Final analysis of the biomarker-directed, randomized, phase 2 KEYNOTE-495/KeyImPaCT study of pembrolizumab (P)–based combination therapy for non–small cell lung cancer (NSCLC).

Abstract

8584 Background: KEYNOTE-495/KeyImPaCT (NCT03516981) evaluated 3 P-based regimens in participants (pts) with advanced NSCLC across 4 prospectively defined biomarker subgroups based on T-cell–inflamed gene expression profile (Tcell inf GEP) and tumor mutational burden (TMB). In interim analysis, ORR with P + lenvatinib (L) in the Tcell inf GEP non-low TMB high subgroup met the prespecified efficacy threshold. We report final analysis results. Methods: Pts with previously untreated NSCLC were assessed for Tcell inf GEP (non-low, ≥−0.16; low, <−0.16) and TMB (high, ≥5 mut/Mb; non-high, <5 mut/Mb; ≈175 mut/exome by WES and 10 mut/Mb on FoundationOne CDx). Pts were assigned to 1 of 4 subgroups (Tcell inf GEP low TMB non-high , Tcell inf GEP low TMB high , Tcell inf GEP non-low TMB non-high , and Tcell inf GEP non-low TMB high ) and adaptively randomized 1:1:1 to P (200 mg IV Q3W) + either L (20 mg PO QD), quavonlimab (Q; 25 mg IV Q6W), or favezelimab (F; 200 mg or 800 mg IV Q3W). The primary end point was ORR per RECIST v1.1 by investigator. Secondary end points included PFS, OS, and safety. Data cutoff: July 30, 2025. Results: 243 pts were treated (P + L, 80; P + Q, 82; P + F 200 mg, 30; P + F 800 mg, 51). Median follow-up was 66.5 mo (range, 43.0-81.2). The Tcell inf GEP non-low TMB non-high subgroup treated with P + L met the prespecified efficacy threshold (≥95% posterior probability of true ORR >20%); PFS and OS were generally consistent with anticipated results among biomarker-defined subgroups (Table). Safety profile of each combination was consistent with the known profiles of each therapy. Conclusions: With longer follow-up, OS benefit was comparable across the 4 biomarker subgroups for the 3 combination therapies, with no new safety signals. These data continue to show the feasibility of prospective biomarker assessment to evaluate P-based therapies in advanced NSCLC. Clinical trial information: NCT03516981 . Tcell inf GEP low TMB non-high Tcell inf GEP low TMB high Tcell inf GEP non-low TMB non-high Tcell inf GEP non-low TMB high ORR, % (95% CI)  P + LP + QP + F 200 mgP + F 800 mg 12.0 (2.5-31.2)11.5 (2.4-30.2)0.0 (0.0-28.5)27.3 (6.0-61.0) 33.3 (9.9-65.1)30.8 (9.1-61.4)33.3 (4.3-77.7)13.6 (2.9-34.9) 40.9 (20.7-63.6)13.6 (2.9-34.9)25.0 (3.2-65.1)- 57.1 (34.0-78.2)52.4 (29.8-74.3)60.0 (14.7-94.7)50.0 (26.0-74.0) Median (95% CI) PFS, mo  P + LP + QP + F 200 mgP+ F 800 mg 5.4 (2.3-8.8)2.8 (2.0-6.0)2.1 (1.9-2.1)4.2 (1.8-12.2) 13.8 (1.5-19.4)3.9 (1.9-17.3)8.1 (1.7-NR)3.5 (2.0-8.2) 8.2 (4.2-19.7)6.1 (2.1-12.8)2.1 (0.9-6.5)- 17.8 (6.0-20.7)17.0 (9.3-29.1)6.3 (0.4-NR)20.2 (6.1-NR) Median ( OS, mo  P + LP + QP + F 200 mgP + F 800 mg 16.0 (5.4-20.2)13.3 (8.4-20.0)8.6 (3.8-35.4)18.6 (3.4-41.2) 16.9 (3.8-33.2)20.1 (7.7-NR)20.8 (1.7-NR)11.1 (5.2-19.6) 22.5 (12.0-41.3)23.7 (7.9-43.1)12.6 (0.9-25.4)- 22.7 (16.9-56.0)51.6 (17.6-NR)NR (13.5-NR)NR (13.0-NR) -, no pts enrolled. NR = not reached.