Oncology Conference Key Updates in the Treatment of HER2-Positive - - PowerPoint PPT Presentation

2020 Spring Oncology Conference

Key Updates in the Treatment of HER2-Positive Breast Cancer

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• 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

Learning Objectives

HER2 = human epidermal growth factor receptor 2.

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Targeted Therapies for HER2+ Breast Cancer

ADC = antibody–drug conjugate; mAb = monoclonal antibody; TKI = tyrosine kinase inhibitor.

• Gajria. Expert Rev Anticancer Ther. 2011;11:263. Pernas. Ther Adv Med Oncol. 2019;11:1758835919833519.

Tucatinib T-DM1 T-DXd T-DM1 T-DXd HER2-Targeted ADCs HER2-Targeted mAbs Trastuzumab Pertuzumab Lapatinib Neratinib HER2-Targeted TKIs

Proteasome

HER2 HER2 HER2 HER2 HER3 P P P P P

P13K AKT mTOR MK-2206 BKM120 BEZ235 Everolimus Temsirolimus hsp90 inhibitor hsp90 Breakdown

• f HER2

P

Endosome T-DM1 T-DXd

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Preferred regimens*

• Taxane + trastuzumab + pertuzumab (THP)†

Guideline-Recommended Regimens for HER2-Positive Recurrent or Stage IV Breast Cancer

Other Recommended Regimens*

• 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.

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10 20 30 40 50 60 70 80 90 100 110 120

CLEOPATRA: Standard First-line Treatment for HER2+ MBC With Docetaxel/Trastuzumab/Pertuzumab

H = trastuzumab; HR = hazard ratio; ITT = intention-to-treat; OS = overall survival; P = pertuzumab; Pbo = placebo; T = docetaxel.

• Swain. ASCO 2019. Abstr 1020.

*Crossover patients were analyzed in the placebo arm.

57.1 40.8 Median OS, Mos HR: 0.69 (95% CI: 0.58-0.82) 100 80 60 40 20 130

OS (%) Mos

Patients at Risk, n THP TH + Pbo 402 406 371 350 318 289 269 230 228 181 188 149 165 115 150 96 137 88 120 75 71 44 20 11 1

THP TH + Pbo

End of Study OS in ITT Population* 8 yrs

Landmark OS: 37% Events: 235 (58.5%)

Landmark OS: 23% Events: 280 (69.0%)

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MARIANNE: First-line T-DM1 ± Pertuzumab versus Docetaxel/Trastuzumab in HER2+ MBC

T-DM1 = trastuzumab emtansine.

• Perez. Cancer. 2019;125:3974.

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 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)

100

80 60 40 20 Day 1

OS (%)

12 Mos 24 Mos 36 Mos 48 Mos 60 Mos 72 Mos

TH T-DM1 T-DM1 + P

Patients at Risk, n TH T-DM1 T-DM1 + P 365 367 363 303 322 309 251 264 257 197 216 217 155 176 172 28 37 41

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MARIANNE: Grade ≥ 3 AEs

Grade ≥ 3 AE, % Trastuzumab + Taxane (n = 353) T-DM1 (n = 361) T-DM1 + Pertuzumab (n = 366) Any 55.8 47.1 48.6

Alopecia 60.1 7.2 9.0 Neutropenia 19.3 4.4 3.8 Febrile neutropenia 6.5 Diarrhea 4.2 0.3 2.7 Hypertension 3.1 4.7 5.5 Anemia 2.8 5.0 7.1 ALT increase 0.8 4.4 6.0 AST increase 0.3 6.9 3.3 GGT increase 0.3 3.3 2.5 Thrombocytopenia 6.6 9.0

AE = adverse event; ALT = alanine aminotransferase; AST = aspartate aminotransferase; CT = chemotherapy; GGT = gamma-glutamyl transferase.

• Perez. Cancer. 2019;125:3974.

Greater incidence with trastuzumab + CT Greater incidence with T-DM1

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100 80 60 40 20

Physician’s choice T-DM1

HR: 0.68 (95% CI: 0.54-0.85; P = .0007)

22.7 15.8 Median OS, mos T-DM1 Physician’s choice 2 4 6 8 10 12 14 16 18 20 22 24 26 OS (%) Mos 28 30 32 34 36

198 (0) 404 (0)

38 40

150 (28) 368 (17) 122 (31) 321 (29) 107 (33) 280 (35) 80 (34) 226 (43) 66 (36) 192 (44) 59 (37) 167 (45) 39 (45) 132 (66) 16 (68) 54 (138) 1 (80) 12 (172)

EMILIA[1]: Randomized phase III study of T-DM1 vs lapatinib + capecitabine for HER2+ MBC with progression on trastuzumab + taxane (N = 991)

EMILIA and TH3RESA: Standard Second-line Therapy for HER2+ MBC With T-DM1 After Progression on HER2-Targeted Agents

TH3RESA[2]: Randomized phase III study of T-DM1 vs physician’s choice for HER2+ MBC with progression on a taxane, lapatinib, and ≥2 HER2-targeted regimens including trastuzumab (N = 602)

Cape = capecitabine; MBC = metastatic breast cancer; T-DM1 = trastuzumab emtansine.

• 1. Verma. NEJM. 2012;367:1783. 2. Krop. Lancet Oncol. 2017;18:743.

30.9 25.1 Median OS, mos T-DM1 Lapatinib + Cape

HR: 0.68 (95% CI: 0.55-0.85; P < .001)

Efficacy stopping boundary: HR of 0.73 or P = .0037 100 80 60 40 20 2 4 6 8 10 12 14 16 18 20 22 24 26 OS (%) Mos 28 30 32 34 36

Patients at Risk, n

496 495 471 485 453 474 435 457 403 439 368 418 297 349 240 293 204 242 159 197 133 164 110 136 86 111 63 86 45 62 27 38 17 28 7 13 4 5

85.2% 64.7% 78.4% 51.8%

Lapatinib + cape T-DM1

Patients at Risk, n (censored)

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• HER2 TKIs

‒ Neratinib ‒ Tucatinib (FDA approved 4/2020)

• HER2 ADCs

‒ Trastuzumab deruxtecan (T-DXd; approved 12/2019) ‒ Trastuzumab duocarmazine/trastuzumab-vc-seco-DUBA (SYD985)

What’s New in HER2-Targeted Agents?

ADC = antibody–drug conjugate; mAb = monoclonal antibody; TKI = tyrosine kinase inhibitor.

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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
• n 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.

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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

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• ≥ 50% of patients with HER2+ MBC will develop

brain metastases[1]

• Lapatinib + capecitabine approved in this

setting but few patients respond ‒ In a pooled analysis, CNS ORR was 21.4%, median PFS was 4.1 mos, median OS was 11.2 mos[1]

• Neratinib + capecitabine approved in this

setting in Feb 2020

• Trastuzumab + capecitabine + tucatinib

approved in this setting in April 2020

• T-DM1, trastuzumab, and pertuzumab do not

penetrate the CNS under normal conditions

In HER2+ MBC, CNS Disease Remains Incurable Despite Current Treatment Options

CNS = central nervous system; ECOG = Eastern Cooperative Oncology Group; MBC = metastatic breast cancer; OR = odds ratio; PS = performance status; T-DM1 = trastuzumab emtansine.

• 1. Petrelli. Eur J Cancer. 2017;84:141. 2. Hurvitz. Clin Cancer Res. 2019;25:2433.

Risk of CNS Metastasis in HER2+ MBC by Subgroup[2]

Ethnicity: Hispanic/Latino No vs Yes Race Other vs black/African American White vs black/African American Age at MBC diagnosis 50-69 vs ≥ 70 years < 50 vs ≥ 70 years ECOG PS 1 vs 0 ≥ 2 vs 0 MBC diagnosis type Recurrent vs de novo Hormone receptor status Negative vs positive 1.181 (0.718-1.943) 1.268 (0.580-2.769) 1.619 (1.072-2.444) 2.042 (1.248-3.341) 3.128 (1.852-5.284) 1.192 (0.876-1.622) 1.900 (1.125-3.201) 1.650 (1.239-2.196) 1.841 (1.359-2.494)

1 2 3 4 5 Higher Risk of CNS Metastasis Lower Risk of CNS Metastasis

OR (95% CI)

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OS

No CNS Mets (n = 678) CNS Mets at Dx (n = 87) CNS Mets After Dx (n = 212) Median OS, mos NE 30.2 38.3 HR(95% CI) vs no CNS mets

• 2.86

(2.05-4.00) P < .0001 1.94 (1.52-2.49) P < .0001

SystHERs Registry Analysis: PFS and OS by CNS Metastasis in HER2+ MBC

CNS = central nervous system; Dx = diagnosis; MBC = metastatic breast cancer; mets = metastases; NE = not estimable.

• Hurvitz. Clin Cancer Res. 2019;25:2433.

PFS

No CNS Mets (n = 678) CNS Mets at Dx (n = 87) CNS Mets After Dx (n = 212) Median PFS, mos 19.1 9.2 9.9 HR (95% CI) vs no CNS mets

• 2.49

(1.93-3.20) P < .0001 2.52 (2.13-2.99) P < .0001 1.0 0.6 0.8 0.2 0.4

Mos on Study Since MBC Diagnosis

4 8 12 16 20 24 28 56 32 36 40 44 48 52 68 60 64 1.0 0.6 0.8 0.2 0.4

Mos on Study Since MBC Diagnosis

4 8 12 16 20 24 28 56 32 36 40 44 48 52 68 60 64

Proportion With PFS Proportion Surviving

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• Randomized phase III study
• Primary endpoint: CNS as first site of relapse
• Secondary endpoints: PFS, OS

Lapatinib 1250 mg/day + Capecitabine 2000 mg/m2/day

• n Days 1-14

CEREBEL: CNS Metastasis at First Relapse in HER2+ MBC With Lapatinib/Cape vs Trastuzumab/Cape

• Trial closed early for futility in lapatinib

+ capecitabine arm

Patients with HER2+ MBC, any line of tx, including prior anthracyclines or taxanes; no CNS metastasis (N = 540) Endpoint L + Cape (n = 251) T + Cape (n = 250) P Value

CNS as first site of progression, n (%) 8 (3) 12 (5) .360 Incidence of CNS progression at any time, n (%) 17 (7) 15 (6) .865 Median time to first CNS progression, mos (range) 5.7 (2-17) 4.4 (2-27) NR Median PFS, mos

• Trastuzumab naive

6.6 6.3 8.1 10.9 .021 NR Median OS, mos 22.7 27.3 .095 ORR, % 27 32 NR

Cape = capecitabine; CNS = central nervous system; L = lapatinib; MBC = metastatic breast cancer; NR = not reported; T = trastuzumab; tx = therapy.

• Pivot. JCO. 2015;33:1564.

Stratified by prior trastuzumab, lines of prior tx for MBC (0 vs ≥ 1) *Loading dose of 8 mg/kg.

21-day cycle Trastuzumab* 6 mg/kg Q3W + Capecitabine 2500 mg/m2/day

• n Days 1-14

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• Pan-HER TKI
• Irreversible inhibition
• Different MoA than trastuzumab

and pertuzumab

Neratinib: Mechanism of Action

HER1 (EGFR) HER2 HER3 HER4

Trastuzumab T-DM1 Pertuzumab MoA = mechanism of action; T-DM1 = trastuzumab emtansine; TKI = tyrosine kinase inhibitor.

• Baselga. Crit Rev Oncol Hematol. 2017;119:113.

Lapatinib Neratinib

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Neratinib + paclitaxel Trastuzumab + paclitaxel TBCRC 022 Cohort 3[2]: Single-arm 2-stage phase II study of neratinib/capecitabine in HER2+ MBC with CNS disease (n = 49)

NEfERT-T and TBCRC 022: Neratinib in HER2+ MBC

NEfERT-T[1]: Randomized phase III study of neratinib/paclitaxel vs trastuzumab/paclitaxel in previously untreated, HER2+ locally recurrent or MBC (N = 479)

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.

Events Median Time to CNS Progression

N + P (n = 242) 20 NE T + P (n = 237) 41 NE

18 responses by volumetric criteria; CNS ORR: 49% (95% CI: 32-66) Best CNS Volumetric Response With Neratinib + Cape in Lapatinib-Naive Patients (n = 37*)

*n = 6 who did not reach first reimaging assigned 0.

†CNS response by RANO-BM criteria.

†

CNS ORR with prior lapatinib: 33% (95% CI: 10-65) 4 8 12 16 20 24 28 56 32 36 40 44 48 52 1.0 0.6 0.8 0.2 0.4 HR:0.449 (95% CI: 0.259-0.780; log-rank P = .0036)

No CNS Progression (%) Mos

100 60 80 20 40

Change From Baseline (%)

†† † †††† †

• 20
• 60
• 40
• 100
• 80

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• International, open-label, randomized phase III trial

NALA: Neratinib/Cape vs Lapatinib/Cape in HER2+ MBC With ≥ 2 Prior Lines of HER2-Targeted Agents

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.

• Saura. ASCO 2019. Abstr 1002. NCT01808573.

Patients with centrally confirmed HER2+ MBC; previously treated with ≥ 2 lines of HER2-targeted agents for MBC; asymptomatic, stable brain metastases allowed (N = 621)

Until PD Survival follow-up

Stratified by no. prior HER2-targeted therapies, disease location, hormone receptor status, geographic location

• Coprimary endpoints: OS, PFS (centrally confirmed)

̶ Study positive if either endpoint statistically significant (OS, P < .04; PFS, P < .01)

• Secondary endpoints: PFS (locally determined), ORR,

DoR, CBR, intervention for CNS metastases, safety, PRO

• No endocrine therapy permitted

*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.

21-day cycle

Lapatinib 1250 mg/day PO continuously + Capecitabine* 2000 mg/m2 PO on Days 1-14 (n = 314) Neratinib 240 mg/day PO continuously + Capecitabine* 1500 mg/m2 PO on Days 1-14† (n = 307)

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NALA: Baseline Characteristics

MBC = metastatic breast cancer; T-DM1 = trastuzumab emtansine.

• Saura. ASCO 2019. Abstr 1002.

Characteristic, n (%) Neratinib + Capecitabine (n = 307) Lapatinib + Capecitabine (n = 314)

Age < 65 yrs 244 (79) 248 (79) Geographic region

• Europe
• North America
• Rest of world

121 (39) 59 (19) 127 (41) 123 (39) 65 (21) 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
• ≥ 3

215 (70) 92 (30) 215 (68) 99 (32) Prior HER2-targeted therapies for MBC

• Trastuzumab only
• Trastuzumab + pertuzumab
• Trastuzumab + T-DM1
• Trastuzumab + pertuzumab + T-DM1

124 (40) 24 (8) 58 (19) 101 (33) 113 (36) 23 (7) 64 (20) 114 (36)

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3 6 9 12 15 18 21 24 27 30 33

NALA: Survival

Cape = capecitabine; L = lapatinib; N = neratinib.

• Saura. ASCO 2019. Abstr 1002.

PFS (Prespecified Means Analysis) OS (Coprimary Endpoint)

Probability of PFS Mos Since Randomization Neratinib + capecitabine Lapatinib + capecitabine

Restriction: 24 mos 307 314 183 183 113 82 69 39 54 24 35 9 20 8 13 3 9 2 7 2 3 2 2 2 2 1 Patients at Risk, n N + Cape L + Cape HR (95% CI) 0.88 (0.72-1.07) Log-Rank P Value .2086 24.0 22.2

Probability of OS Mos Since Randomization

1.0 0.8 0.6 0.4 0.2 3 6 9 12 15 18 21 24 27 30 36 39 42 45 48 51 54 Restriction: 48 mos Mean OS, Mos Neratinib + capecitabine Lapatinib + capecitabine

307 314 294 303 275 273 244 240 220 208 182 170 142 132 112 107 82 84 64 67 47 47 34 36 28 27 Patients at Risk, n N + Cape L + Cape 18 22 15 17 13 12 6 8 4 4 2 3 1 1

8.8 6.6 Mean PFS, Mos

1.7 mos

2.2 mos

Restricted mean analysis P = .0003 57 33 36 1.0 0.8 0.6 0.4 0.2

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NALA: Time to Intervention for CNS Metastases

CNS = central nervous system.

• Saura. ASCO 2019. Abstr 1002.

Intervention, % Radiation therapy Surgery/procedure Anticancer medication Neratinib + Capecitabine (n = 55/307) 11 2 1 Lapatinib + Capecitabine (n = 75/314) 15 3 1 100 80 60 40

Cumulative incidence (%)

6 12 18 24 30 36 42 48 54 60

Mos Since Randomization Neratinib + capecitabine Lapatinib + capecitabine Overall cumulative incidence (Gray’s test): 22.8% vs 29.2%; P = .043

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NALA: Safety

*No grade 4 diarrhea observed. AE = adverse event.

• Saura. ASCO 2019. Abstr 1002.

Treatment-Emergent AE, % Neratinib + Capecitabine (n = 303) Lapatinib + Capecitabine (n = 311) 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

neratinib vs lapatinib (5.7 vs 4.4 mos)

• Discontinuation due to treatment-emergent AEs:

neratinib arm, 10.9%; lapatinib arm, 14.5%

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1 2 3 4 5 6 7 8 9 10 11 12 13 1 2 3 4 5 6 7 8 9 10 11 12 13

Loperamide (LPM)

LPM 4 mg TID D1-14, then BID D15-56

• 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)

Phase II CONTROL Trial: Antidiarrheal Prophylaxis for Neratinib- Associated Diarrhea in Early HER2+ BC

All prophylaxis cohorts Neratinib 240 mg/day (13 cycles) LPM + Budesonide

LPM 4 mg TID D1-14, then BID D15-56 Budesonide 9 mg QD for 1 cycle

LPM + Colestipol

LPM 4 mg TID D1-14, then BID D15-28 Colestipol 2 g BID for 1 cycle

Colestipol + LPM prn

Colestipol 2 g BID for 1 cycle; LPM as needed (16 mg/day max)

Neratinib dose-escalation cohorts Neratinib 120 mg/day D1-7 → 160 mg/day D8-14 → 240 mg/day (13 cycles) Neratinib 160 mg/day D1-14 → 200 mg/day D15-28 → 240 mg/day (13 cycles) LPM as needed (16 mg/day max) LPM as needed (16 mg/day max)

*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.

• Chan. SABCS 2019. Abstr P5-14-03. Chan. Lancet Oncol. 2016;17:367. Hurvitz. SABCS 2017. P3-14-01.

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• 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.

• Chan. SABCS 2019. Abstr P5-14-03. Chan. Lancet Oncol. 2016;17:367. Hurvitz. SABCS 2017. P3-14-01.

20.4% 10.9% 3.7% Discontinuation rate due to diarrhea:

CONTROL*

Loperamide (n = 137) LPM + Budesonide (n = 64) LPM + Colestipol (n = 136)

40% 32% 23% 5% 31% 25% 24% 20% 28% 33% 25% 14%

None Grade 1 Grade 2 Grade 3

35% 28% 17% 21%

3.3% Neratinib Dose Escalation + LPM prn (n = 60)

15% 42% 40% 3%

ExteNET vs CONTROL: Antidiarrheal Prophylaxis Reduces Incidence, Severity of Diarrhea With Neratinib

ExteNET*: Adj Neratinib in Trastuzumab-Treated HER2+ EBC (N = 1408)

25

60

• Less EGFR-associated toxicity than other

HER2-targeted TKIs

• CNS penetration
• Well tolerated and active in combinations (eg,

with T-DM1, capecitabine, or trastuzumab)

Tucatinib: HER2-Selective TKI

Agent Cellular Selectivity, IC50 (nM) HER2 EGFR

Tucatinib 8 4000 Neratinib 7 8 Lapatinib 49 31

CNS = central nervous system; MBC = metastatic breast cancer; T-DM1 = trastuzumab emtansine; TKI = tyrosine kinase inhibitor.

• Borges. ASCO 2016. Abstr 513. Borges. JAMA Oncol. 2018;4:1214-1220.

Phase Ib: Tucatinib + T-DM1 in HER2+ MBC Overall Response in Patients with Measurable Disease 40 20

• 20
• 40
• 60
• 80
• 100

O N NH N N H N O N N N

1 prior HER2 agent ≥ 2 prior HER2 agents Max change in sum of diameter of target lesions (%)

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Phase Ib Study: Tucatinib + Capecitabine/Trastuzumab in HER2+ MBC

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.

No brain mets (n = 14) Brain mets (n = 9) P Prior pertuzumab (n = 18)

Tucatinib + Capecitabine/Trastuzumab (n = 23)

ORR: 61% (14/23) mDoR: 10 mos (95% CI: 2.8-19.3) Bars represent change in measurable lesions, but some patients also have nonmeasurable lesions. n = 4 patients with nonmeasurable lesions only not included here.

Tucatinib at RP2D in Evaluable Patients With Measurable CNS Disease (n = 12)

CNS ORR: 42% (5/12)

n = 29 of 52 patients had brain mets at baseline, 17 with nonmeasuarable lesions only n = 1 patient did not have follow-up scan

• 100

40 20

• 20
• 40
• 60
• 80

Max Change in Sum of Tumor Diameters (%) P P P P P P P P P P P P P P P P P P

• 100

40 20

• 20
• 40
• 60
• 80

Tucatinib + cape Tucatinib + Tz Tucatinib + cape + Tz Screening Post Cycle 6 (Images selected to demonstrate longest axis of lesions) Max Change in Sum of Tumor Diameters (%)

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• 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

HER2CLIMB: Phase II Study Design

Patients with HER2+ MBC; prior trastuzumab, pertuzumab, and T-DM1; ECOG PS 0/1; brain mets allowed* (N = 612) Tucatinib 300 mg PO BID + Trastuzumab 6 mg/kg Q3W (loading dose: 8 mg/kg C1D1) + Capecitabine 1000 mg/m2 PO BID on Days 1-14 (n = 410) Placebo PO BID + Trastuzumab 6 mg/kg Q3W (loading dose: 8 mg/kg C1D1) + Capecitabine 1000 mg/m2 PO BID on Days 1-14 (n = 202)

*Including previously treated stable mets, untreated mets not needing immediate local therapy, and previously treated progressing mets not needing immediate local tx.

21-day cycles Stratified by brain mets (yes vs no), ECOG PS (0 vs 1), and region (US or Canada vs rest of world)

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.

• Murthy. SABCS 2019. Abstr GS1-01. Murthy. NEJM. 2019;382:597.
• Primary endpoint: PFS (RECIST v 1.1 by BICR) among

first 480 randomized patients ̶ 90% power with 288 events at α = 5%, HR: 0.67

• Secondary endpoints (total population): OS, PFS in

patients with brain mets, ORR in patients with measurable disease, safety in patients who received ≥ 1 dose of study tx

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HER2CLIMB: Baseline Characteristics (Total Population)

ECOG = Eastern Cooperative Oncology Group; PS = performance status.

• Murthy. SABCS 2019. Abstr GS1-01. Murthy. NEJM. 2019;382:597.

Characteristic Tucatinib + Trastuzumab/Capecitabine (n = 410) Placebo + Trastuzumab/Capecitabine (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 ▪ ER and PgR negative 243 (60) 161 (40) 127 (63) 75 (37) Median prior lines of therapy, n (range) ▪ Overall ▪ Metastatic setting 4.0 (2-14) 3.0 (1-14) 4.0 (2-17) 3.0 (1-13) Presence or history of brain metastases, n (%) ▪ Treated, stable ▪ Untreated ▪ Treated, progressing 198 (48) 118 (59.6) 44 (22.2) 36 (18.2) 93 (46) 55 (59.1) 22 (23.7) 16 (17.2)

• Baseline characteristics balanced between endpoint populations and treatment arms

29

46.3

HER2CLIMB: PFS (Primary Endpoint Population)

Cape = capecitabine.

• Murthy. SABCS 2019. Abstr GS1-01. Murthy. NEJM. 2019;382:597.

Events, n/N 7.8 (7.5-9.6) 5.6 (4.2-7.1) Median PFS, Mos (95% CI) Tucatinib + Trastuzumab/Cape Placebo + Trastuzumab/Cape 178/320 97/160 33 (27-40) 12 (8-21) 1-Yr PFS, % (95% CI) 46% reduction in risk of disease progression HR: 0.54 (95% CI: 0.42-0.71; P < .00001)

100 80 60 40 20 3 6 9 12 15 18 21 24 27 30 36

Patients Alive and Free From Disease Progression (%) Mos Since Randomization

Patients at Risk, n Tucatinib arm Placebo arm 320 160 235 94 152 45 98 27 40 6 29 4 15 2 10 1 8 1 4 2 1 62.9 12.3 33.1 33

30

HER2CLIMB: PFS in Patients With Brain Metastases (Total Population)

Cape = capecitabine.

• Murthy. SABCS 2019. Abstr GS1-01. Murthy. NEJM. 2019;382:597.

Events, n/N 7.6 (6.2-9.5) 5.4 (4.1-5.7) Median PFS, Mos (95% CI) Tucatinib + Trastuzumab/Cape Placebo + Trastuzumab/Cape 106/198 51/93 25 (17-34) 1-Yr PFS, % (95% CI) 52% reduction in risk of disease progression HR: 0.48 (95% CI: 0.34-0.69; P < .00001)

100 60 40 20 3 6 9 12 18 21 24 27 30 33 36

Patients Alive and Free From Disease Progression (%) Mos Since Randomization

Patients at Risk, n Tucatinib arm Placebo arm 60.4 33.9 24.9 198 93 144 49 78 12 45 4 14 8 2 1 1 1 1 1 80 15

31

100 80 60 40 20 3 6 9 12 15 18 21 24 27 30 33 36

26.6

HER2CLIMB: OS (Total Population)

Cape = capecitabine.

• Murthy. SABCS 2019. Abstr GS1-01. Murthy. NEJM. 2019;382:597.

21.9 (18.3-31.0) 17.4 (13.6-19.9) Median OS, Mos (95% CI) Tucatinib + trastuzumab/cape Placebo + trastuzumab/cape 130/410 85/202 45 (37-53) 27 (16-39) 2-Yr OS, % (95% CI) HR: 0.66 (95% CI: 0.50-0.88); P = .0048) 34% reduction in risk of death Events, n/N Patients Alive (%) Mos Since Randomization

410 202 388 191 322 160 245 119 178 77 123 48 80 32 51 19 34 7 20 5 10 2 4 1

44.9 75.5 62.4

Patients at Risk, n Tucatinib Arm Placebo Arm

32

Favors Tucatinib Arm Favors Placebo Arm

HER2CLIMB: OS Subgroup Analysis

Subgroup Total Age ≥ 65 yrs < 65 yrs Race White Nonwhite Hormone receptor status Positive for ER, PgR, or both Negative for ER and PgR Baseline brain metastasis Yes No ECOG PS 1 Geographic region United States and Canada Rest of world

0.1 1.0 10.0

Event/N 215/612 53/116 162/496 160/444 55/168 128/370 87/242 114/291 101/319 81/298 134/314 148/369 67/243 OS in Total Population 0.66 (0.50-0.88) 0.58 (0.32-1.06) 0.69 (0.50-0.95) 0.69 (0.50-0.96) 0.51 (0.28-0.93) 0.85 (0.59-1.23) 0.50 (0.31-0.80) 0.58 (0.40-0.85) 0.72 (0.48-1.08) 0.51 (0.33-0.80) 0.84 (0.59-1.20) 0.68 (0.48-0.95) 0.63 (0.39-1.03)

HR for Death (95% CI)

ECOG = Eastern Cooperative Oncology Group; PS = performance status.

• Murthy. SABCS 2019. Abstr GS1-01. Murthy. NEJM. 2019;382:597.

33

100

HER2CLIMB: Most Common Adverse Events (≥ 20% in Tucatinib Arm)

ALT = alanine aminotransferase; AST = aspartate aminotransferase; Cape = capecitabine; PPE = palmar–plantar erythrodysesthesia.

• Murthy. SABCS 2019. Abstr GS1-01.

Grade 1 Grade ≥ 3

Tucatinib + trastuzumab/cape Placebo + trastuzumab/cape

Grade 2

Frequency (%)

80 60 40 20

34

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

CNS = central nervous system; MBC = metastatic breast cancer; TKI = tyrosine kinase inhibitor.

35

• 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

Tucatinib Approval

AEs = adverse events; ALT = alanine aminotransferase; AST = Aspartate transaminase; BC = breast cancer. Tucatinib PI.

36

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

RCB = residual cancer burden; T-DM1 = trastuzumab emtansine.

37

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

ADC = antibody–drug conjugate; MBC = metastatic breast cancer; T-DM1 = trastuzumab emtansine; T-DXd = trastuzumab deruxtecan.

38

• Tumor antigen: abundant in tumors,

minimal in normal tissues; internalized upon ADC binding

• 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

tumor cells; not hydrophobic; must be potent since limited number of molecules can be attached to antibody

Structure of Antibody–Drug Conjugates

ADC = antibody–drug conjugate; mAb = monoclonal antibody; PK = pharmacokinetics.

• Thomas. Lancet Oncol. 2016;17:e254.

Antigen- binding Site mAb that targets tumor-specific or tumor-associated antigens Potent cytotoxic payload Stable linker releases payload only in target cell Tumor antigen

39

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 breast cancer. Licensed under Creative Commons Attribution 3.0 Unported License (CC BY 3.0).

40

• Early generation

‒ Mouse antibodies; immunogenic ‒ Unstable in circulation ‒ Unable to release cytotoxic drug within tumor cell ‒ Cytotoxic payload: chemotherapy drugs such as doxorubicin, vinca alkaloids (eg, vinblastine), or methotrexate

Early- vs New-Generation Antibody–Drug Conjugates

• New generation

— Chimeric or humanized antibodies; reduced immunogenicity — Stable in circulation — Efficient linker technology able to release cytotoxic drug within tumor cell (eg, disulfide, dipeptide, or hydrazone linkage) — Cytotoxic payload: highly potent agents with subnanomolar IC50 such as calicheamicin, maytansine derivative (eg, DM1, DM4), or auristatin (eg, MMAE, MMAF)

• Thomas. Lancet Oncol. 2016;17:e254.

41

• Tumor antigen: HER2
• Antibody: monoclonal antibody

trastuzumab

• Linker: systemically stable thioether,

not cleavable

• Cytotoxic drug payload: Emtansine

(DM1), a highly potent tubulin destabilizer

Structure of ado-Trastuzumab-Emtansine (T-DM1), a HER2-Targeted ADC

ADC = antibody–drug conjugate. Lewis Phillips et al. Cancer Res. 2008;68:9280.

Trastuzumab (HER2-targeted mAb) Cytotoxic agent: DM1 Thioether linker

42

• High drug:antibody

ratio: ~ 8

• Stable linker-payload
• Tumor-selectable

cleavable linker

• High potency,

membrane-permeable payload with short systemic half-life

• Bystander killing effect

HER2-Targeted ADC: Trastuzumab Deruxtecan (DS-8201)

ADC = antibody–drug conjugate; mAb = monoclonal antibody.

• Nakada. Chem Pharm Bull (Tokyo). 2019;67:173. Trail. Pharmacol Ther. 2018;181:126. Ogitani. Cancer Sci. 2016;107:1039.

Humanized anti-HER2 IgG1 mAb with same amino acid sequence as trastuzumab

Tetrapeptide-based cleavable linker

Cysteine residue Drug/linker

Topoisomerase I inhibitor (DXd) payload (exatecan derivative)

HO O F NH O O O N N OH OH H N O O O O O O O O O O O O H N N H N H N H N N N F H N

Cys

43

• Open-label, multicenter, 2-part phase II study

DESTINY-Breast01: Trastuzumab Deruxtecan (T-DXd) in Advanced HER2+ Breast Cancer

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.

• Krop. SABCS 2019. Abstr GS1-03. Modi. NEJM. 2020;382:610-621.

Adult patients with HER2+ unresectable and/or metastatic BC; prior T-DM1; ECOG PS 0/1; stable, treated brain metastases allowed; history of significant ILD excluded

Newly enrolled patients Pharmacokinetics (n = 65)

• Primary endpoint: ORR by ICR (RECIST v1.1)
• Secondary endpoints: investigator-assessed ORR,

DCR, DoR, CBR, PFS, OS, PK, safety

*5.4 mg/kg confirmed as RP2D.

Dose Finding* (n = 54) Continuation (n = 134)

Part 1 Part 2

Total enrolled at 5.4 mg/kg: n = 184

T-DM1 Intolerant (n = 4) T-DM1 R/R (n = 249)

• Data cutoff: August 1, 2019

‒ 79 (42%) continuing treatment ‒ 105 (57.1%) d/c (mostly for PD, 28.8%)

T-DXd 6.4 mg/kg (n = 22) T-DXd 7.4 mg/kg (n = 23) T-DXd 5.4 mg/kg (n = 22) T-DXd 5.4 mg/kg (n = 28) T-DXd 6.4 mg/kg (n = 26) T-DXd 5.4 mg/kg (n = 130) T-DXd 5.4 mg/kg (n = 4)

44

DESTINY-Breast01: Baseline Characteristics

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.

Characteristic T-DXd 5.4 mg/kg (N = 184)

Median age, yrs (range) 55 (28-96) Female, % 100 Region, % ▪ Asia ▪ North America ▪ Europe 34.2 28.8 37.0 ECOG PS, % ▪ 0/1 ▪ 2 55.4/44.0 0.5 Hormone receptor status, % ▪ Positive ▪ Negative ▪ Unknown 52.7 45.1 2.2

Characteristic T-DXd 5.4 mg/kg (N = 184)

Median prior lines of treatment, n (range) ▪ Trastuzumab, % ▪ T-DM1, % ▪ Pertuzumab, % ▪ Other anti-HER2 therapy, % ▪ Hormone therapy, % ▪ Other systemic therapy, % 6 (2-27) 100 100 65.8 54.3 48.9 99.5 Visceral disease, % 91.8 History of brain metastases, % 13.0 HER2 expression, % ▪ IHC 3+ ▪ IHC 2+, ISH+ ▪ IHC 1+, ISH+ 83.7 15.2 1.1

45

100 80 60 40 20

• 100
• 80
• 60
• 40
• 20

DESTINY-Breast01: Response

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.

• Krop. SABCS 2019. Abstr GS1-03. Modi. NEJM. 2020;382:610.

Response (ITT) T-DXd 5.4 mg/kg (N = 184)

ORR* (by ICR; n = 112), % (95% CI) 60.9 (53.4-68.0)

• CR (n = 11)

6.0

• PR (n = 101)

54.9

• SD (n = 67)

36.4

• PD (n = 3)

1.6

• Not evaluable (n = 2)

1.1 DCR, % (95% CI) 97.3 (93.8-99.1) 6-mo CBR, % (95% CI) 76.1 (69.3-82.1) Median DoR, mos (95% CI) 14.8 (13.8-16.9) Median time to response, mos (95% CI) 1.6 (1.4-2.6)

Best Change in Tumor Size (by ICR; n = 168)

Line at 20% indicates PD; line at −30% indicates PR.

Patients (N = 168) Best Percentage Change From Baseline in Sum of Diameters *Patients who received T-DXd 5.4 mg/kg.

46

100 80 60 40 20 70 50 30 10 90

DESTINY-Breast01: ORR by Subgroup

ECOG = Eastern Cooperative Oncology group; HT = hormone therapy; PS = performance status; tx = therapy.

• Modi. NEJM. 2020;382:610.

Yes No Positive Negative ≥ 3 < 3 Yes No Yes No Asia North America Europe 1 Yes No IHC 3+ IHC 1+ or 2+, ISH positive 112/184 78/121 34/63 56/97 55/83 99/167 13/17 14/24 98/160 102/169 10/15 37/63 33/53 42/68 67/102 45/81 36/56 76/128 97/154 13/28 Objective Response, % (95% CI) 61 (53-68) 64 (55-73) 54 (41-67) 58 (47-68) 66 (55-76) 59 (51-67) 76 (50-93) 58 (37-78) 61 (53-69) 60 (53-68) 67 (38-88) 59 (46-71) 62 (48-75) 62 (49-73) 66 (56-75) 56 (44-67) 64 (50-77) 59 (50-68) 63 (55-71) 46 (28-66) Subgroup Events/ Total Patients, n/N All patients Previous pertuzumab use Hormone receptor

• No. of regimens excluding HT

Brain metastasis Presence of visceral disease Geographic region ECOG PS T-DXd tx immediately after T-DM1 HER2-positive tumor

47

1.0 0.8 0.6 0.4 0.2 0 1 2 0.4

DESTINY-Breast01: Survival

Mets = metastases; mPFS = median PFS; NR = not reached; T-DXd = trastuzumab deruxtecan.

• Modi. NEJM. 2020;382:610.

mPFS: 16.4 mos (95% CI: 12.7-NR) mPFS in 24 patients with brain mets: 18.1 mos (95% CI: 6.7-18.1)

PFS OS

mOS: NR Censored: 68.5% Events: 31.5%

Probability of PFS Mos

184 182 174 155 153 135 121 107 103 94 69 54 38 17 11 10 9 4 3 1 0

3 4 5 6 7 8 9 1011121314151617181920

Patients at Risk, n

10 Censored: 86.4% Events: 13.6%

184 183 182 179 174 171 167 161 155 147 133 101 66 36 21 16 12 9 8 4 0

1.0 0.8 0.6 0.2 1 2 3 4 5 6 7 8 9 11121314151617181920

Mos Probability of OS

Patients at Risk, n

• Median follow-up: 11.1 mos (range: 0.7-19.9)

48

Cough

DESTINY-Breast01: AEs in Overall Population

AE = adverse events; WBC = white blood cell count.

• Krop. SABCS 2019. Abstr GS1-03. Modi. NEJM. 2020;382:610.

Nausea Fatigue Alopecia Vomiting Constipation Neutropenia Decreased appetite Anemia Diarrhea Decreased WBC count Thrombocytopenia Headache 10 20 40 30 50 60 70 90 80 100 Grade 1/2 Grade ≥ 3

49

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

T-DM1 = trastuzumab emtansine; THP = docetaxel/trastuzumab/pertuzumab, Q3W = every 3 weeks.

50

• 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

DESTINY-Breast01: Interstitial Lung Disease

AE, n (%) T-DXd 5.4 mg/kg (N = 184) Grade 1 Grade 2 Grade 3 Grade 4 Grade 5 Any Grade ILD 5 (2.7) 15 (8.2) 1 (0.5) 4 (2.2) 25 (13.6)

AE = adverse events; ILD = interstitial lung disease; T-DXd = trastuzumab deruxtecan.

• Krop. SABCS 2019. Abstr GS1-03.

51

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

ILD = interstitial lung disease; MBC = metastatic breast cancer; T-DXd = trastuzumab deruxtecan.

52

Grade 1 Grade 2 Grade 3/4

• Monitor with close follow-up in 2-7 days for
• nset of clinical symptoms, pulse oximetry
• Consider follow-up imaging in 1-2 wks (or as

clinically indicated)

• Consider initiating systemic steroids (≥ 0.5

mg/kg/day prednisone or equivalent) until improvement, followed by gradual taper over at least 4 wks

• If ILD worsens despite initiation of

corticosteroids, follow grade 2 guidelines

• Restart T-DXd if ILD resolves within 28 days

after onset

• Restart T-DXd at reduced dose if ILD resolves

> 28 days after onset

• Permanently discontinue T-DXd if grade 1 ILD
• ccurs beyond cycle Day 22 and has not

resolved within 49 days from last infusion

• Immediately begin systemic steroids (≥ 1

mg/kg/day prednisone or equivalent) until clinical improvement, followed by gradual taper over at least 4 wks

• Monitor symptoms closely
• Re-image as clinically indicated
• For worsening symptoms or no improvement

within 5 days: ⎻ Consider increasing dose of steroids to 2 mg/kg/day prednisone or equivalent and/or switch to IV administration with methylprednisolone ⎻ Reconsider additional workup for alternative etiologies as described above ⎻ Escalate care as clinically indicated

• Permanently discontinue T-DXd
• Hospitalization required
• Immediately begin empiric high-dose

methylprednisolone IV (500-1000 mg/day for 3 days), followed by ≥ 1 mg/kg/day of prednisone (or equivalent) until clinical improvement, followed by gradual taper over at least 4 wks

• Re-image as clinically indicated
• For no improvement within 3-5 days:

⎻ Reconsider additional workup for alternative etiologies as described above ⎻ Consider other immunosuppressants and/or treat per local practice

• Permanently discontinue T-DXd

Guidelines for the Management of Trastuzumab Deruxtecan–Induced Interstitial Lung Disease

ILD = interstitial lung disease; T-DXd = trastuzumab deruxtecan.

• Krop. SABCS 2019. Abstr GS1-03.

53

• On December 20, 2019, the FDA approved fam-trastuzumab deruxtecan-nxki for treatment
• f 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

Trastuzumab Deruxtecan Approval

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.

Future Directions in HER2+ MBC

55

• Randomized, double-blind, phase III trial

HER2CLIMB-02: Tucatinib or Placebo + T-DM1 in Unresectable HER2-Positive Breast Cancer

Patients with HER2+ unresectable LA

• r metastatic BC; previous treatment

with trastuzumab and a taxane; previous pertuzumab permitted but not required; untreated brain mets not requiring immediate therapy or previously treated and stable brain mets permitted (planned N = 460) Placebo 300 mg PO BID + T-DM1 3.6 mg/kg IV Q3W

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. NCT03975647.

• Primary endpoint: PFS (RECIST v 1.1 by investigator assessment)
• Secondary endpoints: OS, PFS (BICR), ORR, DoR, CBR, rate of AEs

Placebo 300 mg PO BID + T-DM1 3.6 mg/kg IV Q3W Tucatinib 300 mg PO BID + T-DM1 3.6 mg/kg IV Q3W

56

• Randomized, open-label, active-controlled phase III trial

Investigator’s Choice of Trastuzumab/Cape

• r Lapatinib/Cape

(planned n = 200) Trastuzumab Deruxtecan 5.4 mg/kg IV Q3W (planned n = 400)

DESTINY-Breast02: T-DXd vs Trastuzumab/Cape or Lapatinib/Cape in HER2+ MBC With Prior T-DM1

Patients with HER2+, unresectable and/or metastatic BC; at least third line; progression on prior HER2- targeted agents including T-DM1; no prior capecitabine; no CNS metastases (planned N = 600)

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.

• Primary endpoint: PFS (RECIST v 1.1 by BICR)
• Secondary endpoints: OS, PFS by investigator assessment, ORR, DoR, CBR

Stratified by hormone receptor status, prior pertuzumab, history of visceral disease

57

• Primary endpoint: PFS (RECIST v 1.1 by BICR)
• Secondary endpoints: OS, ORR, DoR, CBR, PFS (investigator assessment)
• Randomized, open-label phase III trial at ~160 sites in North America and Europe

DESTINY-Breast03: Second-line T-DXd vs T-DM1 in HER2+ MBC After Progression on Trastuzumab/Taxane

Patients with HER2+, unresectable and/or metastatic BC; previous treatment with trastuzumab and a taxane; no prior HER2-targeted ADC; CNS metastases allowed (planned N = 500)

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. NCT03529110.

Stratified by hormone receptor status, prior pertuzumab, history of visceral disease

T-DM1 3.6 mg/kg IV Q3W (Planned n = 250) Trastuzumab Deruxtecan 5.4 mg/kg IV Q3W (Planned n = 250)

58

Efficacy of Trastuzumab Deruxtecan in HER2-Low MBC

BL = baseline; DoR = duration of response; ILD = interstitial lung disease; MBC = metastatic breast cancer; NR = not reported; PD = progressive disease.

• Modi. JCO. 2020: JCO1902318.

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

• Best % Change in

Tumor Size From BL Change in Tumor Size From BL (%)

% Change in Tumor Size by HER2 IHC Status

Line at 20% indicates PD; line at -30% indicates PR.

Best % Change in Tumor Size by HER2 IHC Status

*Hormone receptor negative

n = 48

* * * * * *

80 60 40 20

• 20
• 40
• 60
• 80
• 100

IHC 2+ IHC 1+

100 80 60 40 20

• 20
• 40
• 60
• 80
• 100

10 20 30 40 50 60 70 80 90 120 110 100 IHC 2+ IHC 1+

Time (weeks)

* * * *

x

*

59

• Randomized, open-label, active-controlled phase III trial

Physician’s Choice of CT: Capecitabine, Eribulin, Gemcitabine, Paclitaxel or nab-Paclitaxel (planned n = 180) Trastuzumab Deruxtecan 5.4 mg/kg IV Q3W (planned n = 360)

DESTINY-Breast04: T-DXd vs Chemotherapy in Unresectable HER2- Low Breast Cancer

Patients with HER2-low (IHC1+ or IHC2+/ISH-), unresectable and/or metastatic BC; previous treatment with trastuzumab and a taxane; progression on endocrine therapy; no prior HER2 positivity (planned N = 540)

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.

• Primary endpoint: PFS (RECIST v 1.1 by BICR)
• Secondary endpoints: OS, PFS (investigator assessment), ORR, DoR

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-)

60

• HER2 antibody with same amino

acid sequence as trastuzumab

• Proteolytic cleavage of linker in

tumor microenvironment leads to activation of prodrug payload

• Active toxin (DUBA) alkylates

DNA, kills dividing and nondividing cells

• Bystander killing effect

HER2-Targeted ADC: Trastuzumab Duocarmazine (SYD985)

ADC = antibody–drug conjugate.

• Dokter. Mol Cancer Ther. 2014;13:2618. Elgersma. Mol Pharm. 2015;12:1813.

Trastuzumab-vc-seco-duocarmycin-hydroxybenzamide-azaindole

O HN O N OH OH H N O O O O O O O O O O O O H N N H N N N S O NH2 N N H N

~2.8

CI

SYD985

Antibody Linker Prodrug

Trastuzumab Maleimide linker Protease- cleavable linker Self- elimination spacers Seco-duocarmycin progrug Valine Citrulline PABC Cyclization spacer

61

• Most drug-related TEAEs mild to moderate

⎻ Ocular toxicity reported in 2/3 of patients; most common reason for treatment discontinuation ⎻ Ocular toxicity, neutropenia most common reason for dose modifications

ORR: 33% (95% CI: 20.4-48.4)

Phase I Study: Trastuzumab Duocarmazine in Locally Advanced or Metastatic HER2+ Breast Cancer

AE = adverse event; BL = baseline; TEAE = treatment-emergent adverse event.

• Banerji. Lancet Oncol. 2019;20:1124.

Best Change in Tumor Size From BL (%)

*Dose-expansion phase. n = 5 patients with 0% best percentage change.

Drug-Related AE, n (%) Dose-Expansion Cohorts (n = 146) Grade 1/2 Grade 3

Fatigue 43 (29) 5 (3) Conjunctivitis 41 (28) 4 (3) Dry eye 44 (30) 1 (1) Increased lacrimation 29 (20) Dry skin 26 (18) Decreased appetite 27 (18) 2 (1) Alopecia 26 (18) Nausea 27 (18) Stomatitis 24 (16) Neutropenia 14 (10) 9 (6) Vomiting 17 (12) Anemia 13 (9) 2 (1) Pyrexia 9 (6)

Best % Change in Tumor Size in HER2+ Cohort

* * * * *

80 60 40 20

• 20
• 100
• 80
• 60
• 40

100

62

• Randomized, active-controlled phase III trial

TULIP: Trastuzumab Duocarmazine vs Physician’s Choice of Tx in Locally Advanced or Metastatic Breast Cancer

Patients with HER2+, unresectable, locally advanced and/or metastatic BC; progression on or after ≥ 2 HER2-targeted regimens or after T-DM1; ECOG PS 0-2 (planned N = 345)

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.

• Primary endpoint: PFS (RECIST v 1.1)
• Secondary endpoints: OS, PFS (investigator assessment), ORR, PROs/QoL

Until PD, toxicity, or withdrawal Survival f/u Q3M

Tumor evaluation Q6W Physician’s Choice: Lapatinib/Capecitabine, Trastuzumab/Capecitabine, Trastuzumab/Vinorelbine, Trastuzumab/Eribulin (planned n = 115)

Trastuzumab Duocarmazine Q3W (planned n = 230)

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• Margetuximab has the same specificity,

affinity to HER2 as trastuzumab with similar ability to disrupt signaling

• However, via Fc engineering with intent to

activate immune responses, margetuximab has altered Fc receptor affinity ‒ Trastuzumab: WT IgG1 effector domains; binds and activates immune cells ‒ Margetuximab: Increased affinity for activating Fcγ RIIIA (CD16A) and decreased affinity for inhibitory Fcγ RIIB (CD32B)

Margetuximab: Novel HER2-Targeted Monoclonal Antibody

ADCC = Antibody-dependent cellular cytotoxicity; APC, antigen presenting cell; WT = wildtype.

• Nordstrom. Breast Cancer Res. 2011;13:R123. Stavenhagen. Cancer Res. 2007;67:8882.
• Nordstrom. ASCO 2019. Abstr 1030. Clynes. Nat Med. 2000;6:443.

HER2-specific Lymphocyte Proliferation

CD32B TAA CD16A Cancer Cell Destruction HER2

Increased CD16A Affinity: Enhance Innate Immunity/More Potent ADCC Stimulation

Perforins Granzymes

Decreased CD32B Affinity: Enhance Adaptive Immunity/Increase Immune Activation

HER2+ Cancer Cell

T-cell APC

NK Cell

64

• 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

• Randomized, open-label phase III trial (data cutoff: September 30, 2019)

SOPHIA: Margetuximab vs Trastuzumab in HER2+ Advanced Breast Cancer After ≥ 2 HER2 Therapies

BC = breast cancer; CBR = clinical benefit rate; CT = chemotherapy; DoR = duration of response; tx = treatment.

• Rugo. SABCS 2019. Abstr GS1-02.

Patients with HER2+ advanced BC with ≥ 2 previous anti-HER2 therapies, including pertuzumab; 1-3 prior lines of tx for metastatic disease; prior brain metastasis allowed if treated/stable (N = 536)

Stratified by CT, no. of prior lines of tx (> 2 vs ≤ 2),

• no. of metastatic sites (> 2 vs ≤ 2)

*Investigators choice of CT: capecitabine, eribulin, gemcitabine, or vinorelbine.

Trastuzumab 8 mg/kg loading → 6 mg/kg Q3W + CT* in 3-wk cycles (n = 270) Margetuximab 15 mg/kg Q3W + CT* in 3 wk cycles (n = 266)

65

30 20 10 100 80 60 40 20

+ + + + +

SOPHIA: Investigator-Assessed PFS

CT = chemotherapy.

• Rugo. SABCS 2019. Abstr GS1-02.

Mos From Randomization PFS (%)

Margetuximab + CT Trastuzumab + CT 266 270 210 192 137 108 100 72 62 42 36 20 25 8 14 4 11 3 6 2 5 2 3 1 2 2

+ + + + + + + + + + + + + + + + + + + + + + + + + ++ + + + + ++ + + + + + + + + + + + + + + ++ + +

5.7 (5.22-6.97) 4.4 (4.14-5.45) Median PFS, Mos (95% CI) 208 222 HR: 0.71 (95% CI: 0.58-0.86; P = .0006) 29% reduction in risk of disease progression Events, n Margetuximab + CT (n = 266) Trastuzumab + CT (n = 270)

Mos From Randomization PFS (%)

Margetuximab + CT Trastuzumab + CT 266 270 206 184 155 130 112 87 72 59 61 45 33 25 32 21 13 5 16 10 8 4 7 3 3 1 2 1 2 1

+ + + + + + + + + + + + + + + + + + + + + + + + ++ + + + + + + + + + + + + + + + + + + + +

5.6 (5.06-6.67) 4.2 (3.98-5.39) Median PFS, Mos (95% CI) 160 177 HR: 0.70 (95% CI: 0.56-0.87; P = .001) 30% reduction in risk of disease progression Events, n Margetuximab + CT (n = 266) Trastuzumab + CT (n = 270)

Investigator-Assessed PFS (Sep 2019 Cutoff) Investigator-Assessed PFS (Oct 2018 Cutoff)

1 1

+ + + + + + + + + + + + ++ + + + + + + + + + + + + + + + + ++ + + + + + + +

100 5 20 10 80 60 40 20 15 25

66

OS (%)

30 20 10

Mos From Randomization

100 80 60 40 20 40 Median difference: 1.8 mos Median follow-up: 15.6 mos

+

SOPHIA: Interim OS Analyses (ITT)

266 270 Margetuximab + CT Trastuzumab + CT

+ + + + + + + + + + + + ++ + + + ++ + + + + + + + ++ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +

259 260 249 246 230 218 214 205 159 160 131 126 107 102 64 57 47 43 35 30 22 16 14 10 9 6 1 3 2 2 2 2 2 239 235 186 183 80 74 31 22

21.6 (18.86-24.05) 19.8 (17.54-22.28) Median OS, Mos (95% CI) Margetuximab + CT (n = 266) Trastuzumab + CT (n = 270) 131 139 Events, n HR: 0.89 (95% CI: 0.69-1.13; P = .326)

Second Interim OS Analysis (Sep 2019 Cutoff) First Interim OS Analysis (Oct 2018 Cutoff)

OS (%) Mos From Randomization

20 30 20 10 100 80 60 40

266 270 Margetuximab + CT Trastuzumab + CT

Median difference: 1.7 mos

++ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +

241 237 174 163 85 92 57 63 42 37 29 24 8 6 3 3 2 2 1 209 194 125 122 17 14

18.9 (16.16-25.07) 17.2 (15.80-33.31) Median OS, Mos (95% CI) Margetuximab + CT (n = 266) Trastuzumab + CT (n = 270) 78 80 Events, n HR: 0.95 (95% CI: 0.69-1.31; P = .758)

+ + + + + ++ + + + + + + + + + + + + + + + + + + ++ + + + + ++ + + + ++ ++ + + + + ++ + + + +

Median follow-up: 9.2 mos

+ + ++ + + + + + ++ + + + + + + + + + + + + + + + + + ++ + ++ ++ + + + + + + + + + + + + + + + + ++ + + + + + + + + + + ++ +

CT = chemotherapy; ITT = intention-to-treat.

• Rugo. SABCS 2019. Abstr GS1-02.

67

100 80 60 40 20 30 20 10 40

SOPHIA: Prespecified Exploratory OS in CD16A-158F Carriers

CT = chemotherapy.

• Rugo. SABCS 2019. Abstr GS1-02.

23.7 (18.89-28.32) 19.4 (16.85-22.28) Median OS, Mos (95% CI) Margetuximab + CT (n = 221) Trastuzumab + CT (n = 216) 103 114 HR: 0.79 (95% CI: 0.61-1.04; P = .087) Median follow-up: 15.6 mos Events, n Mos From Randomization OS (%)

221 216 219 210 212 201 204 192 196 176 157 145 135 123 111 98 91 81 68 57 42 30 31 21 27 16 19 11 1 13 9 8 6 1 2 1 2 2 2

+ + + + ++ + + + + + + + + +++ + + + + + + + + + + + + + + + ++ + +++ + + + + + + + + + + ++ + + + + + + ++ + + + + + + + + + + + + + + + + + Median difference: 4.3 mos

Margetuximab + CT Trastuzumab + CT

+ + + + + + + + + + + + + + + + + + + + + + + + + + +

181 165 55 43

Data Cutoff: September 2019.

• CD16A-158F carriers (FF or FV): 437/506 (86%) of genotyped patients

68

SOPHIA: Safety

AEs, n (%) Margetuximab + CT (n = 264) Trastuzumab + CT (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

• IRR
• Discontinuation due to IRR
• LV dysfunction resulting in delayed dosing or discontinuation

All Grade 35 (13.3) 2 (0.6) 4 (1.5) Grade ≥ 3 4 (1.5) All Grade 9 (3.4) 6 (2.3) Grade ≥ 3

*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.

69

• 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?)

Implications for Practice

MBC = metastatic breast cancer; T-DM1 = trastuzumab emtansine; T-DXd = trastuzumab deruxtecan; TKI = tyrosine kinase inhibitor.

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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

ILD = interstitial lung disease; T-DXd = trastuzumab deruxtecan; TKI = tyrosine kinase inhibitor.

2020 Spring Oncology Conference