Adagrasib provides antitumor activity against metastatic KRAS G12C-mutated colorectal cancer as monotherapy and in combination with cetuximab.

1. The overall tumor response to monotherapy with adagrasib was 23% and 46% in combination with cetuximab.

2. The median progression-free survival was 5.6 months on adagrasib monotherapy and 6.9 months on combination therapy with cetuximab.

The level of classification of evidence: 2 (good)

Study rundown: An oncogene homolog of the Kirsten rat sarcoma virus (Brochure) It is responsible for the formation of tumors in approximately half of patients diagnosed with colorectal cancer (CRC). The prognosis is worse for patients with Brochure G12C allele. Small-molecule adagrasib is a covalent inhibitor of KRAS G12C and renders it inactive. This Phase 1-2 clinical trial investigated the use of adagrasib as a monotherapy agent for metastatic CRC (mCRC) with mutated KRAS G12C as well as in combination with cetuximab in previously severely treated patients. The primary outcome of this study was the activity of adagrasib monotherapy as determined by objective response. Secondary outcomes include progression-free survival (PFS), overall survival (OS), and study drug safety. The objective response to adagrasib was 23% compared to 46% in combination therapy patients. The median PFS was 5.6 months in the single-treatment adagrasib group, while it was 6.9 months in the combination group. Median OS was 19.8 months in the adagrasib group and 13.4 months in the combination therapy group. Adverse events (AEs) occurred in the majority of patients including 93% in the adagrasib group and 100% in the combination group. Diarrhea was common among the groups, as was nausea and vomiting. Limitations of this study include that it was a non-randomized trial, which prevents direct comparison of the two treatment groups and that the study enrolled small numbers of patients in each group, which limits the generalizability of the results. Overall, the results of this study provide evidence that adagrasib monotherapy and its combination with cetuximab as a treatment for mCRC pretreated with Brochure The G12C mutation is a potentially beneficial treatment that requires further investigation.

Click to read the study in the New England Journal of Medicine

Related reading: KRAS G12C metastatic colorectal cancer: specific features of new onset

target population.

in depth [prospective cohort]: This open-label, non-randomised trial was recruited and adult patients with an mCRC and KRAS G12C mutation who received standard treatment with fluoropyrimidine-based chemotherapy, but who had no other standard-of-care treatment options available at enrolment, were recruited. Forty-four patients with mCRC were given adagrasib monotherapy, while 32 patients received a combination of adagrasib and cetuximab. Of the monotherapy group, only 43 patients were clinically evaluated, whereas only 28 patients of the combination group were evaluated. The activity of adagrasib was determined by the overall response to the drug. According to a central blinded review, 23% of those receiving monotherapy had a response (95% confidence interval (CI), 12-39%). Objective response to combination therapy was 46% of the 28 patients (95% CI, 28–66%). The median PFS in the monotherapy group was 5.6 months (95% CI, 4.1–8.3 months) and the median OS was 19.8 months (95% CI, 12.5–23.0). The median PFS among all 32 combination therapy patients was 6.9 months (95% CI, 5.4–8.1 months) and the median OS was 13.4 months (95% CI, 9.5–20.1 months). 93% of patients in the monotherapy group experienced AEs of any degree compared to 100% of patients in the combination therapy. Grade 3 and above adverse events occurred in 34% of the monotherapy arm compared to 16% in the combination arm.

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