Safety and efficacy of olomorasib + immunotherapy in first-line treatment of patients with <i>KRAS</i> G12C-mutant advanced NSCLC: Update from the LOXO-RAS-20001 trial.

Abstract

8519 Background: Olomorasib, a potent, highly selective second-generation KRAS G12C inhibitor has demonstrated promising activity and a favorable safety profile in KRAS G12C-mutant NSCLC when combined with pembrolizumab. Here, we report updated results from LOXO-RAS-20001, a phase 1/2 trial (NCT04956640) of olomorasib, in patients (pts) with KRAS G12C-mutant NSCLC receiving olomorasib + pembrolizumab, and focus on pts receiving the combination as first-line (1L) therapy. Methods: Pts with advanced KRAS G12C-mutant NSCLC (tissue or plasma) in the 1L metastatic setting were eligible. Any PD-L1 level (0-100%) was permitted. Two dose levels of olomorasib (50 and 100 mg, orally twice daily) + pembrolizumab were evaluated. Adverse events (AE) were assessed across all treated pts; objective response rate (ORR) per RECIST v1.1 was assessed in pts with at least one post-baseline response assessment or who discontinued treatment before the first response assessment. Results: As of 13 November 2024, a total of 43 pts received olomorasib + pembrolizumab (50 mg, n=21; 100 mg, n=22) in the 1L setting with a median age of 70 years (range, 58-83); 10 (23%) were PD-L1 negative, 13 (30%) were PD-L1 1-49%, 19 (44%) were PD-L1 ≥50% and 1 (2%) was unknown. Median duration of follow-up was 5.5 months (range, 0.1-24.4). All grade TRAEs in ≥10% of pts (olomorasib- and/or pembrolizumab-related) were ALT/AST increased (33%/30%), diarrhea (28%), fatigue (16%), nausea (14%), pruritus (12%) and decreased appetite (12%); grade 3 TRAEs in ≥10% of pts were ALT/AST increased (26%/16%). Hepatic events were overall manageable with dose adjustments and/or corticosteroids. No pts had co-occurring total bilirubin increased or discontinued both study treatments due to hepatic events. Pneumonitis was reported in 2 pts (grades 2 and 4). The AE profile was generally comparable across doses. TRAEs led to olomorasib dose reduction in 16% of pts and discontinuation of combination treatment in 5% (2) pts. At time of data-cut, 33 pts remain on treatment and 10 discontinued. Among the 40 efficacy-evaluable 1L pts, at a median follow-up of 9 months (95% CI, 6-12), ORR was 70% (28/40; 95% CI, 54-83; 1 CR, 23 PR, 4 unconfirmed PR pending/ongoing) across all PD-L1 expression levels and disease control rate (DCR) was 90% (36/40; 95% CI, 76-97). In pts with PD-L1 ≥50%, ORR was 82% (14/17; 95% CI, 57-96) and DCR was 94% (16/17; 95% CI, 71-99). Median duration of response was not reached and progression free survival rate at 6 months was 80%. Conclusions: Olomorasib + pembrolizumab in the 1L metastatic setting demonstrated favorable safety and encouraging antitumor activity in pts with KRAS G12C-mutant advanced NSCLC across all PD-L1 expression levels. A global, registrational study investigating this combination in 1L NSCLC is currently enrolling (SUNRAY-01, NCT06119581). Clinical trial information: NCT04956640 .