Patients with KRAS (G12C)-mutated, metastatic colorectal cancer (CRC) benefit from combination sotorasib and panitumumab
Of all metastatic colorectal tumors, about 3% harbor a Kirsten rat sarcoma viral oncogene homologue (KRAS) gly12-to-cys (G12C) mutation, which is associated with poor prognosis.1 Sotorasib is a selective KRAS inhibitor targeting the protein arising from the KRAS (G12C) mutation. In the phase 1b CodeBreak 101 trial (NCT04185883), the combination of sotorasib with the epidermal growth factor receptor (EGFR) inhibitor panitumumab showed a promising objective response rate (ORR, 30%) in participants with advanced KRAS (G12C)-mutated colorectal cancer (CRC).2 The current CodeBreak 300 trial (NCT05198934) is a randomized phase 3 study to further explore the clinical efficacy and safety of the combination of sotorasib and panitumumab in participants with KRAS (G12C)-mutated CRC. Dr. Filippo Pietrantonio of the Istituto Nazionale dei Tumori, Italy, presented the first results.3
The study enrolled 159 participants who had been previously treated with at least 1 line of therapy for metastatic CRC. Participants were randomized into 3 arms: sotorasib 960 mg daily plus panitumumab (Arm A), sotorasib 240 mg daily plus panitumumab (Arm B), or the control arm (investigator’s choice: trifluridine/tipiracil or regorafenib). The primary endpoint of the study is progression-free survival (PFS).
After a median follow-up of 7.8 months, sotorasib (both doses) plus panitumumab significantly improved PFS. Median PFS was 5.6 months in Arm A, 3.9 months in Arm B, and 2.2 months in the control arm (Arm A: HR, 0.48; 95% CI, 0.30-0.80; P=.006 and Arm B: HR, 0.58; 95% CI, 0.36-0.93; P=.30, both vs control arm). PFS benefit was seen in all prespecified subgroups. ORR was significantly improved in Arm A: 26% versus 6% in Arm B and 0% in the control arm. Overall survival data were not mature at the data cut-off date. “Both sotorasib doses plus panitumumab were well tolerated with no new safety signals and no fatal treatment-related adverse events, supporting a dose of 960 mg daily as the sotorasib dose in CRC,” highlighted Dr. Pietrantonio.
These data suggest sotorasib plus panitumumab as a potential new standard of care for patients with pretreated KRAS (G12C)-mutated metastatic CRC. “However, overall survival data needs to be awaited,” cautioned discussant Dr. Miriam Koopman of University Medical Center Utrecht, the Netherlands.
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