Istituto Oncologico Veneto IRCCS tnAcity trial: Nab-paclitaxel in combination with gemcitabine or carboplatin vs gemcitabine/carboplatin as first lile treatment in TNMBC Maria Vittoria Dieci Department of Surgery, Oncology and Gastroenterology – University of Padova Istituto Oncologico Veneto IRCCS

Rationale mTNBC has a poor prognosis and an aggressive clinical course Although there is no standard of care for mTNBC, chemotherapy (including taxane-based regimens) is recommended by the NCCN nab-P has demonstrated greater efficacy and favorable safety vs paclitaxel in a phase III trial of metastatic breast cancer1 nab-P–based regimens have also shown activity as first-line treatment of mTNBC in phase II trials2-4 nab-P in combination with carbo and bevacizumab resulted in an ORR of 85% and a median PFS of 9.2 months3 nab-P in combination with Gem resulted in an ORR of 77%4 tnAcity is a phase II/III study designed to evaluate the efficacy and safety of nab-P doublet chemotherapy regimens in mTNBC (NCT01881230) 1. Gradishar WJ, et al. J Clin Oncol. 2005;23:7794-7803. 2. Lobo C, et al. Breast Cancer Res Treat. 2010;123:427-435. 3. Hamilton E, et al. Clin Breast Cancer. 2013;13:416-420. 4. Roy V, et al. Ann Oncol. 2009;20:449-453.

tnAcity - Study Design N = 730 subjects (Phase 2 = 180 (240) ; Phase 3 = 550), 150 sites First Line TNMBC nab-Paclitaxel + Gemcitabine N = 60 Gemcitabine + Carboplatin RANDOMIZE nab-Paclitaxel arm selected by combination of efficacy + safety Winner of the 2 nab-Paclitaxel arms N = 275 Phase 2 Phase 3 End Points Primary – PFS (central) Secondary – ORR, OS, DCR, DOR, Safety Stratification Disease free interval ≤ 1 year vs > 1 year Prior taxane neo/adjuvant therapy (Ph 3 only) End Points Primary – PFS (investigator) Secondary – ORR, % of patients initiating cycle 6, OS, Safety Abraxane 125mg/m2, Gemcitabine 1000mg/m2 D1,8 q21d Carboplatin AUC2 Due to the changing treatment landscape, this study was stopped after the phase 2 portion was concluded Ph2 Patients will not be included in Ph3 analysis

ABI-007-MBC-001 nab®-Paclitaxel + Carboplatin or Gemcitabine vs Gemcitabine + Carboplatin as First-Line Treatment for Patients With Triple-Negative Metastatic Breast Cancer: Results From the Randomized Phase II Portion of the tnAcity Trial Yardley D, Coleman R, Conte P, Cortes J, Brufsky A, Shtivelband M, Young R, Bengala C, Ali H, Eakel J, Schneeweiss A, de la Cruz Merino L, Wilks S, O’Shaughnessy J, Glück S, Li H, Beck R, Barton D, Harbeck N, on behalf of the tnAcity investigators Yardley D et al, Poster at SABCS 2016 [abstract 874].

Objective To report the phase II portion of the tnAcity trial, which evaluated the safety and efficacy of 3 common chemotherapy regimens as first-line treatment for patients with mTNBC.

Endpoints - Phase 2 Primary Endpoint: Secondary Endpoints: PFS (investigator assessment of response -RECIST 1.1) Secondary Endpoints: Efficacy ORR, investigator-determined, Percentage of subjects who initiated Cycle 6 OS Safety Incidence/Grade of treatment-emergent adverse events (TEAEs), SAEs, laboratory abnormalities Incidence of subjects experiencing dose modifications (dose interruptions and reductions) Percentage of subjects who discontinued for adverse event Biomarkers: Tumor sample (paraffin block and/or slides) will be collected to evaluate molecular profiles (protein, tumor cell mutations and gene expression) and identify potential predictive markers of clinical response and to determine possible correlation with efficacy outcomes. The most recently obtained tumor sample will be submitted for receptor/biomarker assessment . Blood samples will be collected at the beginning of cycle 1 and of cycle 3 to assess treatment efficacy vs. subject pharmacogenomic characteristics, tumor DNA and miRNA characteristics, and tumor-derived exosome characteristics. Exploratory analysis of CTCs will be performed to assess any significant correlation of CTC levels with relevant clinical benefits. Sample collection for this exploratory analysis may be limited to selected clinical centers.

Key Inclusion Criteria Female, age ≥ 18 years, no prior chemotherapy for metastatic disease Prior use of neo/adjuvant anthracycline or medically unfit for anthracycline use. Pathologically confirmed TNMBC as per ASCO guidelines ECOG 0-1 Measurable disease (RECIST 1.1) Bone cannot be the only site of metastatic disease No brain metastasis Adequate hematology and organ function Prior immunotherapy/MAB therapy, or neo/adjuvant chemo/RT acceptable Prior treatments must have been discontinued ≥ 30 d prior to start of study Toxicities must have resolved to ≤ Grade 1. Prior RT must have completed ≥ 2 w before randomization, with full recovery. Target lesions must be outside radiation portal or there must be unequivocal progressive disease within the radiation portal

Exclusion Criteria Male patients with breast cancer Concurrent chemotherapy or any other antitumor therapy for BC History of or known current evidence of brain metastasis Patients with bone as the only site of metastatic disease History of other primary malignancy in the last 5 years Baseline peripheral neuropathy grade ≥ 2 by NCI CTCAE v4.0

Statistical plan An algorithm ranking 5 key efficacy and safety endpoint parameters was used to identify the «winning» nab-P experimental arm based on the rank sum of: - HR of PFS (nab-P/G vs nab-P/C) - ratio of ORR - percentage of patients initiating cycle 6 receiving a doublet - percentage of patients with myelosuppression-related events - percentage of patients who discontinued from all study treatment due to Aes PFS and ORR carried twice the weight as the remaining 3 endpoints

tnAcity: Baseline Characteristics Characteristic (N = 191 in Phase II) nab-P/C (n = 64) nab-P/G (n = 61) G/C (n = 66) Age, median (min - max), years < 65, n (%) 55 (27 - 82) 48 (75) 53 (27 - 80) 43 (71) 59 (30 - 79) 49 (74) ECOG PS, n (%)a 1 38 (59) 26 (41) 34 (56) 25 (41) 42 (64) 22 (33) Race, n (%) White Black or African American Not collected or reported 55 (86) 6 (9) 3 (5) 50 (82) 9 (15) 2 (3) 54 (82) 8 (12) 4 (6) Region, n (%) North America Western Europe South America Australia 31 (48) 24 (38) 9 (14) 29 (48) 26 (43) 6 (10) 31 (47) 30 (46) 1 (2) Yardley D et al, Poster at SABCS 2016 [abstract 874].

tnAcity: Baseline Characteristics 2 Characteristic (N = 191 in Phase II) nab-P/C (n = 64) nab-P/G (n = 61) G/C (n = 66) Disease-free interval, n (%) ≤ 1 year > 1 year Missing 17 (27) 47 (73) 17 (28) 43 (71) 1 (2) 20 (30) 45 (68) Triple negative at primary diagnosis, n (%) 53 (83) 51 (84) 48 (73) Site of metastasis, n (%) Lymph node(s) Lung/thoracic Bone Liver 50 (78) 42 (66) 20 (31) 16 (25) 38 (62) 42 (69) 23 (38) 51 (77) 41 (62) 24 (36) 23 (35) Prior neoadjuvant/adjuvant therapy, n (%) Anthracyclinesa Taxanes 43 (67) 36 (56) 37 (61) 41 (67) 42 (64) Yardley D et al, Poster at SABCS 2016 [abstract 874].

tnAcity Phase II: PFS (Primary End-point) nab-P/C nab-P/G G/C Median PFS, months 7.4 5.4 6.0 HR (95% CI) P value – 0.60 (0.39 - 0.93) 0.02a 0.61 (0.39 - 0.94) 0.03a 12-month PFS rate, % 27 13 11 a Compared with nab-P/C. Yardley D et al, Poster at SABCS 2016 [abstract 874].

tnAcity Phase II: Overall Survival nab-P/C nab-P/G G/C Median OS, months 16.4 12.1 12.6 HR (95% CI) P value – 0.66 (0.42 - 1.04) 0.07a 0.74 (0.48 - 1.16) 0.18a a Compared with nab-P/C. Yardley D et al, Poster at SABCS 2016 [abstract 874].

tnAcity Phase II: Response Rates Response, n (%) nab-P/C n = 64 nab-P/G n = 61 G/C n = 66 ORR CR PR 46 (72) 7 (11) 39 (61) 24 (39) 5 (8) 19 (31) 29 (44) 24 (36) SD >16 weeks 14 (22) 27 (44) 21 (32) Yardley D et al, Poster at SABCS 2016 [abstract 874].

tnAcity Phase II - Safety Selected Grade ≥ 3 TEAEs Yardley D et al, Poster at SABCS 2016 [abstract 874].

tnAcity Phase II – Ranking Algorithm Safety and Efficacy Endpoints nab-P/C nab-P/G Value Rank HR of PFS (nab-P/G/nab-P/C) — 2 1.68 ORR ratio (nab-P/G/nab-P/C) 0.55 Patients initiating cycle 6 with a doublet, % 64 1 56 Patients with myelosuppression-related events, %b 53 42 Patients discontinuing all study treatment due to AEs, % 27 22 Rank sum 5 Rank sum of the algorithm for key efficacy and safety endpoints favored nab-P/C Yardley D et al, Poster at SABCS 2016 [abstract 874].

tnAcity Phase II - Conclusions nab-P/C demonstrated a significantly longer PFS and a better risk-benefit profile than nab-P/G or G/C as first-line treatment of patients with mTNBC Treatment duration and exposure were greater with nab-P/C than with nab-P/G or G/C The combination of nab-P/C is active in mTNBC and may be considered a therapeutic option in this patient population Due to the evolving landscape including ongoing phase III trials with immunotherapy and other novel agents, this trial is not progressing to phase III. However, nab-P is being used as a backbone chemotherapy with novel agents in both mTNBC and the neoadjuvant setting (NCT02425891, NCT02685059, NCT02620280)