Phase III Investigation of Neoadjuvant Carboplatin ± Veliparib in Combination With Chemotherapy in Early-Stage TNBC 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 TNBC, triple-negative breast cancer. This activity is supported by educational grants from AbbVie, Amgen, AstraZeneca, Celgene Corporation, Genentech, Halozyme, Incyte, and Merck & Co., Inc.

Neoadjuvant Chemotherapy + Carboplatin ± Veliparib for Early TNBC: Background Achieving pCR with neoadjuvant therapy correlates with improved EFS and OS in TNBC vs pts with residual disease[1] Veliparib: potent, orally available PARP 1/2 inhibitor Preclinical evidence for increasing chemotherapy antitumor activity[2] I-SPY2 pilot study suggested high probability for successful phase III trial of veliparib + carboplatin added to weekly T  AC as neoadjuvant therapy in TNBC[3] Current phase III study evaluated addition of carboplatin ± veliparib to neoadjuvant T  AC in early stage TNBC, with particular interest in veliparib contribution to increased pCR rate[4] AC, doxorubicin/cyclophosphamide; EFS, event-free survival; pCR, pathologic CR; T, paclitaxel; TNBC, triple-negative breast cancer. 1. Cortazar P, et al. Lancet. 2014;384:164-172. 2. Donowho CK, et al. Clin Cancer Res. 2007;13:2728-2737. 3. Rugo HS, et al. N Engl J Med. 2016;375:23-34. 4. Geyer CE, et al. ASCO 2017. Abstract 520. Slide credit: clinicaloptions.com

Neoadjuvant Chemotherapy + Carboplatin ± Veliparib for Early TNBC: Phase III Study Design Stratified by BRCA status (mut vs no mut vs unknown), node stage (N0 vs N1-2), AC schedule (Q2W vs Q3W) 12 weeks Veliparib + Carboplatin + Paclitaxel (n = 316) Previously untreated women with resectable stage II-IIIA TNBC with documented gBRCA testing (N = 634) Doxorubicin + Cyclophosphamide (4 cycles) Placebo + Carboplatin + Paclitaxel (n = 160) Surgery Placebo + Placebo + Paclitaxel (n = 158) Veliparib 50 mg PO BID; carboplatin AUC 6 mg/mL Q3W; paclitaxel 80 mg/m2 Q1W. AUC, area under the concentration curve; BCS, breast conserving surgery; EFS, event-free survival; gBRCA, germline BRCA; mut, mutation; MRD, minimal residual disease; pCR, pathologic CR; QoL, quality of life; TNBC, triple-negative breast cancer. Primary objectives: pCR in breast and ipsilateral axillary nodes (ypT0/Tis, pN0) Secondary objectives: conversion to BCS eligibility, EFS, OS, safety Tertiary objectives: clinical response rate at Wk 12, pCR + MRD, QoL Slide credit: clinicaloptions.com Geyer CE, et al. ASCO 2017. Abstract 520.

Veliparib + Carboplatin + T  AC Neoadjuvant Chemotherapy + Carboplatin ± Veliparib for Early TNBC: Pt Characteristics Characteristic Veliparib + Carboplatin + T  AC (n = 316) Carboplatin + T  AC (n = 160) T  AC (n = 158) Median age (range), yrs > 50 yrs, % 51.0 (26-79) 52.2 49.0 (23-76) 45.6 50.0 (22-75) 48.7 Deleterious gBRCA mutation, % 14.2 15.6 14.6 Tumor stage, % T1 T2 T3-T4a 11.7 72.5 15.8 12.5 66.9 20.6 9.5 74.1 16.5 Lymph node stage N0/N1-N2, % 57.0/43.0 57.5/42.5 59.5/40.5 Planned AC schedule Q2W/Q3W, % 54.7/44.3 55.0/43.8 56.3/43.7 Longest tumor diameter > 30 mm, % 54.1 55.6 50.0 AC, doxorubicin/cyclophosphamide; gBRCA, germline BRCA; T, paclitaxel; TNBC, triple-negative breast cancer. Slide credit: clinicaloptions.com Geyer CE, et al. ASCO 2017. Abstract 520.

Rate of Clinical Response Neoadjuvant Chemotherapy + Carboplatin ± Veliparib for Early TNBC: Efficacy pCR Rate of Intent for BCS P = .139 P < .001 100 100 P = .132 P = .357 75 75 Pts (%) 50 Pts (%) 50 25 25 53.2 57.5 31.0 61.6 44.1 44.1 V + Cb + T → AC (n = 316) Cb + T → AC (n = 160) T → AC (n = 158) V + Cb + T → AC (n = 73) Cb + T → AC (n = 34) T → AC (n = 34) Rate of Clinical Response Rate of MRD P < .001 P < .001 P = .961 100 100 P = .739 AC, doxorubicin/cyclophosphamide; BCS, breast conserving surgery; Cb, carboplatin; MRD, minimal residual disease; pCR, pathologic CR; T, paclitaxel; TNBC, triple-negative breast cancer; V, veliparib. 75 75 Pts (%) 50 Pts (%) 50 25 25 83.4 83.3 55.7 68.3 70.0 47.2 V + Cb + T → AC (n = 316) Cb + T → AC (n = 160) T → AC (n = 158) V + Cb + T → AC (n = 268) Cb + T → AC (n = 140) T → AC (n = 125) Slide credit: clinicaloptions.com Geyer CE, et al. ASCO 2017. Abstract 520. Reproduced with permission.

Neoadjuvant Chemotherapy + Carboplatin ± Veliparib for Early TNBC: pCR by Subgroup Favors Cb + T → AC Favors V + Cb + T → AC Favors T → AC Favors V + Cb + T → AC Risk Difference (95% CI) Risk Difference (95% CI) All Pts -4.34 (-13.8 to 5.1) All Pts 22.15 (13.1 to 31.2) BRCA1 and/or BRCA2 mutation 6.52 (-18.1 to 31.1) BRCA1 and/or BRCA2 mutation 15.61 (-9.4 to 40.7) No mutation in BRCA1 or BRCA2 -6.23 (-16.4 to 4.0) No mutation in BRCA1 or BRCA2 23.18 (13.5 to 32.9) N0 -1.15 (-13.7 to 11.4) N0 27.96 (15.8 to 40.2) Lymph node stage Lymph node stage N1-2 -8.39 (-22.5 to 5.7) N1-2 15.09 (1.7 to 28.5) AC, doxorubicin/cyclophosphamide; Cb, carboplatin; pCR, pathologic CR; T, paclitaxel; TNBC, triple-negative breast cancer; V, veliparib. Q2W -0.50 (-13.2 to 12.2) Q2W 25.00 (12.9 to 37.1) AC dose AC dose Q3W -9.15 (-23.3 to 5.0) Q3W 18.57 (4.9 to 32.2) -50 -40 -30 -20 -10 10 20 30 40 50 -50 -40 -30 -20 -10 10 20 30 40 50 Risk Difference (95% CI) Risk Difference (95% CI) Slide credit: clinicaloptions.com Geyer CE, et al. ASCO 2017. Abstract 520. Reproduced with permission.

Veliparib + Carboplatin + T  AC Neoadjuvant Chemotherapy + Carboplatin ± Veliparib for Early TNBC: TEAEs TEAE, % Veliparib + Carboplatin + T  AC (n = 313) Carboplatin + T  AC (n = 158) T  AC (n = 157) Any grade 3/4 85.9 84.8 45.2 Any serious 30.4 26.6 14.0 AE leading to discontinuation of Veliparib/placebo Carboplatin/placebo Paclitaxel 5.8 5.4 11.5 5.7 6.3 7.0 2.5 0.6 Fatal AE 0.3 Deaths, including non-tx related 2.9 AC, doxorubicin/cyclophosphamide; AE, adverse event; T, paclitaxel; TEAE, treatment-emergent adverse event; TNBC, triple-negative breast cancer; tx, treatment. Higher incidence of hematologic and gastrointestinal AEs with carboplatin No increase in sensory neuropathy seen with carboplatin Slide credit: clinicaloptions.com Geyer CE, et al. ASCO 2017. Abstract 520.

Veliparib + Carboplatin + Neoadjuvant Chemotherapy + Carboplatin ± Veliparib for Early TNBC: TEAEs TEAE in ≥ 10% of pts in any arm during T tx segment, % Veliparib + Carboplatin + T  AC (n = 313) Carboplatin + T  AC (n = 158) T  AC (n = 157) Any Grade Grade 3/4 Neutropenia 70.0 57.2 61.4 53.2 9.5 2.5 Anemia 61.0 24.6 69.6 17.1 10.8 Thrombocytopenia 47.9 10.5 37.3 6.3 Leukopenia 12.8 4.2 15.9 5.1 3.8 0.6 Nausea 60.4 1.3 62.0 28.7 Diarrhea 32.3 1.9 26.0 26.1 Vomiting 20.1 28.4 Stomatitis 19.5 14.6 Fatigue 51.8 52.6 42.7 Peripheral neuropathy 37.7 1.0 40.5 40.1 Myalgia 18.5 16.5 17.8 Arthralgia 10.2 10.1 Heme GI AC, doxorubicin/cyclophosphamide; GI, gastrointestinal; Heme, hematologic; T, paclitaxel; TEAE, treatment-emergent adverse event; TNBC, triple-negative breast cancer; tx, treatment. Other Geyer CE, et al. ASCO 2017. Abstract 520.

Neoadjuvant Chemotherapy + Carboplatin ± Veliparib for Early TNBC: Conclusions Veliparib + carboplatin + T  AC significantly increased pCR rate over T  AC alone (53.2% vs 31.0%; P < .0001) Addition of veliparib did not increase pCR rate over carboplatin + T  AC (53.2% vs 57.5%; P = .36) pCR improvement likely due to carboplatin, without additional benefit with veliparib Some toxicities, including hematologic and GI, increased with carboplatin addition Carboplatin use increased T dose reductions and administration time AC, doxorubicin/cyclophosphamide; GI, gastrointestinal; pCR, pathologic CR; T, paclitaxel; TEAE, treatment-emergent adverse event; TNBC, triple-negative breast cancer. Slide credit: clinicaloptions.com Geyer CE, et al. ASCO 2017. Abstract 520.

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