SACI-IO HR+: A randomized phase II trial of sacituzumab govitecan with or without pembrolizumab in patients with metastatic hormone receptor-positive/HER2-negative breast cancer

Background Sacituzumab govitecan (SG), a TROP2-directed topoisomerase I-inhibitor (TOP1i) antibody-drug conjugate, is approved for chemo-refractory hormone receptor-positive/HER2-negative (HR+/HER2-) metastatic breast cancer (MBC). To evaluate if pembrolizumab (PD-1 inhibitor) enhances the activity of SG, we conducted a randomized phase II study comparing SG with or without pembrolizumab in HR+/HER2- MBC. Methods 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+pembrolizumab or SG. Primary endpoint was progression-free survival (PFS). Key secondary endpoints included PFS in the PD-L1-positive population (pharmDx 22C3 CPS ≥1), overall survival (OS), objective response rate (ORR), and toxicity. Baseline tumor tissue and plasma samples were collected for correlative analyses. Results Between 03/2021-01/2024, 104 patients started treatment; 47% (49) 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 vs 6.7 months; HR 0.76, 95% CI 0.48-1.19, p=0.12). Median OS was 20.0 vs 18.0 months (p=0.18); ORR was 28.8% vs 19.2% (p=0.36). In the PD-L1-positive population (44%; 39/88 with tissue), median PFS (11.1 vs 5.6 months; HR 0.51, 95% CI 0.24-1.12, p=0.09) and OS (18.5 vs 12.5 months; HR 0.59, 95% CI 0.18-1.98, p=0.39) numerically increased with the combination. Most frequent grade ≥2 adverse events were neutropenia, alopecia, fatigue, anemia, nausea, leukopenia, and diarrhea. Neither TROP2 expression by immunohistochemistry, immunofluorescence, or plasma epigenome-based analysis, or tumor-infiltrating lymphocytes were associated with outcomes. Higher ctDNA fraction and PIK3CA mutations were associated with worse PFS. Plasma epigenome-pathway analysis suggested that high cell-cycle or EMT activation may confer sensitivity or resistance to SG, respectively. Conclusion Addition of pembrolizumab to SG did not significantly improve outcomes in HR+/HER2- MBC unselected by PD-L1. In the PD-L1-positive population, the trend in PFS and OS favoring SG+pembrolizumab warrants further investigation in larger randomized trials.