A single-arm, phase II study of sotorasib plus carboplatin/pemetrexed in advanced non-squamous non-small cell lung cancer patients with KRAS G12C mutation (WJOG14821L, SCARLET).

Abstract

Background: The efficacy and safety of sotorasib plus platinum-doublet chemotherapy in KRAS G12C-mutated non-squamous non-small cell lung cancer (non-Sq NSCLC) were previously reported with limited follow-up period.

Method: SCARLET was a single-arm phase II study of chemotherapy-naïve patients with KRAS G12C-mutated non-Sq NSCLC. Participants received sotorasib 960 mg daily plus four cycles of carboplatin (area under the curve, 5)/pemetrexed 500 mg/m², followed by sotorasib/pemetrexed until disease progression. The primary endpoint was the overall response rate (ORR); secondary endpoints were progression-free survival (PFS), overall survival (OS), and safety. Using plasma samples, next-generation sequencing was performed at baseline, 3 weeks, and disease progression (jRCT2051210086).

Results: Thirty patients were enrolled between Oct 2021 and Jul 2022, with a median follow-up of 14.8 months. ORR was 88.9% (80% confidence interval [CI], 78.5-94.8%; 95% CI, 70.8-97.6%), median PFS was 6.6 months (95% CI, 5.3-16.7 months), and median OS was 20.6 months (95% CI, 8.1 months-not estimated). Among patients with programmed death ligand 1 expression levels ≥ 1% and < 1%, ORRs were 82.3 and 100% and median PFS was 7.6 and 9.7 months, respectively. Using plasma samples, patients without KRAS G12C at baseline, without KRAS-related pathway co-alterations, or who cleared KRAS G12C at 3 weeks had better median PFS (16.7, 13.9, 8.7 months, respectively). TP53 mutation and epidermal growth factor receptor (EGFR) and MET amplification were detected acquired resistances.

Conclusion: In patients with KRAS G12C-mutated non-Sq NSCLC, sotorasib plus carboplatin/pemetrexed demonstrated favorable efficacy especially in PD-L1 <1%, with manageable toxicity.