Sotorasib for previously treated colorectal cancers with KRAS G12C mutation (CodeBreaK100): a prespecified analysis of a single-arm, phase 2 trial
Mené dans 11 pays sur 62 patients atteints d'un cancer colorectal présentant la mutation G12C du gène KRAS, cet essai de phase II évalue l'efficacité, du point de vue du taux de réponse objective, et la toxicité du sotorasib en monothérapie, après l'échec d'une chimiothérapie à base de fluoropyrimidine, d'oxaliplatine et d'irinotécan
Background : Sotorasib, a specific, irreversible KRASG12C protein inhibitor, has shown monotherapy clinical activity in KRASG12C-mutated solid tumours, including colorectal cancer, in the CodeBreaK100 phase 1 trial.We aimed to investigate the activity and safety of sotorasib in phase 2 of the trial. Methods : In this single-arm, phase 2 trial, adult patients with KRASG12C-mutated advanced solid tumours were enrolled, from 59 medical centres in 11 countries,if they were aged 18 years or older, had at least one measurable lesion accordingto the Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1, and hadan Eastern Cooperative Oncology Group performance status of 1 or lower. Only datafor patients with colorectal cancer, enrolled at 33 medical centres in nine countries,are presented from this basket trial. To be enrolled, the patients had to have progressed after receiving fluoropyrimidine, oxaliplatin, and irinotecan treatment. These patients were administered 960 mg sotorasib orally once per day until disease progression,development of unacceptable side-effects, withdrawal of consent, or death. The primaryendpoint was objective response (complete or partial response) as assessed by blindedindependent central review. Response was evaluated in patients who received at leastone dose of sotorasib and had at least one measurable lesion at baseline; safety wasevaluated in patients who received at least one dose of sotorasib. This analysis isa prespecified analysis triggered by the phase 2 colorectal cancer cohort. This studyis registered with ClinicalTrials.gov, NCT03600883, and is active but no longer recruiting. Findings : On March 1, 2021, at data cutoff, 62 patients with KRASG12C-mutant colorectal cancer had been enrolled between Aug 14, 2019, and May 21, 2020,and had received at least one dose of sotorasib monotherapy. Objective response wasobserved in six (9·7%, 95% CI 3·6–19·9) of 62 patients, all with partial response.Treatment-related adverse events at grade 3 occurred in six (10%) patients, the mostcommon of which was diarrhoea (two [3%] of 62 patients), and at grade 4 occurred inone (2%) patient (blood creatine phosphokinase increase); no fatal events were recorded.Serious treatment-related adverse events occurred in two (3%) patients (back painand acute kidney injury). Interpretation : Although the 9·7% overall response rate did not reach the benchmark, oral administrationof sotorasib once per day showed modest anti-tumour activity and manageable safetyin these heavily pretreated chemorefractory patients. Sotorasib is under evaluationin combination with other therapeutics to increase potential activity and overcomepotential resistance mechanisms.
The Lancet Oncology 2021