In a prespecified analysis of the phase II CodeBreaK100 trial reported in The Lancet Oncology, Marwan Fakih, MD, and colleagues found that the KRAS G12C protein inhibitor sotorasib showed modest activity in patients with previously treated KRAS G12C–mutant colorectal cancer.
Marwan Fakih, MD
The analysis included 62 patients enrolled at sites in nine countries between August 2019 and May 2020 whose disease progressed after they received treatment with fluoropyrimidine, oxaliplatin, and irinotecan. Patients received oral sotorasib at 960 mg once daily until disease progression or unacceptable toxicity. Overall, 73% of patients had received three or more prior lines of systemic therapy, with 42% receiving four or more.
The primary endpoint was objective response on blinded independent central review, with a benchmark response rate of 10%.
Objective responses (all partial) were observed in 6 patients (9.7%, 95% confidence interval [CI] = 3.6%–19.9%); an additional 45 patients (73%) had stable disease. Disease control was achieved in 51 patients (82.3%, 95% CI = 70.5%–90.8%). Median time to response was 2.0 months (interquartile range [IQR] = 1.4–2.8 months), and median duration of response was 4.2 months (IQR = 2.9–8.5 months); two responders remained on treatment with ongoing response of longer than 11 months at data cutoff.
At a median follow-up of 11.0 months, median progression-free survival was 4.0 months (95% CI = 2.8–4.2 months), with estimated 6- and 12-month rates of 21.9% and 11.7%. At a median follow-up of 11.4 months, median overall survival was 10.6 months (95% CI = 7.7–15.6 months), with an estimated 12-month rate of 42.5%.
Treatment-related grade 3 adverse events occurred in six patients (10%) patients, the most common being diarrhea (3%), and a grade 4 event occurred in one patient (2%; increased creatine phosphokinase). Serious treatment-related adverse events occurred in two patients (3%; back pain and acute kidney injury). Adverse events led to treatment discontinuation in one patient (2%). No fatal adverse events were reported.
The investigators concluded, “Although the 9.7% overall response rate did not reach the benchmark, oral administration of sotorasib once per day showed modest antitumor activity and manageable safety in these heavily pretreated chemorefractory patients. Sotorasib is under evaluation in combination with other therapeutics to increase potential activity and overcome potential resistance mechanisms.”
Dr. Fakih, of City of Hope Comprehensive Cancer Center, is the corresponding author for The Lancet Oncology article.
Disclosure: The study was funded by Amgen. For full disclosures of the study authors, visit thelancet.com.