CELL INTELLIGENCE · 肿瘤细胞治疗研究

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.