 (2) 6 (3) 2 (1) -- *Excludes crossover. Woyach. ASH 2018. Abstr 6. Woyach. NEJM. 2018;379:2517. 19 19 Phase III ELEVATE TN (ACE-CL-007): Study Design Stratified by del(17p) status, ECOG PS 0/1 vs 2, geographic region Acalabrutinib 100 mg PO BID + Obinutuzumab* (n = 179) Patients with treatment- naive CLL who are ≥ 65 years or Acalabrutinib 100 mg PO BID < 65 years with CIRS (n = 179) Crossover allowed to score > 6 or CrCl acalabrutinib after IRC- < 70 mL/min confirmed progression Obinutuzumab † + Chlorambucil 0.5 mg/kg PO D1, 15 (N = 535) (n = 177) *1000 mg IV on D1, 2, 8, 15 of 28-day cycle 2; Day 1 of subsequent cycles for total of 6 cycles. † 1000 mg IV on D1, 2, 8, 15 of 28-day cycle 1; Day 1 of cycles 2-6. • Primary endpoint: PFS by IRC with acalabrutinib + obinutuzumab vs obinutuzumab + chlorambucil • Key secondary endpoints: PFS of acalabrutinib vs obinutuzumab + chlorambucil, ORR by IRC and investigators, time to next treatment, OS, safety 20 Sharman. ASH 2019. Abstr 31. 20 ELEVATE TN: Progression-Free Survival (IRC Assessed) 100 93% HR (95% CI) 87% 80 Acala-O 0.10 (0.06-0.17) vs Chl-O P < .0001 60 Acalabrutinib 0.20 (0.13-0.30) PFS (%) 47% vs Chl-O P < .0001 Acala-O 0.49 (0.26-0.95) 40 vs Acalabrutinib Acalabrutinib + Obinutuzumab 20 Acalabrutinib Chlorambucil + Obinutuzumab (Median PFS: 22.6 months; 95% CI: 20.2-27.6) 0 0 6 12 18 24 30 36 42 Number at Months risk 109 104 46 41 4 2 Acalabrutinib 179 176 170 168 163 160 159 155 179 166 161 157 153 150 148 147 103 94 43 40 4 3 Acalabrutinib + O Chlorambucil-O 177 162 157 151 136 113 102 86 46 41 13 13 3 2 21 Sharman. ASH 2019. Abstr 31. 21 2020 PCE Spring Oncology Series 7

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