A phase 3 study of first-line sotorasib, panitumumab, and FOLFIRI versus FOLFIRI with or without bevacizumab-awwb for patients with <i>KRAS</i> G12C–mutated metastatic colorectal cancer (CodeBreaK 301).

Abstract

TPS326 Background: CodeBreaK 300 (NCT05198934) evaluated sotorasib, a selective inhibitor that irreversibly binds to the Kirsten rat sarcoma ( KRAS ) G12C mutant protein, in combination with panitumumab, an anti–epidermal growth factor receptor inhibitor, and showed that 960 mg sotorasib + panitumumab provided a statistically and clinically significant improvement in progression-free survival compared with trifluridine/tipiracil or regorafenib in patients with chemorefractory metastatic colorectal cancer (mCRC) (1). In CodeBreaK 101 (NCT04185883) subprotocol H expansion cohort 2F, the addition of folinic acid, fluorouracil, and irinotecan (FOLFIRI) to this combination in the first-line setting demonstrated a manageable safety profile and promising response rate of 78% in patients with KRAS G12C–mutated mCRC (2). The current study aims to evaluate whether the combination of sotorasib, panitumumab, and FOLFIRI is superior to FOLFIRI with or without bevacizumab-awwb, a VEGF inhibitor, in the first-line setting for mCRC. Methods: CodeBreaK 301 (NCT06252649) is a phase 3, multicenter, randomized, open-label, active-controlled study of sotorasib, panitumumab, and FOLFIRI versus FOLFIRI with or without bevacizumab-awwb as first-line therapy for patients with KRAS G12C–mutated mCRC. Key eligibility criteria include mCRC with KRAS G12C mutation confirmed by central molecular testing, and no prior therapy for metastatic disease. Approximately 450 patients will be randomized 1:1 to receive either sotorasib, panitumumab, and FOLFIRI, or FOLFIRI with or without bevacizumab-awwb. The primary endpoint is progression-free survival assessed by a blinded independent central review of disease response per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1). The key secondary endpoint is overall survival, and additional secondary endpoints include objective response rate and depth of response. Global enrollment is ongoing. 1. Fakih, NEJM 2023. 2. Siena, ESMO 2024. Clinical trial information: NCT06252649 .