1L olomorasib plus pembrolizumab +/- chemotherapy in <i>KRAS</i> G12C-mutant NSCLC patients +/- a prior cycle of SOC: Results from LOXO-RAS 20001 and SUNRAY-01.

Abstract

8570 Background: Real-world data suggests allowing 1 cycle of standard of care (SOC) prior to enrollment into first-line (1L) NSCLC trials of targeted therapies could expand the potential enrollable population by accommodating molecular testing turnaround time and enabling a more representative patient (pt) population. Here, we report results from 1L pts who did or did not receive 1 prior cycle of SOC in LOXO-RAS-20001 and the dose optimization/safety lead-in of SUNRAY-01, which investigated olomorasib, a KRAS G12C inhibitor, with pembrolizumab +/- chemotherapy. Methods: Pts with advanced KRAS G12C-mutant NSCLC, PD-L1 0-100% and ECOG PS 0-1 were eligible to receive olomorasib (50 or 100 mg, orally BID) with either pembrolizumab (doublet) or pembrolizumab + chemotherapy (quad) at their physician’s discretion. One cycle of SOC prior to enrollment was permitted when timely initiation of treatment was clinically indicated, this included pembrolizumab (doublet) and pemetrexed + platinum +/- pembrolizumab, or pembrolizumab alone (quad). ORR was assessed in the efficacy evaluable population, defined as pts with ≥1 post-baseline response assessment or who discontinued treatment before the first response assessment. Safety was assessed across all treated pts. Results: As of 6 June 2025, 85 pts received the doublet and 77 pts received the quad; 13 pts (15%) and 23 pts (30%) received 1 prior cycle of SOC, respectively. Baseline characteristics of pts who did and did not receive 1 prior cycle of SOC were comparable. Accounting for small sample sizes, efficacy and safety were broadly similar across both the doublet and the quad among those who did and did not receive a prior cycle of SOC (Table). Conclusions: Treatment with 1 cycle of SOC prior to enrollment appeared to have no detrimental effect on safety and efficacy outcomes of olomorasib in combination with pembrolizumab +/- chemotherapy in pts with KRAS G12C NSCLC. This is the first analysis of the clinical impact of 1 prior cycle of SOC in a NSCLC clinical trial, allowing early access to treatment if clinically indicated. Implementation of this strategy in SUNRAY-01 and other 1L NSCLC trials may expand enrollment and allow for a more representative pt population. Clinical trial information: NCT04956640 , NCT06119581 . 1L treatment outcomes. Olomorasib + Pembrolizumab Olomorasib + Pembrolizumab + Chemotherapy 1 prior cycle of SOCn=13 No priorSOCn=72 1 prior cycle of SOCn=23 No priorSOCn=54 ORR, (%) (95 %, CI) 76.9(46.2, 95.0) 71.8(59.9, 81.9) 73.9(51.6, 89.8) 55.6(41.4, 69.1) DCR, %(95 %, CI) 100(75.3, 100.0) 88.7(79.0, 95.0) 95.7(78.1, 99.9) 87.0(75.1, 94.6) TRAE All Grade / Grade 3+ (%) 100 / 30.8 87.5 / 41.7 95.7 / 26.1 96.3 / 59.3 Grade ≥3 Hepatic Events* (%) 15.4 22.2 0 22.2 Grade ≥3 Diarrhea (%) 7.7 6.9 4.3 5.6 Grade ≥3 Neutropenia (%) 0 0 4.3 16.7 Discontinuation of regimen 15.4 11.1 0 11.1 Median Duration of Treatment, mo (IQR) 10.3 (5.6-13.3) 7.9 (3.8-9.9) *Consolidated term.