A phase Ib, open-label, clinical trial of JAB21822 combined with second-line chemotherapy for metastatic colorectal cancer with <i>KRAS</i> G12C mutation.

3544 Background: Glecirasib (JAB-21822), a novel, covalent, small molecule KRAS G12C-GDP covalent inhibitor, has been shown to be effective and safe as monotherapy or in combination with cetuximab in treating patients with refractory, unresectable locally advanced or metastatic colorectal cancer (mCRC) harboring KRAS G12C mutation. There are few data regarding the efficacy and safety of KRAS G12C inhibitor in the second-line setting. This multicenter, phase Ib, open label, single arm study aims to investigate the efficacy and safety of glecirasib in combination with the standard second-line chemotherapy and bevacizumab in patients with mCRC with KRAS G12C mutation who failed first-line treatment (NCT06838338). Methods: Patients (pts) with mCRC harboring KRAS G12C mutation were enrolled and treated with glecirasib (800mg QD) combined with standard second-line chemotherapy (FOLFIRI or FOLFOX) and bevacizumab until disease progression or intolerable toxicity or patient-initiated withdrawal from the study. The primary endpoint was confirmed objective response rate (ORR). The secondary endpoints included overall survival (OS), progression-free survival (PFS), disease control rate (DCR), duration of response (DoR) and safety. Results: As of Dec 10, 2025, 26 pts were enrolled and received glecirasib combined with chemotherapy and bevacizumab in four centers. The median age was 58 years with female (54%)/male (46%), ECOG 0 (8%)/1 (92%). A total of 20 subjects had at least one post-baseline tumor assessment. The confirmed ORR and DCR were 50% (10/20) and 100% (10/20), respectively. Median DoR was 10.1 months (95%CI: 2.9, NE), median PFS was 11.5 months (95%CI: 5.5, NE). Any grade treatment-related adverse events (TRAEs) occurred in 23/26 (88.5%) pts, the most common ones (&gt;20%) being diarrhea, nausea and anemia. Grade 3-4 TRAEs occurred in 6 (23.1%) pts. No grade 5 TRAEs occurred. Conclusions: Glecirasib in combination with the second-line standard chemotherapy and bevacizumab demonstrated encouraging efficacy and tolerable safety in the second-line treatment of mCRC patients with KRAS G12C mutation. Clinical trial information: NCT06838338 .