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

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 3 HER2 = human epidermal growth factor receptor 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 hsp90 P P Lapatinib P inhibitor MK-2206 P BKM120 Neratinib HER2-Targeted P13K Proteasome BEZ235 Tucatinib TKIs T-DM1 hsp90 AKT T-DXd Breakdown Everolimus of HER2 mTOR P Temsirolimus Endosome T-DM1 T-DXd ADC = antibody – drug conjugate; mAb = monoclonal antibody; TKI = tyrosine kinase inhibitor. 4 Gajria. Expert Rev Anticancer Ther. 2011;11:263. Pernas. Ther Adv Med Oncol. 2019;11:1758835919833519.

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. 5 Wang. Signal Transduct Target Ther. 2019;4:34. Pernas. Ther Adv Med Oncol. 2019:11:1758835919833519.

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 40.8 TH + Pbo 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 70 0 10 20 30 40 50 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. 6 Swain. ASCO 2019. Abstr 1020.

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. 7 Perez. Cancer. 2019;125:3974.

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 60.1 7.2 9.0 Alopecia with trastuzumab + CT 19.3 4.4 3.8 Neutropenia 6.5 0 0 Febrile neutropenia 4.2 0.3 2.7 Diarrhea Greater incidence 3.1 4.7 5.5 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. 8 Perez. Cancer. 2019;125:3974.

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 EMILIA [1] : Randomized phase III study of T-DM1 vs lapatinib + capecitabine for HER2+ MBC with progression on trastuzumab + choice for HER2+ MBC with progression on a taxane, lapatinib, and ≥2 HER2 -targeted regimens including trastuzumab (N = 602) taxane (N = 991) Median OS, mos T-DM1 30.9 100 Median OS, mos 100 Lapatinib + Cape 25.1 85.2% T-DM1 22.7 80 80 Physician’s choice 15.8 78.4% 64.7% OS (%) 60 OS (%) 60 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 28 30 32 34 36 38 40 2 4 8 10 12 14 16 18 20 22 24 26 0 6 0 4 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 2 6 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) 80 (34) 66 (36) 39 (45) 16 (68) 1 (80) 0 107 (33) 59 (37) choice T-DM1 495 485 474 457 439 418 349 293 242 197 164 136 111 86 62 38 28 13 5 404 (0) 368 (17) 132 (66) T-DM1 321 (29) 280 (35) 226 (43) 192 (44) 167 (45) 54 (138) 12 (172) 0 Cape = capecitabine; MBC = metastatic breast cancer; T-DM1 = trastuzumab emtansine. 9 1. Verma. NEJM. 2012;367:1783. 2. Krop. Lancet Oncol. 2017;18:743.

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) ADC = antibody – drug conjugate; mAb = monoclonal antibody; TKI = tyrosine kinase inhibitor. 10

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 11 ER = estrogen receptor, PgR = progesterone receptor, PR = partial response; T-DM1 = trastuzumab emtansine.

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 12

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 • No vs Yes 1.181 (0.718-1.943) Lapatinib + capecitabine approved in this Race setting but few patients respond Other vs black/African American 1.268 (0.580-2.769) ‒ White vs black/African American In a pooled analysis, CNS ORR was 21.4%, 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) • MBC diagnosis type Trastuzumab + capecitabine + tucatinib Recurrent vs de novo 1.650 (1.239-2.196) approved in this setting in April 2020 Hormone receptor status • Negative vs positive T-DM1, trastuzumab, and pertuzumab do not 1.841 (1.359-2.494) penetrate the CNS under normal conditions 0 1 2 3 4 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. 13 1. Petrelli. Eur J Cancer. 2017;84:141. 2. Hurvitz. Clin Cancer Res. 2019;25:2433.