Outcomes with KRAS G12C inhibitors in metastatic colorectal cancer: A systematic review and meta-analysis.

Abstract

e15544 Background: KRAS G12C inhibitors are potential treatment options for patients with KRAS G12C mutated colorectal cancer (CRC) patients, who make up to 3% of CRC patients. This systematic review and meta-analysis aimed at exploring the outcomes of KRAS G12C inhibitors in treating metastatic KRAS G12C mutated CRC patients. Methods: A systematic search was conducted on PubMed, Cochrane, and ClinicalTrials.gov following PRISMA guidelines and four studies reporting outcomes of KRAS G12C inhibitors in treating metastatic KRAS G12C mutated CRC patients were included after screening of 45 studies. The inter-study variance was assessed using the Der Simonian-Laird Estimator and pooled analysis was conducted with 95% confidence intervals using the ‘meta’ package in R (version 4.16-2). Results: A total of 331 patients from 4 studies (2023-2024) were included for analysis. The median age was 59.5 (24- 82) years and the majority were female (52%, n=173). One of the included studies was phase III while three were phase I/II trials. Adagrasib 51% (38% received Adagrasib in combination with cetuximab], Sotorasib 32%, and Divarasib 17% used KRAS G12C inhibitors. The median number of prior therapies was 3 (1-9) and fluoropyrimidines were the most used regimen (98%, n=323) followed by oxaliplatin (97%, n=320), and irinotecan (89%, n=296). The median follow-up time was 14.7 (0.1-13.9) months. The pooled rates of overall response (OR), stable disease (SD), and progressive disease (PD) were 26% (95% CI 0.21-0.31, I 2 =70%, p=0.02, n=326), 54% (95% CI 0.49-0.59, I 2 =0%, p=0.45, n=326), and 12.2% (95% CI 0.09-0.16, I 2 =76%, p<0.01, n=326), respectively. The pooled rates for complete remission (CR) and partial remission (PR) were 1.4% (95% CI 0.00- 0.03, I 2 =85%, p<0.01, n=326), and 26.1% (95% CI 0.21-0.31, I 2 =79%, p<0.01, n=326), respectively. At a median follow-up of 6 months, pooled progression-free survival (PFS) was 53.7% (95% CI 0.48-0.59, I 2 =0%, p=0.69, n=326) and pooled overall survival (OS) was 91.9% (95% CI 0.87-0.96, I 2 =66%, p=0.09, n=165). The median duration of response was 5.8 (2.3-8.3) months. Nausea (48%, n=160), diarrhea (46%, n=152), and vomiting (38%, n=126) were the most commonly reported adverse events. Conclusions: KRAS G12C inhibitors demonstrated promising efficacy in metastatic KRAS G12C mutated CRC with an acceptable toxicity profile. However, large studies with randomization are needed to consolidate these findings.