First-line (1L) olomorasib + pembrolizumab in patients with <i>KRAS</i> G12C–mutant advanced NSCLC, and PD-L1 expression 0-49%, from the dose optimization cohorts of LOXO-RAS-20001 and SUNRAY-01.

Abstract

8628 Background: For patients (pts) with 1L KRAS G12C-mutant advanced NSCLC and PD-L1 expression &lt;50%, the current SOC is pembrolizumab + platinum-based chemotherapy. Combining olomorasib, a KRAS G12C inhibitor, with pembrolizumab may overcome the limited efficacy of single-agent pembrolizumab in this population, while offering a chemotherapy-sparing targeted approach. Here we report an integrated analysis of 1L pts with PD-L1 expression 0-49% (&lt;1% and 1-49%) who received olomorasib + pembrolizumab from the dose optimization cohorts of LOXO-RAS-20001 and SUNRAY-01. Methods: Pts with advanced KRAS G12C-mutant NSCLC, known PD-L1 expression and ECOG PS 0-1 were randomized to olomorasib (50 or 100 mg, orally BID) with pembrolizumab (200 mg Q3W). One cycle of SOC pembrolizumab prior to enrollment was permitted. Objective response rate (ORR) was assessed in the efficacy evaluable population, with PD-L1 0-49% Other efficacy endpoints included best overall response (BOR) and disease control rate (DCR). Safety was assessed across all treated pts (PD-L1 0-100%). Results: As of 6 June 2025, 85 pts received olomorasib + pembrolizumab, of which 31 pts had tumors with PD-L1 expression 0-49% (&lt;1%: n=13; 1-49%: n=18). In pts with PD-L1 expression &lt;1%, no pts received a prior cycle of SOC, 23% of pts had baseline brain metastases, and 38% had an ECOG score of 1. For the pts with PD-L1 expression of 1-49%, 17% received 1 prior cycle of SOC, 17% had baseline brain metastases, and 56% had an ECOG score of 1. The ORR was 58% in pts with PD-L1 &lt;1%, 67% in pts with PD-L1 1-49% (Table). Across all treated pts the most common any grade treatment-related adverse events (TRAEs) were diarrhea (31%) and ALT/AST increased (26/24%). TRAEs led to permanent discontinuation of study treatment in 12% of pts (n=10). Conclusions: Olomorasib + pembrolizumab demonstrated promising efficacy in pts with 1L KRAS G12C-mutant advanced NSCLC, and PD-L1 expression &lt;1% and 1-49% with ORRs that compare favorably with historical outcomes for pembrolizumab and chemo-immunotherapy in unselected advanced NSCLC. Olomorasib + pembrolizumab is under evaluation in pts with 1L KRAS G12C-mutant metastatic NSCLC (SUNRAY-01, NCT06119581) and early-stage NSCLC (SUNRAY-02, NCT06890598). Clinical trial information: NCT04956640 , NCT06119581 . Response and time-to-event endpoints in the Efficacy evaluable population with PD-L1 0-49% (N=30*). Endpoint Pts with PD-L1 &lt;1%n=12 Pts with PD-L1 1-49%n=18 ORR † , % (n/N) 58.3 (7/12) 66.7 (12/18) BOR, n (%) CR † 1 (8.3) 1 (5.6) PR † 6 (50.0) 11 (61.1) SD 4 (33.3) 4 (22.2) PD 1 (8.3) 1 (5.6) NE 0 (0.0) 1 (5.6) DCR, % (n/N) 91.7 (11/12) 88.9 (16/18) † Includes responses confirmed and pending. *Data for 1 patient are not shown in the table due to incomplete target lesion assessment. CR, confirmed response; NE, not evaluable, PD, progressive disease; PR, partial response; SD, stable disease.