Colorectal cancer with KRAS mutations: adagrasib with or without cetuximab shows promise

Context

KRAS is the oncogene that most frequently has mutations in human cancers, including colorectal cancer.
Adagrasib was recently approved by the U.S. Food and Drug Administration for advanced non-small cell lung cancer.
Adagrasib is a highly targeted, oral-acting inhibitor of the G12C mutation-mutated protein KRASKRAS G12C indicates the glycine to cysteine mutation in codon 12 of the KRAS gene).
This clinical trial evaluated whether adagrasib alone or in combination with cetuximab (an anti-epidermal growth factor receptor inhibitor antibody) achieves an objective response against colorectal cancer with the mutation KRAS G12C.The combination has demonstrated activity in preclinical studies.

Conclusions

The KRYSTAL-1 clinical trial reports that adagrasib alone or in combination with cetuximab achieves an objective response of 19%–46% in metastatic colorectal cancer with the mutation KRAS G12C.
The median duration of response in the combination therapy group was>6 months.
Adverse events were frequent in both groups.

Study design

Phase 1–2, non-randomized, open-label clinical trial of adagrasib monotherapy (600 mg orally twice daily administered to 44 patients) and adagrasib in combination with intravenous cetuximab once weekly at a dose of 250 mg/m2 administered to 32 patients.
Primary outcomes: Safety and objective response (complete or partial) based on blinded, investigator-confirmed independent central review.
Funding: Targeted Therapeutics.

Main results

The median follow-up was 20.1 months in the monotherapy group and 17.5 months in the combination therapy group.
In the monotherapy group:
- objective response rate of 19% (95% CI, 8%–33%), for a median duration of response of 4.3 months (95% CI: 2.3–8.3 months);
- median progression-free survival (PFS) of 5.6 months (95% CI, 4.1–8.3 months).
In the combination therapy group:
- objective response rate of 46% (95% CI, 28%–66%), for a median duration of response of 7.6 months (95% CI, 5.7 months–not estimable);
- Median PFS of 6.9 months (95% CI, 5.4–8.1 months).
Grade 3 or 4 adverse events were observed in 34% of the monotherapy group and 16% of the combination therapy group, with diarrhoea as the single most frequent event.
No grade 5 adverse events occurred.

objective response rate of 19% (95% CI, 8%–33%), for a median duration of response of 4.3 months (95% CI: 2.3–8.3 months);
median progression-free survival (PFS) of 5.6 months (95% CI, 4.1–8.3 months).

objective response rate of 46% (95% CI, 28%–66%), for a median duration of response of 7.6 months (95% CI, 5.7 months–not estimable);
Median PFS of 6.9 months (95% CI, 5.4–8.1 months).

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Source — https://www.univadis.it/viewarticle/tumore-colorettale-con-mutazioni-di-kras-adagrasib-con-o-senza-cetuximab-si-dimostra-promettente

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