There is no uniform standard of care for HER2+ breast cancer (BC) after disease progression on T-DM1. [Fam-] trastuzumab deruxtecan (DS-8201a) is a novel HER2-targeted antibody-drug conjugate with a humanized HER2 antibody, topoisomerase I inhibitor payload, and cleavable peptide-based linker. In an ongoing phase 1 trial, [fam-] trastuzumab deruxtecan showed promising antitumor activity in T-DM1-pretreated HER2+ BC (confirmed objective response rate [ORR] of 54.5%; April 2018 data cutoff). The pivotal, phase 2 DESTINY-Breast01 trial in this population is ongoing.
This multicenter, open-label, phase 3 trial will assess efficacy and safety of [fam-] trastuzumab deruxtecan in subjects with HER2 + (IHC 3+ or IHC 2+/ISH+; confirmed by centralized testing) unresectable and/or metastatic BC whose disease progressed on or after T-DM1 (NCT03523585, DESTINY-Breast02). Approximately 600 subjects will be randomized (2:1) to [fam-] trastuzumab deruxtecan (5.4 mg/kg IV q3wk) or investigator’s choice (trastuzumab/capecitabine or lapatinib/capecitabine). Randomization is stratified by hormone receptor status, prior pertuzumab treatment, and history of visceral disease. The primary efficacy endpoint is progression free survival (PFS) based on blinded, independent central review using RECIST v1.1; overall survival (OS) is the key secondary endpoint. Other secondary efficacy endpoints are ORR, duration of response, clinical benefit rate, and PFS based on investigator assessment. Primary analysis for PFS will occur when approximately 372 PFS events are observed; providing 90% power to detect a hazard ratio of 0.70 in PFS (a 43% improvement in median PFS from 3.3 months with investigator’s choice to 4.7 months with [fam-] trastuzumab deruxtecan) with a 1-sided alpha of 0.025. An interim OS analysis is planned at the time of PFS analysis. Final OS analysis will occur when approximately 428 OS events have been observed. Long-term follow-up will continue after the primary analysis every 3 months until death, withdrawal of consent, loss to follow-up, or study closure. Efficacy analyses will include all randomized subjects, and safety analyses will include all subjects receiving ≥1 dose of study treatment.
Marie-Louise Ricketts, PhD; and Stefan Kolata, PhD, of AlphaBioCom, LLC.
NCT03523585; release date May 14, 2018.
Daiichi Sankyo, Inc., Basking Ridge, NJ, USA.
Daiichi Sankyo, Inc, Basking Ridge, NJ, USA.
F. André: Fees: Pfizer, Lilly, AstraZeneca. J. Shahidi, C. Lee, K. Wang: Salaried employee: Daiichi Sankyo, Inc. I. Krop: Consulting fees: Daiichi Sankyo, Inc.