Adagrasib Shows Antitumor Activity in Metastatic Colorectal Cancer With Mutant KRAS G12C

In a phase 1/2 study, the oral small-molecule inhibitor of mutant KRAS G12C protein adagrasib, showed promising clinical activity for heavily pretreated patients with metastatic colorectal cancer and a KRAS G12C mutation. This activity was greater when in combination with the anti-EGFR monoclonal antibody cetuximab.

Currently, there are no KRAS G12C targeted therapies approved for the treatment of colorectal cancer. Preliminary data has indicated clinical activity with adagrasib for pretreated patients with KRAS G12C mutations across several tumor types, including colorectal cancer. Rona Yaeger, MD, Memorial Sloan Kettering Cancer Center, New York, and coauthors wrote, “Combining cetuximab with adagrasib may enhance the inhibition of KRAS-dependent signaling or overcome adaptive feedback to delay resistance and improve outcomes.”

In this open-label, nonrandomized clinical trial, patients with metastatic colorectal cancer with mutant KRAS G12C who had been heavily pretreated were assigned to either 600 mg adagrasib orally twice a day alone (n = 44), or the same dose of adagrasib plus intravenous cetuximab once a week (initial dose of 400 mg/m² followed by 250 mg/m², n = 32). The primary outcome for the monotherapy group was objective response with secondary end points including duration of response, progression-free survival, and safety. The primary outcome of the combination group was safety with secondary end points including objective response, duration of response, and progression-free survival.

At the data cutoff date of June 16, 2022, the median follow-up duration was 20.1 months in the monotherapy group and 17.5 months in the combination group. Of 43 evaluable patients in the monotherapy group, 19% had a response reported (95% confidence interval [CI], 8 to 33). In the monotherapy group, the median response duration was 4.3 months (95% CI, 2.3 to 8.3), and the median progression-free survival was 5.6 months (95% CI, 4.1 to 8.3). Of 28 evaluable patients in the combination group, 46% had a response reported (95% CI, 28 to 66). In the combination group, the median response duration was 7.6 months (95% CI, 5.7 to not estimable), and the median progression-free survival was 6.9 months (95% CI, 5.4 to 8.1).

Among the 44 patients in the monotherapy group, 34% experienced a grade 3/4 treatment-related adverse event. The most common of these events, occurring in >5% of patients, were anemia (9%) and diarrhea (7%). Dose reduction due to treatment-related adverse events occurred in 39% of patients. There were no incidences of treatment discontinuation of grade 5 treatment-related adverse events.

Among the 32 patients in the combination group, 16% experienced a grade 3/4 treatment-related adverse event, with none occurring in more than 1 patients. Treatment-related adverse events led to dose reduction of cetuximab in 31% of patients, and of adagrasib in 3% of patients. Discontinuation of cetuximab due to treatment-related adverse events occurred in 16% of patients (due to infusion-related reactions in 3 patients, malaise in 1 patient, and vascular flushing in 1 patient). There were no incidences of adagrasib discontinuation due to treatment-related events or grade 5 treatment-related adverse events.

Dr Yaeger et al concluded both the monotherapy and combination therapy “produced reversible toxic effects in the majority of patients and resulted in no new safety concerns.” They continued, “Adagrasib showed promising clinical activity in heavily pretreated patients with metastatic colorectal cancer with a KRAS G12C mutation. The biologic activity of adagrasib appeared to be even greater in combination with cetuximab and supports ongoing clinical investigation.”

Source:

Yaeger R, Weiss J, Pelster MS, et al. Adagrasib with or without cetuxumab in: colorectal cancer with mutated KRAS G12C. N Engl J Med. Published online: December 21, 2022. doi:10.1056/NEJMoa2212419