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

Abstract

e16206 Background: Pancreatic cancer remains one of the most challenging malignancies to treat, marked by a 5-year survival rate as low as 5%. The KRAS G12C mutation, a variant of the KRAS oncogene, accounts for 1–2% of cases. Novel therapies targeting these mutations have showcased promising efficacy. This study aimed to assess the effectiveness and safety of KRAS G12C inhibitors in patients with metastatic pancreatic cancer. Methods: Following PRISMA guidelines, we conducted a comprehensive search on PubMed, Cochrane Register, and ClinicalTrials.gov using MeSH terms ‘Pancreatic Cancer’ AND ‘KRAS(G12C) inhibitor’ up to January 10, 2025. Of 155 articles identified, 2 studies on KRAS G12C inhibitors in pancreatic cancer met inclusion criteria after excluding irrelevant and review articles. Inter-study variance was calculated using the Der Simonian-Laird Estimator. Proportions along with 95% confidence Interval (CI) were extracted to compute pooled analysis using the ‘meta’ package by Schwarzer et al. in the R programming language (version 4.16-2). Results: A total of 59 patients from two studies (2022-2023) reporting outcomes of KRAS G12C inhibitors in pancreatic cancer were included in the analysis. The median age was 65 (21-89) years and the majority were male (66%, n = 39). Both studies were phase I/II trials. The median follow-up time was 16.8 months and all the patients had metastatic KRAS p.G12C-mutated pancreatic cancer. 64% (n = 38) received Sotorasib (960 mg daily) while the remaining received 36% (n = 21) Adagrasib (600 mg twice daily). Median number of prior therapies was 2 (1-8). Platinum-based chemotherapy was the most commonly used regimen (85%, n = 50) followed by gemcitabine (71%, n = 42) and taxanes (68%, n = 40). The pooled rates of overall response (OR) and complete response (CR) were 25.1% (95% CI 0.15-0.37, I 2 = 4%, p = 0.31, n = 59) and 0% (95% CI 0.00-0.03, I 2 = 0%, p = 0.84, n = 59). The median duration of response was 5.5 (1.6-7.3). Bekaii-Saab et al reported a median progression-free survival (PFS) and overall survival (OS) of 5.4 (3.9-8.2) and 8.2 (5.2-11.8) months, respectively. Strickler et al. reported 6- and 9-month PFS of 31.6% (16.6-47.7) and 9.9% (2-25.6) while 12-month OS was 19.6% (7.2-36.3). Treatment-related adverse events were reported in 42% (n = 16) by Strickler et al. which included grade ≥2 (35%, n = 9) and grade ≥3 (23%, n = 6). Conclusion Sotorasib and Adagrasib exhibited favorable therapeutic activity in KRAS p.G12C-mutated pancreatic cancer patients with tolerable side effects. While the results are promising, the data highlights the need for further investigations to optimize clinical outcomes. Conclusions: Sotorasib and Adagrasib exhibited favorable therapeutic activity in KRAS p.G12C-mutated pancreatic cancer patients with tolerable side effects. While the results are promising, the data highlights the need for further investigations to optimize clinical outcomes.