Long-term safety and efficacy of sotorasib plus panitumumab and FOLFIRI for previously treated <i>KRAS</i> G12C-mutated metastatic colorectal cancer (mCRC): CodeBreaK 101 (phase 1b).

3506 Background: In the phase 3 CodeBreaK 300 trial (NCT05198934), the combination of sotorasib (KRAS G12C inhibitor) and panitumumab (monoclonal anti-EGFR antibody) improved clinical outcomes in patients with chemorefractory KRAS G12C-mutated mCRC. CodeBreaK 101 is a phase 1b trial where FOLFIRI was added to sotorasib and panitumumab in previously treated patients with KRAS G12C-mutated mCRC. For the first time, we report mature overall survival (OS) and progression-free survival (PFS), as well as updated safety and response data. Methods: Patients with KRAS G12C-mutated mCRC who received ≥1 prior systemic treatment but were KRAS G12C inhibitor-naïve, were enrolled into the expansion cohort of the CodeBreak 101 subprotocol H (NCT04185883) phase 1b trial. As defined from dose exploration cohort, patients received the recommended phase 2 dose (RP2D) of sotorasib (960 mg orally daily) plus panitumumab (6 mg/kg intravenous every 2 weeks [Q2W]) and standard dose FOLFIRI (intravenous Q2W). The primary endpoint was safety and secondary endpoints included confirmed response, OS, and PFS, assessed by investigator per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Results: By November 2024, 40 patients were enrolled (female: 47.5%; median age: 56.0 years; median [range] prior lines of systemic therapy: 2 [1-6]). The most common treatment-related adverse events (TRAEs) were dermatitis acneiform and dry skin (n = 27 [67.5%] each), decreased neutrophil count (n = 20 [50.0%]), and stomatitis (n = 17 [42.5%]). Grade ≥3 TRAEs occurred in 20 (50.0%) patients with no new safety signals. Discontinuation of sotorasib, panitumumab, or FOLFIRI (5-FU, irinotecan, or leucovorin/levoleucovorin) due to AEs was observed in 1 (2.5%), 1 (2.5%), and 16 (40.0%) patients, respectively. A total of 7 patients are still continuing the study, of whom 5 are off-treatment and under follow-up. Updated objective response rate (95% CI) was 57.5% (40.9, 73.0) and disease control rate (95% CI) was 92.5% (79.6, 98.4). Median time to response was 1.6 months and duration of response was 6.6 months. After a median follow-up of 29.2 months, the median (95% CI) PFS was 8.2 (7.0, 10.8) months and median OS was 17.9 (12.9, 25.1) months. Conclusions: Sotorasib plus panitumumab and FOLFIRI showed promising long-term safety and efficacy in pretreated KRAS G12C-mutated mCRC. AEs were consistent with the safety profile of the drugs administered. The ongoing phase 3 study, CodeBreaK 301 (NCT06252649), aims to evaluate this combination against standard of care in first-line patients with KRAS G12C-mutated mCRC. Clinical trial information: NCT05198934 .