The therapeutic landscape of metastatic colorectal cancer (mCRC) is moving towards biomarker-selected strategies. The ongoing KRYSTAL-1 phase I/II trial provides clinical evidence that KRAS G12C can be targeted in heavily pre-treated patients with mCRC, with activity observed for adagrasib as monotherapy and in combination with cetuximab.
Adagrasib is an oral small-molecule inhibitor of the mutant KRAS G12C protein that previously demonstrated clinical activity in pre-treated patients with several tumour types, including colorectal cancer (CRC). In addition, preclinical studies suggested that combining a KRAS G12C inhibitor with an epidermal growth factor receptor antibody could be an effective clinical strategy. The ongoing KRYSTAL-1 phase I/II trial therefore evaluated the use of adagrasib as monotherapy or in combination with cetuximab in patients with previously treated metastatic CRC with mutant KRAS G12C. In this open-label trial, heavily pre-treated patients with mutant KRAS G12C CRC received adagrasib monotherapy at a dose of 600 mg twice daily or adagrasib in combination with intravenous cetuximab once a week (initial loading dose of 400 mg/m2 of body-surface area, followed by dosing of 250 mg/m2) or every two weeks (dose of 500 mg/m2). Primary endpoints of the trial are objective response (complete or partial), and safety.
As of June 2022, a total of 44 patients had received adagrasib monotherapy and 32 patients had received the combination with cetuximab. Median follow-up time was 20.1 and 17.5 months for the monotherapy and combination regimen, respectively. Of the 43 patients who received adagrasib monotherapy in the clinically evaluable population, the response was 23% according to blinded independent central review (BICR) and 19% according to investigator assessment. The median duration of response was 4.3 months and the median time to response was 1.5 months. Among all 44 patients in this cohort, the median progression-free survival (PFS) was 5.6 months and the median overall survival (OS) was 19.8 months. Among the 28 patients who received adagrasib plus cetuximab in the clinically evaluable population, the response was 46% according to BICR and to investigator assessment. The median duration of response was 7.6 months and the median time to response was 1.4 months. Among all 32 patients in this cohort, the median PFS was 6.9 months and the median OS was 13.4 months. Grade 3-4 treatment-related adverse events were reported in 34% of patients in the monotherapy group and in 16% of patients in the combination-therapy group. No grade 5 adverse events occurred.
In this phase I/II trial of adagrasib as monotherapy and in combination with cetuximab, both treatments produced reversible toxic effects in the majority of patients and resulted in no new safety concerns. Adagrasib showed promising clinical activity in heavily pre-treated 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.