TY - JOUR
T1 - Sotorasib with panitumumab in chemotherapy-refractory KRAS G12C-mutated colorectal cancer
T2 - a phase 1b trial
AU - Kuboki, Yasutoshi
AU - Fakih, Marwan
AU - Strickler, John
AU - Yaeger, Rona
AU - Masuishi, Toshiki
AU - Kim, Edward J.
AU - Bestvina, Christine M.
AU - Kopetz, Scott
AU - Falchook, Gerald S.
AU - Langer, Corey
AU - Krauss, John
AU - Puri, Sonam
AU - Cardona, Panli
AU - Chan, Emily
AU - Varrieur, Tracy
AU - Mukundan, Lata
AU - Anderson, Abraham
AU - Tran, Qui
AU - Hong, David S.
N1 - Publisher Copyright:
© 2024, The Author(s), under exclusive licence to Springer Nature America, Inc.
PY - 2024/1
Y1 - 2024/1
N2 - 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 KRAS G12C-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 KRAS G12C-mutated metastatic colorectal cancer. ClinicalTrials.gov identifier: NCT04185883 .
AB - 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 KRAS G12C-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 KRAS G12C-mutated metastatic colorectal cancer. ClinicalTrials.gov identifier: NCT04185883 .
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U2 - 10.1038/s41591-023-02717-6
DO - 10.1038/s41591-023-02717-6
M3 - Article
C2 - 38177853
AN - SCOPUS:85181482550
SN - 1078-8956
VL - 30
SP - 265
EP - 270
JO - Nature medicine
JF - Nature medicine
IS - 1
ER -