Randomized phase 2 trial of sacituzumab govitecan with or without pembrolizumab for metastatic HR-positive/HER2-negative breast cancer

Sacituzumab govitecan (SG), a TROP2-directed topoisomerase I-inhibitor (TOP1i) antibody-drug conjugate, is approved for chemo-refractory hormone receptor-positive HER2-negative metastatic breast cancer (HR+ HER2- mBC). The multicenter, randomized phase 2 SACI-IO HR+ trial evaluated addition of pembrolizumab to SG in this setting. Patients with HR+ HER2- mBC pretreated with endocrine therapy and 0-1 chemotherapy regimens for mBC (no prior TOP1i) were randomized 1:1 to receive SG plus pembrolizumab or SG alone. Primary endpoint was progression-free survival (PFS). A total of 104 patients started treatment; 47% had not received chemotherapy for mBC. At 15.5-month median follow-up, SG+pembrolizumab did not significantly improve PFS compared to SG (8.4 versus 6.7 months; p=0.12); median overall survival (OS) was 20.0 versus 18.0 months (p=0.18); objective response rate (ORR) was 28.8% versus 19.2% (p=0.36). In the PD-L1 positive population (pharmDx 22C3 CPS ≥ 1; 44%), median PFS (11.1 versus 5.6 months; HR 0.51; p=0.09) and OS (18.5 versus 12.5 months; HR 0.59; p=0.39) numerically increased with the combination. Most frequent grade ≥2 adverse events were neutropenia, alopecia, fatigue, anemia, nausea, leukopenia, and diarrhea. The authors conclude that addition of pembrolizumab to SG did not significantly improve outcomes among unselected HR+ HER2- mBC. In the PD-L1-positive population, the trend in PFS and OS favoring SG plus pembrolizumab warrants further investigation in larger randomized trials.