A pivotal phase 2 single-arm study of glecirasib (JAB-21822) in patients with NSCLC harboring KRAS G12C mutation.

468214 Background: KRAS G12C mutation occurs in approximately 4% of non-small cell lung cancers (NSCLC) in China. Glecirasib (Jacobio, Beijing, PRC) is a potent and highly selective covalent oral inhibitor of KRAS G12C. Methods: This phase 2 single-arm study (NCT05009329) of glecirasib was conducted in China at 43 sites, enrolling participants with locally advanced or metastatic KRAS G12C mutated NSCLC. Subjects must have received prior platinum-based therapy and an immune checkpoint inhibitor (ICI) as well as appropriate targeted agents for any actionable mutations per local standards. Primary study objective is overall response rate (ORR) assessed by independent review committee (IRC). The secondary study objectives include duration of response (DOR), progression-free survival (PFS), overall survival (OS), disease control rate (DCR) and safety. Here we report topline results from this pivotal study. Results: A total of 119 patients with NSCLC harboring KRAS G12C mutation were enrolled and treated with single agent glecirasib at 800mg daily (median follow up 10.4 months). The median age was 62 years, 79% was male and 21% was female, and 80.7% had ECOG PS 1. The prior lines of therapy include 1-3, with 94.1% (112/119) patients having received prior platinum-based therapy and ICI. Confirmed ORR was 47.9% (56/117; 95% CI, 38.5%-57.3%) and confirmed DCR was 86.3% (101/117; 95% CI, 78.7%-92%) assessed by IRC. Median PFS per IRC was 8.2 months (95% CI, 5.5 – 13.1), and median OS was 13.6 months (95% CI, 10.9 – NE). Median DOR has not been reached (95% CI, 7.2 – NE ). Overall, treatment-related adverse events (TRAEs) of any grade were observed in 97.5% of subjects. Most common TRAEs [≥15%] were anemia (56.3%), blood bilirubin increased (48.7%), alanine aminotransferase increased (35.3%), aspartate aminotransferase increased (35.3%), hypertriglyceridemia (28.6%) and γ-Glutamyl transferase increased (15.1%). Grade 3 and 4 TRAEs were observed in 39.5%. No grade 5 TRAEs occurred. Most of patients can stay on the treatment and 5.0% patients discontinued the treatment due to TRAE. In contrast to other FDA approved KRAS G12C inhibitor, Gleciasib has 6.7% of nausea, 7.6% vomiting, 3.4% diarrhea in which only one grade 3 nausea is reported. Conclusion: The pivotal phase 2 study of Glecirasib has met the primary endpoints and demonstrates impressive ORR and PFS with promising clinical activity for patients with KRAS G12C mutated advanced NSCLC. Glecirasib is well tolerated, with an extremely low gastrointestinal toxicity profile, which may improve patient compliance with oral therapy. Clinical trial information: NCT05009329 .