DESTINY-Breast08: a phase 1b study of trastuzumab deruxtecan in combination with other anticancer therapies in patients with HER2-low metastatic breast cancer

Abstract Purpose: 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). Experimental Design: DESTINY-Breast08 was a two-part, open-label, multicenter, phase 1b 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 2 doses (RP2Ds); secondary endpoints included objective response rate (ORR, per investigator). Results; 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 (G)≥3 adverse events (AEs) occurred in 55.0% (11/20) of patients; ORR: 60.0%. For T-DXd+capivasertib, G≥3 AEs occurred in 67.5% (27/40) of patients; ORR: 60.0%. For T-DXd+anastrozole, G≥3 AEs occurred in 47.6% (10/21) of patients; ORR: 71.4%. For T-DXd+fulvestrant, G≥3 AEs occurred in 55.0% (11/20) of patients; ORR: 40.0%. Adjudicated drug-related interstitial lung disease/pneumonitis events were reported for T-DXd+capecitabine (3/20; G2, n=2; G5, n=1), T-DXd+capivasertib (8/40; all G≤2), and T-DXd+fulvestrant (5/20; all G2). Conclusions: 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.