Efficacy and safety of glecirasib (JAB-21822) monotherapy and in combination with cetuximab in patients with KRAS G12C-mutated advanced colorectal cancer.

191 Background: Glecirasib (JAB-21822), a highly selective, covalent and oral KRAS G12C inhibitor, has demonstrated a favorable safety profile and promising efficacy result as a monotherapy in NSCLC. We previously reported preliminary data of glecirasib monotherapy (NCT05009329) and in combination with cetuximab (NCT05194995) in KRAS G12C-mutated advanced Colorectal Cancer (CRC); here, we present the updated efficacy results. Methods: Patients (pts) with advanced CRC harboring KRAS G12C mutation were enrolled and treated with either single agent glecirasib (800mg QD) or glecirasib (800mg QD) combined with cetuximab. The primary endpoint was overall response rate (ORR). The secondary endpoints included duration of response (DoR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS) and safety. Results: As of June 30, 2024, 44 pts received glecirasib (median follow up was 21.9 months). The median age was 55.5 years with female (38.6%) /male (61.4%), ECOG PS 0 (25.0%) /1 (75.0.%), and 79.5% having received ≥ 2 prior lines of therapy. The confirmed ORR and DCR were 22.7% (10/44) and 86.4% (38/44), respectively. Median DoR was 4.4months (95%CI: 4.2, 9.7) , median PFS was 5.6 months (95%CI: 4.1, 7.0), and median OS was 16.0 months (95%CI: 8.8, 26.3). Any grade treatment-related adverse events (TRAEs) occurred in 41 (93.2%) pts, the most common ones (>20%) being anemia, blood bilirubin increased, hypertriglyceridemia and white blood cell count decreased. Grade 3-4 TRAEs occurred in 9 (20.5%) pts. No grade 5 TRAEs occurred. No patient discontinued treatment due to TRAEs. Among the47 pts treated with combination regimen (median follow up was 18.7 months), the median age was 54.8 years with female (53.2%)/ male (46.8%), ECOG PS 0 (44.7%) /1 (55.3%), and 74.5% having received ≥ 2 prior lines of therapy. The confirmed ORR and DCR were 50% (23/46) and 87.0% (40/46), respectively. Median DoR was 5.1 months (95%CI: 4.1, 6.9), median PFS was 6.9 months (95%CI: 5.4-6.9), and median OS was 19.3 months (95%CI: 13.1, NE). Any grade TRAEs occurred in 46 (97.9%) pts, the most common ones (>20%) being rash, skin fissures, blood bilirubin increased, ALT increased, AST increased, anemia and proteinuria. Grade 3-4 TRAEs occurred in 9 (19.1%) pts. No grade 5 TRAEs occurred. 2(4.3%) pts discontinued treatment due to TRAEs. Conclusions: Glecirasib in combination with cetuximab demonstrated better efficacy compared with glecirasib monotherapy in advanced KRAS G12C mutated advanced CRC, while maintaining a favorable safety profile. Clinical trial information: NCT05009329 , NCT05194995 .