Sotorasib plus panitumumab versus standard-of-care for chemorefractory KRAS G12C-mutated metastatic colorectal cancer (mCRC): CodeBreak 300 phase III study

We report the first Phase 3 primary results for sotorasib (soto), a KRASG12C-inhibitor, plus panitumumab (pani), an anti-EGFR antibody, vs standard of care (SOC) in patients (pts) with chemorefractory KRAS G12C-mutated mCRC. In the CodeBreaK 300 (NCT05198934) global, open label study, 160 pts with chemorefractory KRAS G12C-mutated mCRC were randomized 1:1:1 to soto 960 mg daily plus pani 6 mg/kg IV (soto960+pani; n=53), soto 240 mg daily plus pani 6 mg/kg IV (soto240+pani, n=53), or investigator’s choice of TAS-102 or regorafenib (n=54). Primary endpoint was progression-free survival (PFS) by blinded independent central review (BICR) per RECIST 1.1. Key secondary endpoints included ORR, DRR, and DCR. The study met its primary endpoint. Both soto+pani arms demonstrated statistically significant superior PFS compared to SOC: soto960+pani HR=0.49 (95% CI: 0.30, 0.80; p=0.006), and soto240+pani HR=0.58 (95% CI: 0.36, 0.93; p=0.03). Secondary efficacy endpoints are shown in the table. OS was immature at data cutoff. Grade ≥3 TRAEs that occurred in ≥5% pts were dermatitis acneiform (11.3%), hypomagnesaemia (5.7%), and rash (5.7%) for soto960+pani; hypomagnesaemia (7.5%), diarrhoea (5.7%) for soto240+pani; and neutropenia (23.5%), anaemia (5.9%), and hypertension (5.9%) for SOC. There were no fatal TRAEs.Table: LBA10Efficacy by BICRSoto960+Pani n=53Soto240+Pani n=53SOC n=54Median PFS, months (95% CI)5.6 (4.21, 6.31)3.9 (3.71, 5.75)2.2 (1.94, 3.91)ORR, % (95% CI)26.4 (15.3, 40.3)5.7 (1.2, 15.7)0 (0.0, 6.6)Number of responders1430Median DOR, months (range)4.4 (1.9+, 6.0+)NR (1.8+, 3.8+)--DCR, % (95% CI)71.7 (57.7, 83.2)67.9 (53.7, 80.1)46.3 (32.6, 60.4)CI, confidence interval; DCR, disease control rate; DOR, duration of response; NR, not reached; ORR, objective response rate Open table in a new tab CI, confidence interval; DCR, disease control rate; DOR, duration of response; NR, not reached; ORR, objective response rate In the first phase 3 study for a KRASG12C-inhibitor plus an anti-EGFR antibody in chemorefractory mCRC, the primary endpoint was met and both doses of soto+pani showed superior PFS vs SOC. Soto960+pani demonstrated clinically meaningful benefit across PFS and key secondary endpoints (ORR, DCR, DOR) and was tolerable with lower rates of Grade ≥3 TRAEs vs SOC.