Oncology Conference Triple-Negative Breast Cancer: Fitting New and - - PowerPoint PPT Presentation

2020 Spring Oncology Conference

Triple-Negative Breast Cancer: Fitting New and Emerging Strategies Into Patient Care

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• 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

Learning Objectives

TNBC = triple-negative breast cancer.

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Common Features Lacks ER, PR, and HER2 Subtypes include “basal-like” (>75% of TNBC), immunomodulatory, mesenchymal, mesenchymal stem-like, and luminal androgen receptor More aggressive clinical course in metastatic setting Tends to be higher grade vs other types of breast cancer More responsive to chemotherapy vs other types of breast cancer Rapid progression from onset of metastasis to death Most deaths occur in first 5 years

Features of TNBC

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; Phipps AI, et al. Cancer Epidemiol Biomarkers Prev. 2011;20:454-463; Phipps AI, et al. J Natl Cancer Inst. 2011;103:470-477.

Risk Factors Younger age Family history of breast cancer African American and Hispanic women High BMI Underlying BRCA1 mutation Low levels of physical activity Higher parity (≥3 children) Low socioeconomic conditions

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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

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• 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. www.nccn.org/professionals/physician_gls/pdf/breast.pdf. Accessed Mar 23, 2020

BRCA Testing in Breast Cancer

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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

AC-T = doxorubicin and cyclophosphamide followed by paclitaxel; mTNBC = metastatic triple-negative breast cancer; RCB = residual cancer burden.

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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.

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

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• 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

PD-L1 Biomarker Testing: Available Assays

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, et al. Appl Immunohistochem Mol Morphol. 2019;27:92-100.

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• Stage I-III:

Neoadjuvant or adjuvant chemotherapy + surgery

• Stage IV:

chemotherapy alone

• Choice and order
• f chemotherapy

depends on multiple factors

Overview: Chemotherapy Options for mTNBC

Ehab M, Elbaz M. Breast Cancer (Dove Med Press). 2016;8:83-91; NCCN Guidelines. Breast cancer. www.nccn.org/ professionals/physician_gls/pdf/breast.pdf. Accessed Mar 23, 2020; Schwartz KL, et al. Cancer. 2018;124:2104-2114.

HER2-Negative

Preferred regimens Anthracyclines

• Doxorubicin, liposomal doxorubicin

Taxanes

• Paclitaxel

Antimetabolites

• Capecitabine, gemcitabine

Microtubule inhibitors

• Vinorelbine, eribulin

PARP inhibitors (for HER2-negative tumors and germline BRCA1/2 mutation)

• Olaparib
• Talazoparib

Platinum (for triple-negative tumors and germline BRCA1/2 mutation)

• Carboplatin
• Cisplatin

Atezolizumab + albumin-bound paclitaxel (for PD-L1-positive TNBC) Other recommended regimens Cyclophosphamide Docetaxel Albumin-bound paclitaxel Epirubicin Ixabepilone Useful in certain circumstances Doxorubicin/cyclophosphamide Epirubicin/cyclophosphamide Cyclophosphamide/methotrexate/ fluorouracil Docetaxel/capecitabine Gemcitabine/paclitaxel Gemcitabine/carboplatin Paclitaxel/bevacizumab Carboplatin/albumin-bound paclitaxel Carboplatin/paclitaxel

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• 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

Paclitaxel vs Nab-Paclitaxel: Taxane Derivatives

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.

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• 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

Immune Checkpoint Inhibitors: Mechanism of Action

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

• 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.

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IMpassion130: Atezolizumab + Nab-Paclitaxel in PD-L1 + mTNBC

• Improved OS in

PD-L1–positive patients

Population Median OS, mo HR (95% CI) A + nab-P P + nab-P PD-L1 IC+ 25.0 18.0 0.71 (0.54, 0.94) PD-L1 IC− 19.6 19.6 0.99 (0.80, 1.23)

3 6 9 12 15 18 21 24 27 30 33 36 39 42 Time (months) 100 90 80 70 60 50 40 30 20 10 OS (%)

A + nab-P (PD-L1+ n = 185) P + nab-P (PD-L1+ n = 184) A + nab-P (PD-L1− n = 266) P + nab-P (PD-L1− n = 267)

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. Schmid P, et al. Lancet Oncol. 2020;21:44-59.

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IMpassion130: Progression-free Survival in PD-L1 + mTNBC

PFS = progression-free survival. Schmid P, et al. Lancet Oncol. 2020;21:44-59.

3 6 9 12 15 18 21 24 27 30 33 36 39 42 100 90 80 70 60 50 40 30 20 10

PFS (%) Months

A + nab-P (PD-L1+ n = 185) P + nab-P (PD-L1+ n = 184) A + nab-P (PD-L1− n = 266) P + nab-P (PD-L1− n = 267)

Population Median OS, mo HR (95% CI) A + nab-P P + nab-P PD-L1+ (41%) 7.5 mo 5.3 mo 0.63 (0.50, 0.80) PD-L1- (59%) 5.6 mo 5.6 mo 0.93 (0.77, 1.11)

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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

Patient Counseling: Nab-Paclitaxel AEs

Abraxane [prescribing information]. Celgene Corporation; 2018; BC Cancer. www.bccancer.bc.ca/drug-database-site/Drug%20Index/nab%20paclitaxel_ handout.pdf. Accessed Mar 23, 2020; Schmid P, et al. N Engl J Med. 2018;379:2108-2121; Tecentriq [prescribing information]. Genentech, Inc; 2019.

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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

Patient Counseling: Nab-Paclitaxel AEs (cont’d)

Abraxane [prescribing information]. Celgene Corporation; 2019; BC Cancer. www.bccancer.bc.ca/drug-database-site/Drug%20Index/nab%20 paclitaxel_handout.pdf. Accessed Mar 23, 2020.

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Setting Trial Name Regimen

Neoadjuvant/ Adjuvant KEYNOTE-522 Carboplatin + paclitaxel + (anthracycline) + cyclophosphamide ± pembrolizumab➔ pembrolizumab NCT03281954 Doxorubicin + cyclophosphamide + paclitaxel + carboplatin ± atezolizumab ➔ atezolizumab IMpassion031 Doxorubicin + cyclophosphamide + nab-paclitaxel ± atezolizumab ➔ atezolizumab NeoTRIPaPDL1 Michelangelo Atezolizumab + carboplatin + nab-paclitaxel Adjuvant IMpassion030 Paclitaxel ➔ dose-dense doxorubicin/epirubicin + cyclophosphamide ± atezolizumab Locally advanced

• r mTNBC

KEYNOTE-355 Abraxane or paclitaxel or carboplatin/gemcitabine ± pembrolizumab IMpassion131 Paclitaxel ± atezolizumab

Select Ongoing Immunotherapy Trials in TNBC

➔ = followed by. Marra A, et al. BMC Med. 2019;17:90; Gianni L, et al. 2019 San Antonio Breast Cancer Symposium; Abstract GS3-04.

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• Greater increase in pCR in patients with

lymph node-positive vs lymph node- negative disease

• Improvement in pCR rates occurred

regardless of PD-L1 status

• In the preoperative TNBC setting with

pembrolizumab plus chemotherapy, PD-L1 does not seem to be a predictive biomarker

KEYNOTE-522: Neoadjuvant Pembrolizumab Plus Chemotherapy in Early TNBC

pCR = pathological complete response. Schmid P, et al. N Engl J Med. 2020;382:810-821. 10 20 30 40 50 60 70 80 90 100

Negative Positive pCR, % (95% CI) 64.8% 44.1%

Δ 6.3 (95% CI,

• 5.3 to 18.2)

Δ 20.6 (95% CI, 8.9 to 31.9) 58/99

64.9% 58.6%

136/210 45/102 124/191 Pembrolizumab + Chemo Placebo + Chemo

Nodal Status

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KEYNOTE-522: Event-free Survival

Schmid P, et al. N Engl J Med. 2020;382:810-821.

3 6 9 12 15 18 21 24 27 100 90 80 70 60 50 40 30 20 10

Patients Without an Event or Death (%) Months

784 780 765 666 519 376 242 73 2 390 386 380 337 264 186 116 35 1

• No. at risk

Pembrolizumab-chemotherapy Placebo-chemotherapy Pembrolizumab-chemotherapy Placebo-chemotherapy

91.3% 85.3%

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• 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

NeoTRIPaPDL1 Michelangelo Study

TRAEs = treatment-related adverse events. Gianni L, et al. 2019 San Antonio Breast Cancer Symposium; Abstract GS3-04.

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• 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

KEYNOTE-355: First-line Pembrolizumab in PD-L1+ Patients With mTNBC

Tucker N. www.targetedonc.com/news/keynote355-meets-a-coprimary-end-point-for-treatment-of-patients-with-mtnbc. Accessed Mar 23, 2020.

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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

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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

Potential irAEs With Immune Checkpoint Inhibitors

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.

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Toxicity Grade Recommendation

Grade 1 Continue checkpoint inhibitors with close monitoring, with the exception of some neurologic, hematologic, and cardiac toxicities Grade 2 Hold for most grade 2 toxicities and consider resuming when symptoms and/or laboratory values return to grade 1 or less 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

Grade 3 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

some toxicities

• Consider resuming checkpoint inhibitors when symptoms and/or laboratory values return to grade 1,

after discussion of risk/benefits with patients Grade 4 Warrants permanent discontinuation of checkpoint inhibitors, with exception of endocrinopathies controlled by hormone replacement

Current Recommendations: Managing irAEs With Immune Checkpoint Inhibitors

Brahmer JR, et al. J Clin Oncol. 2018;36:1714-1768; Postow MA, et al. N Engl J Med. 2018;378:158-168.

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• 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- types/immunotherapy. Accessed Mar 23, 2020; Postow MA, et al. N Engl J Med. 2018;378:158-168.

Immune Checkpoint Inhibitors: Patient and Caregiver Education

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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

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• 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 Inhibition in TNBC

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. Adv Exp Med Biol. 2017;1026:271-286. DNA Repair DNA Damage BER Pathway NAD+ PARP Inhibition DNA Collapse Cell PARP Apoptosis PARP

BER indicates base excision repair

Inactivated Survival

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100 90 80 70 60 50 40 30 20 10

OlympiAD: Olaparib Therapy Significantly Improved PFS

TPC = treatment of physician’s choice. Lynparza [prescribing information]. AstraZeneca Pharmaceuticals LP; 2019; Robson M, et al. N Engl J Med. 2017;377:523-533.

• Olaparib vs chemotherapy evaluated in BRCA-mutated, high-risk, HER2-negative primary breast

cancer previously treated with two lines of chemotherapy

Olaparib (n = 205) Chemotherapy TPC (n = 97) Events (%) 163 (79.5) 71 (73.2) Median PFS, months 7.0 4.2 Olaparib Standard therapy

Time From Randomization (months) PFS (%)

2 4 6 8 10 12 14 16 18 20 22 24 26 28 30

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1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0

OlympiAD: Overall Survival Analysis

Robson ME, et al. Annals Oncol. 2019;30:558-566.

Olaparib TPC

4 8 12 16 20 24 28 32 36 40

No prior chemotherapy

Olaparib TPC Deaths, n (%) 30 (50.8) 21 (75.0) Median OS, mo 22.6 14.7

Time From Randomization (months)

• No. at risk

Olaparib 59 57 53 44 40 32 17 7 5 4 TPC 28 25 20 17 12 9 7 4 1

Probability of OS

TPC

4 8 12 16 20 24 28 32 36 40 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0

Olaparib TPC Deaths, n (%) 130 (63) 62 (64) Median OS, mo 19.3 17.1

• No. at risk

Olaparib 205 199 178 146 124 92 55 23 11 6 TPC 97 85 74 62 48 40 30 15 5 2

Time From Randomization (months) Probability of OS

Olaparib

• 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

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EMBRACA: Talazoparib Significantly Improved PFS

Litton JK, et al. N Engl J Med. 2018;379:753-763; Talzenna [prescribing information]. Pfizer Inc.; 2019.

• Talazoparib vs standard chemotherapy for

locally advanced or metastatic breast cancer with a germline BRCA1/2 mutation

Talazoparib (n = 287) Standard Therapy (n = 144) Events (%) 186 (65) 83 (58) Median, months (95% CI) 8.6 (7.2, 9.3) 5.6 (4.2, 6.7)

Talazoparib Standard therapy

PFS (%) Months

3 6 9 12 15 18 21 24 27 30 33 36 39 42 100 90 80 70 60 50 40 30 20 10

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Talazoparib and the EMBRACA Trial: No Significant Improvement in OS*

*These findings represent immature interim data. Litton JK, et al. N Engl J Med. 2018;379:753-763. Talazoparib (n = 287) Standard Therapy (n = 144) Events (%) 108 (38) 55 (38) Median, months (95% CI) 22.3 (18.1-26.2) 19.5 (16.3-22.4)

3 6 9 12 15 18 21 24 27 30 33 36 39 42 100 90 80 70 60 50 40 30 20 10

Talazoparib Standard therapy

Months OS (%)

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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

Management of Toxicities Associated With PARP Inhibitors

CBC = complete blood count; GFR = glomerular filtration rate. LaFargue CJ, et al. Lancet Oncol. 2019;20:e15-e28.

• Majority of AEs typically occur during first cycles of treatment

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Toxicity Management Strategy

Laboratory abnormalities

• Increased cholesterol and serum aminotransferase common
• 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

LaFargue CJ, et al. Lancet Oncol. 2019;20:e15-e28.

Management of Toxicities Associated With PARP Inhibitors (cont’d)

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Grade Management Strategies

1

• Continue PARP inhibitor
• Symptomatic treatment if necessary

2

• Continue PARP inhibitor
• Consider dose interruption, reduction, or both, if toxicity remains uncontrolled

despite symptomatic or prophylactic therapies 3 or 4

• Withhold until resolution of AE: for olaparib, ≤grade 1
• Might continue treatment if AE is nausea, vomiting, or diarrhea, and controlled on

medication

• If treatment was interrupted, consider dose reduction upon resumption

(particularly if after second time withholding) 3 or 4 lasting more than 28 days with the lowest dose of PARP inhibitor

• Discontinue PARP inhibitor

Management of Nonhematologic AEs for PARP Inhibitors by Grade

LaFargue CJ, et al. Lancet Oncol. 2019;20:e15-e28.

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Case Conclusion

• Carol’s pulmonary nodules show minor response for 6 months,

then progress

• She is started on eribulin

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• 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

Later-line Therapy

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= Triple+Negative+Breast+Cancer&phase=2&draw=2&rank=3. Accessed Mar 23, 2020.

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✓ 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 Action Plan

PCE Promotes Practice Change

2020 Spring Oncology Conference