WSG-ADAPT: Trastuzumab Emtansine ± ET vs Trastuzumab + ET in HER2+/HR+ Early Breast Cancer CCO Independent Conference Coverage*: The 2015 Annual Meeting of the CTRC-AACR San Antonio Breast Cancer Symposium, December 8-12, 2015 San Antonio, Texas *CCO is an independent medical education company that provides state-of-the-art medical information to healthcare professionals through conference coverage and other educational programs. ET, endocrine therapy; HR, hormone receptor; T-DM1, trastuzumab emtansine. This program is supported by educational grants from Genentech and Novartis.

WSG-ADAPT HER2+/HR+: Background Current standard neoadjuvant chemotherapy plus anti- HER2 therapy in pts with HER2+ EBC independent of HR status Triple-positive (HER2+/HR+) EBC distinct entity Outcomes after standard therapy differ according to HR status; endocrine + anti-HER2 tx may be effective option Outcome data for neoadjuvant T-DM1 ± endocrine therapy is lacking for this pt population Current study[1] compared safety, efficacy of T-DM1 ± endocrine therapy vs trastuzumab + endocrine therapy in HER2+/HR+ EBC Interim analysis[2] (n = 130) previously presented EBC, early breast cancer; HR, hormone receptor; T-DM1, trastuzumab emtansine; tx, treatment. 1. Harbeck N, et al. SABCS 2015. Abstract S5-03. 2. Harbeck N, et al. ASCO 2015. Abstract 506. Slide credit: clinicaloptions.com

WSG-ADAPT HER2+/HR+: Study Design International, prospective, randomized phase II trial Primary endpoint: pCR (no invasive carcinoma in breast/nodes) Secondary endpoints: dynamic testing evaluation, EFS, OS, safety Wk 12 T-DM1 3.6 mg/kg Q3W (n = 119) Pts with ER+ and/or PgR+, HER2+, cT1c - cT4a-c, cN, cM0 BC and adequate organ function, LVEF ≥ 50%, normal ECG (N = 375) Surgery† T-DM1 3.6 mg/kg Q3W + ET* (n = 127) Trastuzumab 8 mg/kg loading dose, then 6 mg/kg Q3W + ET* (n = 129) BC, breast cancer; ECG, electrocardiogram; EFS, event-free survival; ET, endocrine therapy; ER, estrogen receptor; HR, hormone receptor; LVEF, left ventricular ejection fraction; pCR, pathologic complete response; PgR, progesterone receptor; T-DM1, trastuzumab emtansine. *Tamoxifen if premenopausal; aromatase inhibitor (of investigator’s choice) if postmenopausal. †Standard chemotherapy (1-yr trastuzumab) recommended after surgery or 12-wk biopsy (if clinical non-pCR). 1. Harbeck N, et al. SABCS 2015. Abstract S5-03. 2. Hofmann D, et al. Trials. 2013;14:261. Slide credit: clinicaloptions.com

WSG-ADAPT HER2+/HR+: Baseline Characteristics T-DM1 (n = 119) T-DM1 + ET (n = 127) Trastuzumab + ET (n = 129) Median age, yrs (range) 50.0 (21-78) 51.0 (27-76) 51.5 (23-77) cT, % 1 ≥ 2 50.4 49.6 48.8 51.2 46.5 53.5 cN, % ≥ 1 71.4 28.5 75.6 24.4 70.5 29.5 PgR, % Negative Positive 17.6 82.4 15.7 83.5 16.3 83.7 ER, % 2.5 97.5 0.8 98.4 3.9 96.1 Central grading 3, % 81.5 81.1 76.0 Median Ki67 (range) 40 (10-90) 40 (15-80) 35 (10-85) ER, estrogen receptor; ET, endocrine therapy; HR, hormone receptor; PgR, progesterone receptor; T-DM1, trastuzumab emtansine. Slide credit: clinicaloptions.com Harbeck N, et al. SABCS 2015. Abstract S5-03.

WSG-ADAPT HER2+/HR+: Efficacy Outcome, n/N (%) T-DM1 T-DM1 + ET Trastuzumab + ET pCR (ypT0 or ypT0/is, ypN0) All pts* Premenopausal women Postmenopausal women 48/117 (41.0) 22/58 (37.9) 26/59 (44.1) 51/123 (41.5) 24/63 (38.1) 27/60 (45.0) 18/119 (15.1) 8/59 (13.6) 10/60 (16.7) Near pCR (ypT1a) 14/117 (12.0) 14/123 (11.4) 5/119 (4.2) Early response† Nonresponders Responders 9/36 (25.0) 24/61 (39.3) 6/25 (24.0) 36/76 (47.4) 5/40 (12.5) 11/62 (17.7) *P < .001 for comparison between each T-DM1 arm vs trastuzumab + ET. †Low cellularity (< 500 tumor cells) or Ki67 decline ≥ 30%in 3-wk biopsy. ET, endocrine therapy; HR, hormone receptor; OR, odds ratio; pCR, pathologic complete response; T-DM1, trastuzumab emtansine. Early response significantly associated with pCR rate (OR: 2.2; 95% CI: 1.24-4.19) 19.8% in nonresponders vs 35.7% in responders Slide credit: clinicaloptions.com Harbeck N, et al. SABCS 2015. Abstract S5-03.

WSG-ADAPT HER2+/HR+: All AEs T-DM1 ± ET Trastuzumab + ET P Value Thrombocytopenia 10.4 < .01 Constipation 4.1 .04 Dry mouth 6.2 0.8 .02 Nausea 20.7 4.9 Fatigue 22.8 11.5 .01 Mucosal inflammation 7.5 1.6 .03 Nasopharyngitis 7.9 Investigations Total ALT AST 23.2 18.7 17.0 9.0 5.7 3.3 Arthralgia 8.3 2.5 Dysgeusia 4.6 Headache 16.2 Hot flush 3.7 AE, adverse event; ALT, alanine aminotransferase; AST, aspartate aminotransferase; ET, endocrine therapy; HR, hormone receptor; T-DM1, trastuzumab emtansine. Slide credit: clinicaloptions.com Harbeck N, et al. SABCS 2015. Abstract S5-03.

WSG-ADAPT HER2+/HR+: AEs Grade ≥ 3 Increase in ALT/AST occurred in 4.1% of T-DM1 pts vs 0% of trastuzumab pts (P = .02) Serious treatment-related AEs Total: n = 18 Elevated ALT, corneal cyst, hypertensive crisis, hypersensitivity Serious AEs ≥ grade 3: T-DM1 ± ET arms (n = 2), trastuzumab + ET (n = 3) No treatment-related deaths AE, adverse event; ALT, alanine aminotransferase; AST, aspartate aminotransferase; ET, endocrine therapy; HR, hormone receptor; SAE, serious adverse event; T-DM1, trastuzumab emtansine. Slide credit: clinicaloptions.com Harbeck N, et al. SABCS 2015. Abstract S5-03.

WSG-ADAPT HER2+/HR+: Conclusions 12-wk T-DM1 increased pCR rate vs trastuzumab + ET in women with HER2+/HR+ EBC 41% vs 15%, respectively (P < .001) Addition of ET to T-DM1 did not raise pCR rate Menopausal status had minimal bearing on results Tolerable safety profile with low toxicity Early response significantly associated with increased pCR rate Detectable after 3 wks Authors conclude further investigation of T-DM1 in pts with EBC warranted ALT, alanine aminotransferase; AST, aspartate aminotransferase; EBC, early breast cancer; ET, endocrine therapy; HR, hormone receptor; pCR, pathologic complete response; T-DM1, trastuzumab emtansine. Slide credit: clinicaloptions.com Harbeck N, et al. SABCS 2015. Abstract S5-03.

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