Abstract S5-05: Trastuzumab emtansine improves overall survival versus treatment of physician's choice in patients with previously treated HER2-positive metastatic breast cancer: Final overall survival results from the phase 3 TH3RESA study
Authors: H Wildiers, S-B Kim, A Gonzalez-Martin, PM LoRusso, J-M Ferrero, R Yu, M Smitt, I Krop
Journal: Cancer Research (2016)

Abstract Introduction The phase 3, randomized, open-label, TH3RESA study (BO25734/TDM4997g; NCT01419197) compared trastuzumab emtansine (T-DM1) with treatment of physician's choice (TPC) in patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC), previously treated with a taxane (any setting), and both trastuzumab and lapatinib (advanced setting). Progression-free survival (PFS) and overall survival (OS) were co-primary endpoints. Results of the primary PFS analysis and the first interim OS analysis showed significantly improved PFS with T-DM1 compared with TPC and a trend for improved OS, although the stopping boundary was not reached (Krop IE, et al. Lancet Oncol 2014). The incidence of grade ≥3 adverse events (AEs) was lower with T-DM1 vs TPC (32% vs 43%). Here we report the results from the second interim analysis of OS from TH3RESA, which will serve as the final OS results. Methods Eligible patients were randomized 2:1 to receive T-DM1 (3.6 mg/kg IV every 3 weeks) or TPC. The pre-specified OS efficacy stopping boundary was an observed hazard ratio (HR) &amp;lt;0.75 or p&amp;lt;0.012. Crossover from TPC to T-DM1 following progressive disease was allowed from Sept 2012 onward. Results From Sept 14, 2011 to Nov 19, 2012, 602 patients were randomized to T-DM1 (n=404) or TPC (n=198). TPC comprised HER2-directed regimens (83%) and single-agent chemotherapy (17%). At the data cutoff for this analysis (Feb 13, 2015), 93 patients (47%) had crossed over from TPC to T-DM1. At a median follow-up time of 30.5 months, OS was significantly longer with T-DM1 vs TPC (median OS 22.7 vs 15.8 months; HR=0.68 [95% CI, 0.54–0.85; p=0.0007]) and these results crossed the OS efficacy stopping boundary. A sensitivity analysis, in which patients were censored when they switched from TPC to T-DM1, also showed an OS benefit with T-DM1 vs TPC (median 22.7 vs 15.6 months; HR=0.58 [95% CI: 0.43–0.77; p=0.0002]). The OS benefit was consistently observed across subgroups defined by age, visceral involvement, hormone receptor status, number of prior regimens, and TPC type. The T-DM1 group had nearly twice the mean exposure to the planned study treatment as the TPC group (7.93 vs 4.08 months). In treated patients, the incidence of grade ≥3 AEs was 40.0% and 47.3% in the T-DM1 and TPC arms, respectively. Grade ≥3 AEs occurring in ≥3% of either treatment arm were neutropenia (T-DM1, 2.5%; TPC, 15.8%), febrile neutropenia (T-DM1, 0.2%; TPC, 3.8%), thrombocytopenia (T-DM1, 6.0%; TPC, 2.7%), anemia (T-DM1, 3.5%; TPC, 3.3%), dyspnea (T-DM1, 2.5%; TPC, 3.8%), diarrhea (T-DM1, 0.7%; TPC, 4.3%), and asthenia (T-DM1, 1.0%; TPC, 3.3%). Conclusions In this population of patients with advanced breast cancer who previously received a taxane, trastuzumab, and lapatinib, treatment with T-DM1 resulted in a statistically significant and clinically meaningful improvement in OS compared with TPC. A lower incidence of grade ≥3 AEs was observed with T-DM1 and its safety profile was consistent with previous studies. These data further solidify the role of T-DM1 in the treatment of previously treated HER2-positive advanced breast cancer. Citation Format: Wildiers H, Kim S-B, Gonzalez-Martin A, LoRusso PM, Ferrero J-M, Yu R, Smitt M, Krop I. Trastuzumab emtansine improves overall survival versus treatment of physician's choice in patients with previously treated HER2-positive metastatic breast cancer: Final overall survival results from the phase 3 TH3RESA study. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr S5-05.