Phase III study of [fam-] trastuzumab deruxtecan (DS-8201a) vs T-DM1 for HER2-positive breast cancer

Background: [Fam-] trastuzumab deruxtecan (DS-8201a) is a novel HER2-targeted antibody-drug conjugate (ADC) with a humanized HER2 antibody, topoisomerase I inhibitor payload, and cleavable peptide-based linker. In an ongoing phase 1 trial, [fam-] trastuzumab deruxtecan had a manageable safety profile and promising antitumor activity in HER2+ breast cancer (BC) previously treated with T-DM1 (confirmed objective response rate (ORR) of 54.5%; April 2018 data cutoff). The pivotal, phase 2 DESTINY-Breast01 trial in this population is ongoing. Trial design: This multicenter, open-label, phase 3 trial will assess the efficacy and safety of [fam-] trastuzumab deruxtecan vs T-DM1 in subjects with HER2 + (IHC 3+ or IHC 2+/ISH+; confirmed by centralized testing) unresectable and/or metastatic BC previously treated with trastuzumab and a taxane (NCT03529110, DESTINY-Breast03). Subjects who previously received a HER2-targeted ADC are excluded. Approximately 500 eligible subjects will be randomized (1:1) to receive [fam-] trastuzumab deruxtecan (5.4 mg/kg) or T-DM1 (3.6 mg/kg) IV once every 3 weeks. Randomization will be stratified by hormone receptor status, prior pertuzumab treatment, and history of visceral disease. For subjects randomized to T-DM1, treatment will be in accordance with the approved label. The primary efficacy endpoint is progression-free survival (PFS) based on blinded, independent central review using RECIST v1.1 criteria. Secondary efficacy endpoints include overall survival (OS), ORR, duration of response, clinical benefit rate, and PFS based on investigator assessment. Safety and health-related quality of life will also be assessed. The primary analysis for PFS will be performed when approximately 331 PFS events are observed. This will provide 90% power to detect a hazard ratio of 0.70 for PFS with a 1-sided alpha of 0.025, assuming a median PFS with T-DM1 of 9.6 months and that PFS follows an exponential distribution. 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 randomized subjects receiving ≥1 dose of study treatment. Editorial acknowledgement: Marie-Louise Ricketts, PhD; and Stefan Kolata, PhD of AlphaBioCom, LLC. Clinical trial identification: NCT03529110; release date May 18, 2018. Legal entity responsible for the study: Daiichi Sankyo, Inc., Basking Ridge, NJ, USA. Funding: Daiichi Sankyo, Inc., Basking Ridge, NJ, USA. Disclosure: S. Verma: Consulting fees: Amgen, AstraZeneca, Eli Lilly, Novartis, Daiichi Sankyo, Roche, Seattle Genetics. J. Shahidi, C. Lee, K. Wang: Salaried employee: Daiichi Sankyo, Inc. J. Cortes: Consulting fees: Roche, Celgene, AstraZeneca, Cellestia Biotech, Biothera, Merus, Seattle Genetics; Fees for non-CME services: Roche, Novartis, Eisai, Celgene, Pfizer.