Alessandra Gennari, MD PhD SNAP A randomized phase II study evaluating three different schedules of nab-paclitaxel as maintenance therapy Alessandra Gennari, MD PhD S.C. Oncologia Medica E.O. Ospedali Galliera Genova

SNAP Background Longer first-line chemotherapy (CT) duration is associated with modest, but significant improvement in PFS and OS in MBC. Prolonging CT until progressive disease (PD) must be weighed against the detrimental effects of continuous delivery.

Why SNAP? SNAP seeks to improve the tolerability of prolonged CT administration strategy by studying alternative treatment schedules, while preserving treatment efficacy. SNAP randomized phase II trial evaluates 3 schedules of nab-Paclitaxel as prolonged CT administration strategy.

SNAP: Objectives Primary: To evaluate the efficacy of 3 different schedules of nab-paclitaxel, in terms of PFS, using the historical reference of PFS (7 mos.) of docetaxel for first-line MBC. Secondary: Tolerability, Feasibility, ORR, OS, QoL.

SNAP: Study Design A B C nab-Pac 150 mg/m2 days 1,15 nab-Paclitaxel RANDOM I ZE A nab-Pac 150 mg/m2 days 1,15 nab-Paclitaxel 150 or 125* mg/m2 days 1,8,15 3 cycles (28-day) B nab-Pac 100 mg/m2 days 1,8,15 C nab-Pac 75 mg/m2 Q8 *30 June 2014, induction dose reduced to 125 mg/m² after a planned safety review. Continue treatment until PD or unacceptable toxicity Tumor evaluations required every 3 mos.

SNAP: Objectives Primary: To evaluate the efficacy of 3 different schedules of nab-paclitaxel, in terms of PFS, using the historical reference of PFS (7 mos.) of docetaxel for first-line MBC. Secondary: Tolerability, Feasibility, ORR, OS, QoL.

SNAP Endpoints Primary endpoint Progression-free survival (PFS) Secondary endpoints Adverse events according to CTCAE v4 Feasibility: completing treatment according to the protocol for at least 24 weeks Disease control: stable disease for ≥24 weeks or confirmed overall partial response or complete response Overall survival Quality of life

SNAP Inclusion/Exclusion Criteria Inclusion Criteria Histologically/cytologically confirmed HER2-negative MBC Measurable/non-measurable, evaluable disease ECOG PS 0 or 1 ER-/ER+ (fail prior ET or candidates for 1st line CT) Prior adjuvant CT allowed, provided DFS >12 months Exclusion criteria Any prior CT for MBC, CNS metastasis, peripheral neuropathy grade 2 or higher (CTCAE version 4)

SNAP Statistical Considerations Sample Size Efficacy measured by PFS (from randomization to PD or death). 88% power to detect 3 months improvement using one- sided log-rank test vs. null of 7 mos. median PFS at alpha error of 0.05. Target accrual 258 Target events per arm 63 Analysis population 255 (2 pts did not start CT; 1 did not have metastatic breast cancer)

SNAP: Accrual Country/Group Enrollment IBCSG Belgium (3 centers) 33 Italy (8 centers) 40 Slovenia (1 center) 7 Switzerland (9 centers) 75 IBCSG Total 155 SOLTI Spain   SOLTI (5 centers) 42 ICORG Ireland ICORG (9 centers) 61 Total 258 SNAP enrolled 258 patients from April 2013 to August 2015.

Patient Characteristics nab-P Maintenance Dose 150 mg/m2 (n = 83) 100 mg/m2 (n = 86) 75 mg/m2 Age, median, years 58 55.5 60 Age > 70 years, % 11 14 16 ECOG PS 0, % 59 69 63 ER positive, % 87 80 Measurable disease, % 82 85 Visceral disease, % 64 77 76 Number of metastatic sites ≤ 3, % 89 83 81 Prior adjuvant chemotherapy, % 53 62 48 Prior taxanes, % 31 33 30 Prior endocrine therapy for MBC, % 36 35 38 Gennari A, et al. Poster at SABCS 2016 [abstract P5-15-05].

Induction Treatment Summary Starting Dose   150mg/m² 125mg/m² Analysis population (N=255) 122 133 Completed induction 108 119 Permanently discontinued during induction 14 Completed induction without dose adjustment 26 41 Dose adjustment/discontinuation due to toxicity 87 78 Dose adjustment/discontinuation not toxicity 9

Maintenance Treatment Summary   Arm A Arm B Arm C Entered maintenance phase (N=199) 66 72 61 Receiving maintenance treatment 5 8 3 Permanently discontinued maintenance 64 58 Dose adjustment/discont due to toxicity 42 41 Dose adjustment/discont not toxicity 24 28 20 Continuing without dose adjustments 2 Maintenance cycles received thus far Median (range)  Patients permanently discont 3 (1, 17) 4 (1, 18) 5 (1, 14) Patients receiving maintenance 13 (11,23) 15 (4,30) 15 (15, 28) All patients 3 (1, 23) 4 (1, 30) 5 (1, 28)

Adverse Events Induction Therapy AE, % nab-P 150 mg/m2 n = 122 nab-P 125 mg/m2 n = 133 Max AE grade 2 3 4 5 Peripheral sensory neuropathy 12 – 8 Decreased neutrophils 46 21 20 18 Decreased platelets 1 Febrile neutropenia Anemia 22 26 Nausea 7 Vomiting Diarrhea Other grade 3-5 adverse event 23 Patients experiencing ≥ 1 AE 98 93

Adverse Events Maintenance Phase AE, %a A n = 66 150 Q14 B n = 72 100 d 1,8,15 Q28 C n = 61 75 Q8 Max AE grade 2 3 4 Peripheral neuropathy 29 9 – 31 6 25 7 Decreased neutrophils 15 5 24 8 21 Febrile neutropenia 1 Anemia 18 10 Nausea Vomiting Diarrhea Patients’ maximum AE grade 40 44 28 41 Patients experiencing ≥ 1 AE 96 97 a Only reporting events grade ≥ 3. Gennari A, et al. Poster at SABCS 2016 [abstract P5-15-05].

nab-P Maintenance Dose SNAP Efficacy PFS Outcome nab-P Maintenance Dose 150 mg/m2 (n = 83) 100 mg/m2 (n = 86) 75 mg/m2 PFS, median (90% CI) 7.9 (6.8 - 8.4) 9.0 (8.1 - 10.9) 8.5 (6.7 - 9.5) P valuea 0.12 0.03 0.20 Feasibilityb, % 48.2 50.0 51.2 Disease control ratesc, % 65.1 68.6 60.5 At a median follow-up of 18.2 months, 182 PFS events occurred a Compared with the historical reference PFS. b Defined as percentage of patients who completed treatment according to the protocol for at ≥ 24 weeks. c Defined as SD ≥ 24 weeks or PR or CR. Gennari A, et al. Poster at SABCS 2016 [abstract P5-15-05].

Progression Free Survival

Progression Free Survival by ER status ER positive ER negative

Progression Free Survival by prior adjuvant taxanes Tax yes Tax no

SNAP Conclusions Alternative maintenance CT schedules with reduced doses after a short induction phase at conventional doses are feasible for first line treatment of MBC, and all resulted in a median PFS greater than the historical reference of 7.0 months One maintenance schedule, 100 mg/m2 on days 1, 8, 15a (Arm B), had significantly longer median PFS of 9.0 months The higher induction dose (150 mg/m2) was not tolerable No new safety signals were observed a Authors’ conclusions had “days 1, 8, and 12;” however, the study design had days 1, 8, and 15. Gennari A, et al. Poster at SABCS 2016 [abstract P5-15-05].