Sotoraxib combined with panitumumab provides an effective targeted therapy option for patients with KRAS G12C+mCRC

WhereasKRAS The U.S. Food and Drug Administration's approval of sotorasib (AMG510) plus panitumumab (Panitumumab) provides a much-needed, highly effective targeted therapy option for patients with G12C-mutated metastatic colorectal cancer (mCRC) who have progressed on standard-of-care (SOC) chemotherapy and have shown low response rates to existing therapies. On January 16, 2025, the U.S. Food and Drug Administration (FDA) approved sotosibu in combination with panitumumab for the treatment of adult patients with KRAS G12C-mutated mCRC who have previously received chemotherapy based on fluoropyrimidine, oxaliplatin, and irinotecan.

This decision is supported bydata from the Phase 3 CodeBreak300 study (NCT05198934). The results of the study showed that 960 mg of sotorracib was taken daily with panitumumab (n=53), and the investigators chose trifluridine, Lonsurf or Regorafe nib) (n=54; HR, 0.48; 95% CI, 0.3-0.78; two-sided P=0.005), the median progression-free survival (PFS) was 5.6 months (95% CI, 4.2-6.3) and 2 months (95% CI, 1.9-3.9). Additionally, 960 mg of sotoraxib plus panitumumab produced an objective response rate (ORR) of 26% (95% CI, 15%-40%) compared with 0% (95% CI, 0%-7%) in the SOC arm.

Approximately4% of mCRC patients have KRAS G12C mutations. Treatment [options] for these patients are similar to other patients with KRAS mutations and are very limited after progression on fluoropyrimidine, oxaliplatin and irinotecan [chemotherapy-based] and bevacizumab [Avastin]. The emergence of targeted therapies for [mCRC patients] harboring the KRAS G12C mutation, combining sotoraxib and panitumumab, with an updated ORR of approximately 30%, brings hope to these patients.

CodeBreak300 is a randomized phase 3 clinical trial that attempts to answer 2 main questions. First, does the combination of sotoraxiband panitumumab improveSOC outcomes? At that time, the SOC was trifluridine/tipiracil or regorafenib. Secondly, is there a better dose of sotoraxib (that should be used)? What are the effects of lower doses of sotorasibr plus panitumumab? Two doses of sotoraxib were evaluated: 240 mg and 960 mg daily.

Although the study did not compare the two doses of sotoraxib (240 mg and 960 mg) as the primary endpoint, at the end of the day, the 960 mg dose Associated with higher ORR, in the updated analysis, the ORR for the 240 mg dose group was 30% [95% CI, 18.3%-44.3%] compared with 8% [95% CI, 2.1%-18.2%]. This is a meaningful difference in ORR. Additionally, PFS differences also favored higher doses.

Sotorasiibshould be used in combination with panitumumab960 mg. This combination is safe. This combination presented no new safety signals and was well tolerated. Panitumumab can cause rashes, but sotoraxib itself has very few adverse effects, most of which are grade 1 or 2. [These] encouraging data support the safety and efficacy of this combination in patients with mCRC harboring KRAS G12C [mutations].

References:https://www.onclive.com/view/sotorasib-plus-panitumumab-provides-effective-targeted-therapy-option-in-kras-g12c-mcrc