369P Irinotecan is superior to oxaliplatin in KRAS-G12C-mutated (K-G12C-m) colorectal cancer (CRC) and should be preferred in combination strategies with K-G12C inhibitors. A multicenter propensity score-matched (PSM) retrospective analysis

Abstract

K-G12C inhibitors have recently become available, yet limited activity has been observed when used as monotherapy in CRC. Given their good safety profile, combination strategies with other targeted agents or chemotherapy (CT) are being considered to increase efficacy. A multicenter analysis was conducted to assess the efficacy of standard first-line CT in K-G12C-m metastatic CRC patients(pts). K-G12D-m pts were used as control group. Only pts treated with first-line FOLFIRI or FOLFOX +/- bevacizumab (bev) were included. Primary and secondary outcome measures were progression free survival (PFS) and objective response rate (ORR), respectively. Both an unmatched and a PSM analysis were conducted. 86 pts were included: 51 K-G12C-, 35 K-G12D-m. Median age was 63 yrs (range 34-83), 49 were male, 37 female. Liver mets were present in 71% of pts, 51% had 2 or more metastatic sites. FOLFIRI, FOLFIRI-bev, FOLFOX and FOLFOX-bev was the first-line for 15, 36, 10 and 25 pts, respectively. In K-G12C-m pts a statistically significant benefit in PFS was demonstrated for FOLFIRI+/-bev vs FOLFOX+/-bev: HR 0.52 (95%CI 0.28-0.98), p 0.04. The benefit was even more pronounced in the PSM analysis based on age, gender, receipt of bev, grading, KPS, metachronous vs synchronous mets, number of metastatic sites, presence of peritoneal mets: HR 0.24 (95%CI 0.08-0.71), p 0.01. No difference in ORR was seen: 48% vs 47%, p 0.87, respectively. Also median PFS was not numerically different: 11.7 vs 11.6 months, however 12-, 18-, 24-month PFS rates were 48%, 43%, 32% and 46%, 18%, 5% for FOLFIRI+/-bev and FOLFOX+/-bev, respectively. In the K-G12D-m group, no significant differences were observed between FOLFIRI+/-bev vs FOLFOX+/-bev for both PFS and ORR, p 0.09 and 0.45, respectively. Irinotecan (i.e. FOLFIRI+/-bev) was significantly superior to oxaliplatin (i.e. FOLFOX+/-bev) in K-G12C-m CRC pts, with a subset of pts (32%) achieving a long-lasting (> 2 yrs) PFS. Irinotecan should be the preferred chemotherapy to be used in combination strategies with K-G12C inhibitors.