Safety and efficacy of sotorasib plus panitumumab and FOLFIRI for previously treated KRAS G12C-mutated metastatic colorectal cancer in the CodeBreaK 101 phase Ib study

Background: In the phase III CodeBreaK 300 trial (NCT05198934), the combination of sotorasib, a KRASG12C inhibitor, and panitumumab improved clinical outcomes in patients with chemorefractory KRAS G12C-mutated metastatic colorectal cancer (mCRC). CodeBreaK 101 (NCT04185883) is a phase Ib trial wherein irinotecan, leucovorin, and 5-fluorouracil (FOLFIRI) was added to sotorasib and panitumumab in previously treated patients with KRAS G12C-mutated mCRC. Patients and methods: Patients with KRAS G12C-mutated mCRC who received ≥1 prior systemic treatment were enrolled in CodeBreaK 101 subprotocol H dose-exploration and dose-expansion cohorts. In the dose-exploration cohort, patients received sotorasib (960 mg orally daily) plus panitumumab [6 mg/kg i.v. Q2W] and standard dose FOLFIRI (i.v. Q2W). This initial dose level was declared the recommended phase II dose and used in the dose-expansion cohort. The primary endpoint was safety, and secondary endpoints were efficacy and pharmacokinetics. Results: A total of 46 patients were enrolled into the dose-exploration (n = 6) and dose-expansion (n = 40) cohorts [n = 21 (46%) female, median age, 54.0 (range, 36-76)]. Patients had received a median of two prior lines of therapy (range, 1-6) with approximately one-third each receiving the study regimen as second-, third-, or fourth-line-or-greater therapy. No dose-limiting toxicities were observed in the dose-exploration cohort at the initial dose level. In the 46 patients in both dose-exploration and dose-expansion cohorts, grade ≥3 treatment-related adverse events (TRAEs) occurred in 23 (50%) patients. The most common TRAEs were dermatitis acneiform (65.2%), dry skin (60.9%), and neutrophil count decreased/neutropenia (56.5%). Confirmed overall response rate was 56.5% [95% confidence interval (CI) 41.1-71.1], median progression-free survival was 8.3 months (95% CI 7.0-11.0), and median overall survival was 17.9 months (95% CI 13.0-23.3). Conclusions: Sotorasib plus panitumumab and FOLFIRI demonstrated a manageable safety profile and promising antitumor activity in previously treated patients with KRAS G12C-mutated mCRC.