ASCENT-04: Analysis of efficacy by biomarker subgroups with sacituzumab govitecan (SG) + pembrolizumab (pembro) vs chemotherapy (chemo) + pembro in participants (pts) with previously untreated PD-L1+ metastatic triple-negative breast cancer (mTNBC).

1013 Background: In the phase 3 ASCENT-04/KEYNOTE-D19 study (NCT05382286) SG + pembro showed significant and clinically meaningful progression-free survival (PFS) improvement vs chemo + pembro in pts with previously untreated PD-L1+ mTNBC. SG + pembro exhibited a manageable safety profile consistent with prior studies for each agent. We present preplanned exploratory efficacy analyses in ASCENT-04 by biomarker subgroups. Methods: 443 pts received (1:1 ratio) SG + pembro in 21-day cycles or chemo (gemcitabine + carboplatin; taxane) + pembro. From centrally tested fresh or archival tumor samples, Trop-2 expression was determined by immunohistochemistry (IHC), tumor BRCA (tBRCA) status by whole exome sequencing, and HER2 expression by in situ hybridization (ISH) + IHC. Pts were grouped by Trop-2 expression quartiles, tBRCA status (wild-type [WT] or mutant [mut] in BRCA1/BRCA2 /both), and HER2 status (IHC 0 vs Low [IHC 1+ or IHC 2+/ISH–]). Biomarker subgroups were analyzed descriptively for association with PFS by blinded independent central review (BICR); other outcomes by biomarker status are forthcoming. Results: Median Trop-2 H-score was 280, ranges: quartile 1 (Q1) 0-224, Q2 225-279, Q3 280-298, Q4 299-300. SG + pembro demonstrated longer PFS by BICR in Q3/Q4 vs Q1/Q2, and benefit was observed for SG + pembro vs chemo + pembro in all quartiles (Table). Hazard ratios (HR; 95% confidence interval [CI]) were: Q1, 0.81 (0.48-1.36); Q2, 0.73 (0.44-1.22); Q3, 0.46 (0.27-0.80); Q4, 0.57 (0.33-0.99). Proportion of pts with tBRCA mutations (~20%) was similar between treatment groups. Longer PFS was observed with SG + pembro with HR (95% CI) of 0.67 (0.49-0.91) in the tBRCA WT and 0.88 (0.45-1.74) in the tBRCA mut subgroups. PFS was longer with SG + pembro vs chemo + pembro in the HER2 IHC 0 and HER2 low subgroups, HR (95% CI) 0.69 (0.46-1.04) and 0.67 (0.48-0.92), respectively. Conclusions: SG + pembro demonstrated longer PFS vs chemo + pembro across all Trop-2, tBRCA, and HER2 subgroups. These analyses strengthen support for the significant, clinically meaningful benefit of SG + pembro as first-line treatment for mTNBC across subgroups. Clinical trial information: NCT05382286 . Efficacy, BICR N Median PFS (95% CI), mo Biomarker Subgroup SG + pembro Chemo + pembro SG + pembro Chemo + pembro HR (95% CI) Trop-2(n = 400) Q1 48 47 9.3(7.4-19.4) 9.0(6.0-10.9) 0.81(0.48-1.36) Q2 50 50 9.6(7.3-16.7) 7.4(6.9-9.7) 0.73(0.44-1.22) Q3 55 50 13.5(9.3-NR) 8.4(5.6-10.8) 0.46(0.27-0.80) Q4 51 49 16.6(8.1-NR) 9.2(5.5-11.3) 0.57(0.33-0.99) tBRCA(n = 332) WT 130 131 9.6(7.6-16.7) 7.4(6.9-9.2) 0.67(0.49-0.91) Mut 39 32 16.6(7.5-NR) 12.9(7.1-NR) 0.88(0.45-1.74) HER2(n = 435) IHC 0 84 82 16.6(9.1-21.2) 9.0(7.2-10.8) 0.69(0.46-1.04) Low <jats