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Sotorasib with panitumumab in chemotherapy-refractory KRASG12C-mutated colorectal cancer: a phase 1b trial
Yasutoshi Kuboki1, Marwan Fakih2, John Strickler3
1National Cancer Center Hospital East, Kashiwa, Japan.
Abstract:
The current third-line (and beyond) treatment options for RAS-mutant metastatic colorectal cancer have yielded limited efficacy. At the time of study start, the combination of sotorasib, a KRAS (Kirsten rat sarcoma viral oncogene homolog)-G12C inhibitor, and panitumumab, an epidermal growth factor receptor (EGFR) inhibitor, was hypothesized to overcome treatment-induced resistance. This phase 1b substudy of the CodeBreaK 101 master protocol evaluated sotorasib plus panitumumab in patients with chemotherapy-refractory KRASG12C-mutated metastatic colorectal cancer. Here, we report the results in a dose-exploration cohort and a dose-expansion cohort. Patients received sotorasib (960 mg, once daily) plus panitumumab (6 mg kg-1, once every 2 weeks). The primary endpoints were safety and tolerability. Secondary endpoints included efficacy and pharmacokinetics. Exploratory biomarkers at baseline were assessed. Forty-eight patients (dose-exploration cohort, n = 8; dose-expansion cohort, n = 40) were treated. Treatment-related adverse events of any grade and grade ≥3 occurred in 45 (94%) and 13 (27%) patients, respectively. In the dose-expansion cohort, the confirmed objective response rate was 30.0% (95% confidence interval (CI) 16.6%, 46.5%). Median progression-free survival was 5.7 months (95% CI 4.2, 7.7 months). Median overall survival was 15.2 months (95% CI 12.5 months, not estimable). Prevalent genomic coalterations included APC (84%), TP53 (74%), SMAD4 (33%), PIK3CA (28%) and EGFR (26%). Sotorasib-panitumumab demonstrated acceptable safety with promising efficacy in chemotherapy-refractory KRASG12C-mutated metastatic colorectal cancer. ClinicalTrials.gov identifier: NCT04185883 .
Insights
Sotorasib plus panitumumab shows promise for patients with advanced KRAS G12C-mutated colorectal cancer, offering a new treatment option with acceptable safety and encouraging efficacy in those refractory to chemotherapy.
Area of Science:
- Oncology
- Medical Genetics
- Pharmacology
Background:
- Metastatic colorectal cancer (mCRC) with RAS mutations, particularly KRAS G12C, has limited third-line treatment options.
- Treatment resistance is a significant challenge in advanced mCRC.
- Epidermal growth factor receptor (EGFR) inhibitors like panitumumab are used, but resistance mechanisms exist.
Purpose of the Study:
- To evaluate the safety, tolerability, and efficacy of combining sotorasib (a KRAS G12C inhibitor) with panitumumab in patients with chemotherapy-refractory KRAS G12C-mutated mCRC.
- To explore the pharmacokinetic profile of this combination therapy.
- To assess exploratory biomarkers at baseline.
Main Methods:
- A phase 1b substudy (CodeBreaK 101) involving a dose-exploration and dose-expansion cohort.
- Patients received sotorasib (960 mg daily) plus panitumumab (6 mg/kg every 2 weeks).
- Primary endpoints: safety and tolerability; Secondary endpoints: efficacy (objective response rate, progression-free survival, overall survival) and pharmacokinetics.
Main Results:
- Forty-eight patients were treated. Treatment-related adverse events occurred in 94% (any grade) and 27% (grade ≥3).
- In the dose-expansion cohort (n=40), the confirmed objective response rate was 30.0%.
- Median progression-free survival was 5.7 months, and median overall survival was 15.2 months.
Conclusions:
- The combination of sotorasib and panitumumab demonstrates acceptable safety and promising efficacy in patients with chemotherapy-refractory KRAS G12C-mutated metastatic colorectal cancer.
- This combination represents a potential new therapeutic strategy for this difficult-to-treat patient population.
- Further investigation into genomic co-alterations like APC, TP53, and PIK3CA may inform treatment strategies.
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