Glecirasib with or without cetuximab in previously treated locally advanced or metastatic colorectal cancer with KRAS G12C mutation (JAB-21822-1002 and JAB-21822-1007): two open-label, non-randomised phase 1/2 trials
Menée à partir des données de deux essais non randomisés de phase I/II incluant 91 patients atteints d'un cancer colorectal avec mutation G12C au niveau du gène KRAS et de stade localement avancé ou métastatique, cette étude évalue l'efficacité, du point de vue du taux de réponse objective, et la toxicité du glécirasib (un nouvel inhibiteur de KRASG12C) seul et en combinaison avec le cétuximab
Background: KRASG12C mutations are present in around 4% of patients with colorectal cancer and are associated with lower treatment response rates and overall survival. EGFR signalling has been identified as a primary mechanism of resistance to KRASG12C inhibitors. We aimed to evaluate the efficacy and safety of a novel, covalent, small molecule KRASG12C inhibitor, glecirasib (JAB-21822), as monotherapy or in combination with the anti-EGFR cetuximab, in patients with KRASG12C-mutated colorectal cancer.
Methods: JAB-21822-1002 was an open-label, non-randomised, dose escalation (phase 1) and expansion (phase 2a) trial evaluating glecirasib monotherapy in KRASG12C-mutated solid tumours. JAB-21822-1007 was an open-label, non-randomised, dose escalation (phase 1b) and expansion (phase 2) study evaluating glecirasib plus cetuximab in KRASG12C-mutated colorectal, small intestine, and appendiceal cancer. Adult participants (aged ≥18 years) were recruited in China from 17 hospitals for the monotherapy trial and 16 hospitals for the combination trial. Here, we report only on patients with colorectal cancer treated with oral glecirasib at the recommended phase 2 dose (800 mg once daily in 21-day treatment cycles [until disease progression, intolerable toxicity, investigator's discretion, or withdrawal of consent]), pooling phase 1 and 2 data together. In the combination trial, cetuximab was administered intravenously with an initial loading dose of 400 mg/m2 in the first week, followed by 250 mg/m2 every week or 500 mg/m2 every 2 weeks. For this analysis, key eligibility criteria were histologically or cytologically confirmed locally advanced or metastatic colorectal cancer with KRASG12C mutation; Eastern Cooperative Oncology Group performance status of 0 or 1; and at least one measurable lesion per Response Evaluation Criteria in Solid Tumors (RECIST). For phase 1 of both trials, patients must not have responded to, were not suitable for, or refused standard of care. For phase 2 of both trials, patients must have received at least first-line standard of care and had disease progression or intolerance. Primary endpoints for the monotherapy trial were safety (treatment-emergent adverse events, serious adverse events, treatment-related adverse events, dose-limiting toxicity, and clinically significant changes in vital signs, physical examination, and electrocardiography, and clinically significant unexpected laboratory values of grade ≥3) for phase 1 and objective response rate (complete and partial response) for phase 2a. Primary endpoints for the combination trial were dose-limiting toxicities, maximum tolerated dose, and recommended phase 2 dose for phase 1b and objective response rate for phase 2. The full analysis set was defined as patients with at least one measurable lesion at baseline who received at least one dose of glecirasib in the monotherapy trial, or at least one dose of glecirasib plus cetuximab in the combination trial. The safety analysis set was defined as patients who received at least one dose of glecirasib in the monotherapy trial, or at least one dose of glecirasib or cetuximab in the combination trial. The trials are registered with ClinicalTrials.gov (NCT05009329 and NCT05194995), and are active but no longer recruiting.
Findings: Between Oct 12, 2021, and Dec 4, 2023, 44 patients with colorectal cancer (27 male and 17 female) in the monotherapy trial received glecirasib 800 mg once daily and comprised the full analysis and safety analysis sets. Between Feb 17, 2022, and Feb 28, 2023, 47 patients with colorectal cancer (22 male and 25 female) in the combination trial received glecirasib 800 mg once daily plus cetuximab and comprised the safety analysis set. One patient was excluded from the full analysis set as they received glecirasib only. Data cutoff was June 30, 2024. Median follow-up was 21·9 months (IQR 20·0–25·5) in the monotherapy trial and 18·7 months (15·9–20·6) in the combination trial. In the monotherapy trial phase 1, 15 patients with colorectal cancer were enrolled. No dose-limiting toxicities, unexpected grade 3 or worse laboratory values, or changes in vital signs, physical examinations, or electrocardiography were observed. 15 (100%) patients had treatment-emergent adverse events (n=8 [53%] grade ≥3), 13 (87%) of 15 reported treatment-related adverse events (n=4 (27%) grade ≥3); five (33%) of 15 patients had serious treatment-emergent adverse events, none were treatment-related. In the combination trial phase 1b, six patients with colorectal cancer were enrolled. No dose-limiting toxicities were observed and the maximum tolerated dose was not reached. The recommended phase 2 dose was chosen as glecirasib 800 mg once daily. Objective response rate was 23% (95% CI 11–38; ten of 44 patients [ten partial responses]) in the monotherapy trial and 50% (35–65; 23 of 46 patients [23 partial responses]) in the combination trial. The most common treatment-related adverse events were anaemia (24 [55%]), blood bilirubin increased (23 [52%]), and conjugated bilirubin increased (17 [39%]) in the monotherapy trial, and rash (39 [83%]), blood bilirubin increased (29 [62%]), conjugated bilirubin increased (17 [36%]), alanine aminotransferase increased (16 [34%]), and anaemia (15 [32%]) in the combination trial. The incidence of grade 3 or 4 treatment-related adverse events was 20% (nine of 44) in the monotherapy trial and 19% (nine of 47) in the combination trial. Two (5%) of 44 patients in the monotherapy trial (febrile neutropenia, n=2) and four (9%) of 47 patients in the combination trial (interstitial lung disease [n=1], pleural effusion and pericardial effusion [n=1], pyrexia [n=1], and rash [n=1]) reported serious treatment-related adverse events. No treatment-related deaths were observed in either trial.
Interpretation: Glecirasib monotherapy and its combination with cetuximab represent potential treatment options for patients with advanced, refractory colorectal cancer harbouring KRASG12C mutations. The promising efficacy and safety support further exploration of glecirasib-based combinations in earlier lines of treatment.
The Lancet Gastroenterology & Hepatology , résumé, 2025