Antibody-drug conjugate plus immunotherapy versus chemotherapy-immunotherapy in PD-L1–positive metastatic triple-negative breast cancer: A trial-anchored analysis.

Abstract

e13122 Background: Pembrolizumab plus chemotherapy is an established first-line for unresectable locally advanced or metastatic triple-negative breast cancer (TNBC) with PD-L1 CPS ≥10. Antibody-drug conjugates (ADCs) have demonstrated activity in metastatic TNBC, and recent phase III data support ADC-immunotherapy in the frontline. However, comparative efficacy and tolerability versus chemotherapy-immunotherapy in PD-L1-positive disease remain undefined. We performed a trial-anchored synthesis in the PD-L1 CPS ≥10 population. Methods: We conducted a synthesis of phase II-III randomized trials in unresectable locally advanced or metastatic TNBC. The primary analysis population was PD-L1 CPS ≥10. Outcomes included progression-free survival (PFS), objective response rate (ORR), duration of response (DoR), and treatment discontinuation due to adverse events (AEs). Given a single randomized head-to-head trial and heterogeneity in PD-L1 assays, a pooled meta-analysis was not performed. Results were synthesized using a trial-anchored framework, with exploratory indirect estimates generated for contextualization. Results: In ASCENT-04/KEYNOTE-D19 (N = 443; PD-L1 CPS ≥10), sacituzumab govitecan plus pembrolizumab improved PFS versus chemotherapy plus pembrolizumab (median 11.2 vs 7.8 months; HR 0.65, 95% CI 0.51 - 0.84), with higher ORR (60% vs 53%) and longer DoR (16.5 vs 9.2 months). Treatment discontinuation due to AEs was lower with ADC-immunotherapy (12% vs 31%). In KEYNOTE-355 (PD-L1 CPS ≥10), pembrolizumab plus chemotherapy improved PFS versus chemotherapy alone (HR 0.65, 95% CI 0.49 - 0.86). An exploratory indirect comparison showed a PFS HR of 0.42 (95% CI 0.29 - 0.62) for ADC + immunotherapy versus chemotherapy alone. Conclusions: In PD-L1 CPS ≥10 metastatic TNBC, an exploratory indirect comparison suggests that ADC plus immunotherapy may substantially improve progression-free survival versus chemotherapy alone, supporting ADC-immunotherapy as a first-line option. Frontline outcomes in PD-L1 CPS ≥10 metastatic TNBC (ASCENT-04/KEYNOTE-D19). Outcome SG plus Pembrolizumab Chemo plus Pembrolizumab Absolute Difference Clinical Interpretation Median PFS (months) 11.2 7.8 +3.4 Longer disease control Objective response rate (%) 60 53 +7 Higher response likelihood Median duration of response (months) 16.5 9.2 +7.3 More durable responses Discontinuation due to AEs (%) 12 31 −19 Improved tolerability Approximate NNT (discontinuation) — — ~5 One discontinuation prevented per ~5 treated Abbreviations: SG, sacituzumab govitecan; PD-L1, programmed death-ligand 1; CPS, combined positive score; PFS, progression-free survival; ORR, objective response rate; DoR, duration of response; HR, hazard ratio; AEs, adverse events; NNT, number needed to treat.