Sotorasib with panitumumab in chemotherapy-refractory KRASG12C-mutated colorectal cancer: a phase 1b trial

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 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 .

Figure 1.. Study schema

Additional cohorts that are not the subject of this manuscript are not shown. * If dose level 1 was deemed not tolerable from toxicity primarily from panitumumab, a dose level using panitumumab at 3 mg/kg Q2W could be explored with or without dose reduction of sotorasib. CRC, colorectal cancer; RP2D, recommended phase 2 dose; Q2W, once every 2 weeks.

Figure 2.. Patient disposition

N, number of patients in the analysis set; n, number of patients with observed data.

Figure 3.. Activity of sotorasib therapy in the dose-expansion cohort

(A) Swimmer plot of duration of treatment and response as of data cutoff. (B) Best percentage change from baseline in sum of diameters (C) Kaplan-Meier curve of progression-free survival; Vertical lines indicate censoring. (D) Kaplan-Meier curve of overall survival; Vertical lines indicate censoring. Part 1A denotes the dose-exploration cohort and Part 2A denotes the dose-expansion cohort. BOR, best objective response; CRC, colorectal cancer; PD, progressive disease; PR, partial response; SD, stable disease.