TRAIN-2 (BOOG 2012-03): Phase III Trial of Neoadjuvant Chemotherapy ± Anthracyclines With Dual HER2 Blockade in HER2+ EBC CCO Independent Conference Highlights* of the 2017 ASCO Annual Meeting; June 2-6, 2017; Chicago, Illinois *Clinical Care Options (CCO) is an independent medical education organization that provides conference coverage and other unique educational programs for healthcare professionals EBC, early breast cancer. This activity is supported by educational grants from AbbVie, Amgen, AstraZeneca, Celgene Corporation, Genentech, Halozyme, Incyte, and Merck & Co., Inc.

Neoadjuvant CT ± Anthracyclines With Dual HER2 Blockade in HER2+ EBC: Background For pts with HER2+ breast cancer: Neoadjuvant treatment with dual HER2 blockade increases pCR rates[1,2] TCH, an anthracycline-free option with a single HER2 inhibitor,[3] is available though treatment duration (18 wks) is shorter than standard sequential therapy (24 wks) Substitution of weekly paclitaxel and an extended treatment duration may be beneficial[4-6] Lack of comparative data on dual HER2 blockade ± anthracyclines in neoadjuvant setting Current analysis designed to compare safety, efficacy of anthracycline- containing vs anthracycline-free regimens of the same duration with dual HER2 blockade in pts with stage II-III HER2+ breast cancer[7] EBC, early breast cancer; pCR, pathologic CR; TCH, docetaxel/carboplatin/trastuzumab. References: 1. Gianni L, et al. Lancet Oncol. 2012;13:25-32. 2. Baselga J, et al. Lancet. 2012;379:633-640. 3. Slamon D, et al. N Engl J Med. 2011;365:1273-1283. 4. Sparano JA, et al. N Engl J Med. 2008;358:1663-1671. 5. van Ramshorst MS, et al. Eur J Cancer. 2017;74:47-54. 6. von Minckwitz G, et al. Breast Cancer Res Treat. 2011;125:145-156. 7. van Ramshorst MS, et al. ASCO 2017. Abstract 507. Slide credit: clinicaloptions.com References in slidenotes.

Surgery + adjuvant therapy‡ TRAIN-2: Study Design Multicenter, randomized phase III study in the Netherlands Primary endpoint: pCR (ypT0/is, ypN0) by local assessment Secondary endpoints: RFS, BCSS, OS, toxicity Stratified by cT (0-2 vs 3-4), cN (neg vs pos), ER (neg vs pos), and age (< 50 vs ≥ 50 yrs) PTC* + Pertuzumab Q3W (n = 219) Treatment-naive pts with HER2-positive, stage II-III breast cancer and LVEF ≥ 50% (N = 438) 9 cycles Surgery + adjuvant therapy‡ FEC-T † + Pertuzumab Q3W (n = 219) PTC* + Pertuzumab Q3W (n = 219) 3 cycles 6 cycles AUC, area under the concentration curve; BCSS, breast cancer-specific survival; ER, estrogen receptor; FEC-T, 5-fluorouracil/epirubicin/cyclophosphamide/trastuzumab; LVEF, left ventricular ejection fraction; pCR, pathologic CR; PTC, paclitaxel/trastuzumab/carboplatin; RFS, recurrence-free survival. *21-day cycles: PTC + pertuzumab Day 1, P Day 8; paclitaxel 80 mg/m2, carboplatin AUC 6 mg.min/mL. †21-day cycles. 5-fluorouracil 500 mg/m2, epirubicin 90 mg/m2, cyclophosphamide 500 mg/m2. Trastuzumab 6 mg/kg with 8-mg/kg loading dose, pertuzumab 420 mg with 840-mg loading dose. ‡To complete 1 yr of adjuvant trastuzumab; endocrine therapy for ER+ and/or PgR+ tumors. Slide credit: clinicaloptions.com van Ramshorst MS, et al. ASCO 2017. Abstract 507.

TRAIN-2: Baseline Characteristics FEC-T + Pertuzumab (n = 219) PTC + Median age, yrs (range) 49 (25-73) 48 (22-75) Clinical T-stage, n (%) cT0-2 cT3-4 148 (68) 71 (32) 154 (70) 65 (30) Clinical N-stage, n (%) cN negative cN positive 83 (38) 136 (62) 76 (35) 143 (65) Disease stage, n (%) II III 141 (64)* 78 (36) 151 (69)† 68 (31) Characteristic, n (%) FEC-T + Pertuzumab (n = 219) PTC + HR status ER- and PgR- ER+ and/or PgR+ 90 (41) 129 (59) 93 (42) 126 (58) Tumor grade 1 2 3 Unknown 7 (3) 102 (46) 17 (8) 12 (5) 99 (45) 94 (42) 14 (6) FEC-T, 5-fluorouracil/epirubicin/cyclophosphamide + trastuzumab; PTC, paclitaxel/trastuzumab/carboplatin. *Includes 1 pt with stage IV disease. †Includes 1 pt with stage I disease. Slide credit: clinicaloptions.com van Ramshorst MS, et al. ASCO 2017. Abstract 507.

TRAIN-2: Treatment Exposure FEC-T + Pertuzumab (n = 219) PTC + Pertuzumab (n = 219) Median number of cycles (range) 9 (3-9) 9 (1-9) Reason for treatment d/c, n (%) AEs Patient decision Other 31 (14) 5 (2) 4 (2)* 26 (12) 7 (3) 4 (2) *Death due to pulmonary embolism, n = 1. AE, adverse event; FEC-T, 5-fluorouracil/epirubicin/cyclophosphamide + trastuzumab; PTC, paclitaxel/trastuzumab/carboplatin. Slide credit: clinicaloptions.com van Ramshorst MS, et al. ASCO 2017. Abstract 507.

P value for interaction .32 TRAIN-2: pCR 100 P = .51 FEC-T + Pertuzumab P = .75 PTC + Pertuzumab 89% 84% 80 67% 68% P = .61 55% 60 51% pCR rate (ypT0/is, ypN0), % 40 20 FEC-T, 5-fluorouracil/epirubicin/cyclophosphamide + trastuzumab; pCR, pathologic CR; PTC, paclitaxel/trastuzumab/carboplatin All Pts ER- and PgR- ER+ and/or PgR+ P value for interaction .32 Slide credit: clinicaloptions.com van Ramshorst MS, et al. ASCO 2017. Abstract 507. Reproduced with permission.

TRAIN-2: pCR Subgroup Analysis FEC-T+Ptz PTC+Ptz Characteristic FEC-T + Pertuzumab PTC + Pertuzumab n pCR, % All pts 212 67 206 68 ER+ and/or PgR+ ER- and PgR- 125 87 51 89 116 90 55 84 < 50 yrs ≥ 50 yrs 96 65 110 71 cT0-2 cT3-4 142 70 64 145 61 cN negative cN positive 80 132 75 131 72 66 II III 135 77 69 1-2 3 99 62 101 91 Favors FEC-T+Ptz Favors PTC+Ptz OR (95%CI) 1.07 (0.70-1.64) 1.17 (0.71-1.95) 0.71 (0.30-1.68) 1.14 (0.65-2.01) 1.00 (0.55-1.81) 1.03 (0.63-1.69) 1.14 (0.55-2.35) 0.86 (0.42-1.75) 1.20 (0.73-1.99) 1.08 (0.65-1.79) 1.03 (0.51-2.07) 1.13 (0.63-2.02) 1.03 (0.55-1.92) ER, estrogen receptor; FEC-T, 5-fluorouracil/epirubicin/cyclophosphamide + trastuzumab; pCR, pathologic CR; PTC, paclitaxel/trastuzumab/carboplatin; Ptz, pertuzumab. 0.2 1 5 Slide credit: clinicaloptions.com van Ramshorst MS, et al. ASCO 2017. Abstract 507. Reproduced with permission.

TRAIN-2: Adverse Events Grade ≥ 3 AEs, % FEC-T + Pertuzumab (n = 220)* PTC + Pertuzumab (n = 218) P Value Grade 3 Grade 4 Hematologic Neutropenia Anemia Thrombocytopenia Febrile neutropenia 41 20 14 10 18 < 1 3 47 21 16 1 6 .34 .91 .71 < .0001 Nonhematologic AEs occurring in ≥ 5% of pts in either arm Diarrhea Peripheral neuropathy† Hypokalemia Fatigue Increased ALT 12 5 8 17 7 4 .14 .56 .02 .67 .49 AEs, adverse events; ALT, alanine aminotransferase; FEC-T, 5-fluorouracil/epirubicin/cyclophosphamide + trastuzumab; PTC, paclitaxel/trastuzumab/carboplatin. *Developed acute myeloid leukemia, n = 1. †Grade 2 neuropathy occurred in 25% of pts in FEC-T + pertuzumab arm vs 24% of pts in PTC + pertuzumab arm (P = .92). Slide credit: clinicaloptions.com van Ramshorst MS, et al. ASCO 2017. Abstract 507.

TRAIN-2: Cardiac Safety Cardiac Outcome FEC-T + Pertuzumab (n = 220) PTC + Pertuzumab (n = 218) P Value Ejection fraction decrease, % LVEF decrease ≥ 10% or LVEF < 50% LVEF decrease ≥ 10% and LVEF < 50% 29 5 17 3 .003 .32 Other grade ≥ 2 cardiac AEs, n Symptomatic LV systolic dysfunction Myocardial infarction Acute coronary syndrome Arrhythmias 2 1 FEC-T, 5-fluorouracil/epirubicin/cyclophosphamide + trastuzumab; LV, left ventricular; LVEF, left ventricular ejection fraction; PTC, paclitaxel/trastuzumab/carboplatin Slide credit: clinicaloptions.com van Ramshorst MS, et al. ASCO 2017. Abstract 507.

TRAIN-2: Conclusions In treatment-naive pts with stage II-III HER2+ EBC, efficacy of neoadjuvant anthracycline-containing vs anthracycline-free regimens with dual HER2 blockade comparable Study did not meet primary endpoint, but pCR rates high (67% to 68%) regardless of treatment arm Long-term follow-up needed to assess survival Febrile neutropenia, LVEF decline significantly reduced with anthracycline-free PTC regimen Study investigators conclude that anthracycline-free regimens may offer treatment alternatives for HER2+ EBC in neoadjuvant setting EBC, early breast cancer; LVEF, left ventricular ejection fraction; pCR, pathologic CR; PTC, paclitaxel/trastuzumab/carboplatin Slide credit: clinicaloptions.com van Ramshorst MS, et al. ASCO 2017. Abstract 507.

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