Dr Tolaney on SG + Pembrolizumab Biomarker Data in First-Line mTNBC

Sara Tolaney, MD, MPH, Dana-Farber Cancer Institute, discusses findings from the phase 3 ASCENT-04/KEYNOTE-D19 study, evaluating the combination of sacituzumab govitecan (SG; Trodelvy) and pembrolizumab (Keytruda) against standard chemotherapy plus pembrolizumab. The trial focused on patients with previously untreated, PD-L1–positive metastatic triple-negative breast cancer (mTNBC). Specifically, this exploratory analysis investigated whether the efficacy of the SG combination varied based on specific tumor biomarkers: Trop-2 expression levels, tumor BRCA mutation status, and HER2 expression levels.

Out of 443 randomized patients, the researchers looked closely at how progression-free survival (PFS)—assessed by blinded independent central review—aligned with these biomarkers:

• Trop-2 Expression: While a stronger PFS benefit was noted in patients with higher Trop-2 expression (Quartiles 3 and 4, with hazard ratios of 0.46 and 0.57 respectively), the SG plus pembro combination outperformed the chemotherapy control group across all 4 quartiles.
• BRCA Status: The combination group achieved longer PFS compared to chemotherapy regardless of genetic status. The benefit was statistically clearer in the BRCA wild-type (nonmutated) subgroup (HR, 0.67), but also extended to the BRCA-mutant subgroup (HR, 0.88), which experienced a median PFS of 16.6 months compared with 12.9 months with chemotherapy.
• HER2 Status: PFS favored the SG plus pembrolizuamb cohort in both HER2 IHC 0 (HR, 0.69) and HER2-low (HR, 0.67) subgroups, with the IHC 0 group reaching a median PFS of 16.6 months.

Ultimately, the authors concluded that first-line treatment with sacituzumab govitecan plus pembrolizumab provides a broad, clinically meaningful survival advantage over standard chemotherapy. Because this benefit persists across all examined Trop-2, BRCA, and HER2 biomarker subgroups, these findings solidify the combination as a robust first-line therapeutic option for patients navigating PD-L1–positive mTNBC.