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 chemorefractory hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC). To evaluate if pembrolizumab (programmed cell death protein 1 inhibitor) enhances the activity of SG, we conducted a randomized phase II study comparing SG with or without pembrolizumab in HR-positive/HER2-negative MBC.

MATERIALS AND

METHODS

Patients with HR-positive/HER2-negative MBC pretreated with endocrine therapy and 0-1 chemotherapy regimens for MBC (no prior TOP1i) were randomly assigned 1:1 to receive SG plus pembrolizumab or SG. Primary endpoint was progression-free survival (PFS). Key secondary endpoints included PFS in the programmed death-ligand 1 (PD-L1)-positive population (pharmDx 22C3 combined positive score ≥1), overall survival (OS), objective response rate (ORR), and toxicity. Baseline tumor tissue and plasma samples were collected for correlative analyses.

RESULTS

Between March 2021 and January 2024, 104 patients started treatment; 47% (49) had not received chemotherapy for MBC. At 15.5-month median follow-up, SG plus pembrolizumab did not significantly improve PFS compared with SG [8.4 versus 6.7 months; hazard ratio (HzR) 0.76, 95% confidence interval (CI) 0.48-1.19, P = 0.12]. Median OS was 20.0 versus 18.0 months (P = 0.18); ORR was 28.8% versus 19.2% (P = 0.36). In the PD-L1-positive population (44%; 39/88 with tissue), median PFS (11.1 versus 5.6 months; HzR 0.51, 95% CI 0.24-1.12, P = 0.09) and OS (18.5 versus 12.5 months; HzR 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 circulating tumor DNA fraction and PIK3CA mutations were associated with worse PFS. Plasma epigenome-pathway analysis suggested that high cell cycle or epithelial-mesenchymal transition activation may confer sensitivity or resistance to SG, respectively.

CONCLUSION

Addition of pembrolizumab to SG did not significantly improve outcomes in HR-positive/HER2-negative MBC unselected by PD-L1. In the PD-L1-positive population, the trend in PFS and OS favoring SG plus pembrolizumab warrants further investigation in larger randomized trials.