DESTINY-Breast08: A Phase Ib Study of Trastuzumab Deruxtecan in Combination with Other Anticancer Therapies in Patients with HER2-Low Metastatic Breast Cancer.

Abstract

Establish the safety, tolerability, and preliminary activity of trastuzumab deruxtecan (T-DXd) in combination with other anticancer therapies in human epidermal growth factor receptor 2 (HER2)-low metastatic breast cancer (mBC). DESTINY-Breast08 was a two-part, open-label, multicenter, phase Ib study. Patients with locally confirmed HER2-low mBC received T-DXd plus capecitabine, durvalumab + paclitaxel, capivasertib, anastrozole, or fulvestrant. Eligibility criteria for hormone receptor status varied across modules and between study parts. Primary objectives were safety/tolerability and determining recommended phase II doses (RP2D); secondary endpoints included objective response rate (ORR; per investigator). In the dose-finding phase, 37 patients were assigned to a module. RP2Ds were determined for T-DXd plus capecitabine, capivasertib, anastrozole, or fulvestrant. For strategic reasons, T-DXd + durvalumab + paclitaxel was not pursued beyond the dose-finding phase (n = 3). In the dose-expansion phase, 101 patients were assigned to a module. For T-DXd + capecitabine, grade ≥3 adverse events (AE) occurred in 55% (11/20) of patients, and the ORR was 60%. For T-DXd + capivasertib, grade ≥3 AEs occurred in 67.5% (27/40) of patients, and the ORR was 60%. For T-DXd + anastrozole, grade ≥3 AEs occurred in 47.6% (10/21) of patients, and the ORR was 71.4%. For T-DXd + fulvestrant, grade ≥3 AEs occurred in 55% (11/20) of patients, and the ORR was 40%. Adjudicated drug-related interstitial lung disease/pneumonitis events were reported for T-DXd + capecitabine (3/20; grade 2, n = 2; grade 5, n = 1), T-DXd + capivasertib (8/40; all grade ≤2), and T-DXd + fulvestrant (5/20; all grade 2). Safety results were generally consistent with known individual profiles for T-DXd and combination drugs. T-DXd plus capecitabine, capivasertib, anastrozole, or fulvestrant demonstrated preliminary clinical activity in patients with HER2-low mBC.