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Review
. 2025 Aug;21(18):2275-2285.
doi: 10.1080/14796694.2025.2524311. Epub 2025 Jul 6.

Adagrasib in the treatment of colorectal cancer

Sara F Haddad  1 , Youssef Bouferraa  2 , Kanika G Nair  2
Affiliations
Review

Adagrasib in the treatment of colorectal cancer

Sara F Haddad et al. Future Oncol. 2025 Aug.

Abstract

KRASG12C mutations occur in 3-4% of metastatic colorectal cancer (mCRC) cases and confer a poor prognosis. Adagrasib is an oral, small molecule that selectively and irreversibly inhibits KRASG12C. The phase I/Ib KRYSTAL-1 study established 600 mg twice daily as a recommended phase II dose. Adagrasib monotherapy showed efficacy in heavily pretreated patients with KRASG12C-mutated mCRC. When combined with cetuximab, an anti-EGFR monoclonal antibody, efficacy was further improved with an ORR of 34% and median OS of 15.9 months, leading to the accelerated approval of the combination by the Food and Drug Administration (FDA) in USA in 2024, but it is not yet approved in the European Union. Adagrasib is a well-tolerated drug as monotherapy and in combination with cetuximab and represents a novel treatment for KRASG12C-mutated mCRC.

Keywords: KRAS inhibitor; KRASG12C; Krazati; Metastatic colorectal cancer; adagrasib; small molecule inhibitor.

Plain language summary

KRASG12C is a specific gene mutation that occurs in 3–4% of metastatic colorectal cancers. When this is present, the cancer is more aggressive and harder to treat. Adagrasib is a pill that specifically targets KRASG12C to block the faulty protein made by this mutation and stop the cancer from growing. Early clinical studies (called KRYSTAL-1) showed taking 600 mg of adagrasib twice a day was the most effective and safe dose. Adagrasib showed positive results in people whose cancer had progressed on other therapies, including multiple types of chemotherapy. When adagrasib is combined with cetuximab, a drug that blocks a protein called EGFR, the results were improved even more – the tumors shrank for 34% of these patients and the average survival time was 16 months. Due to these results, the U.S. Food and Drug Administration gave the combination accelerated approval in 2024 for treating colorectal cancers with a KRASG12C mutation. It has not yet been approved in the European Union. Adagrasib is tolerated well, both on its own and in combination with cetuximab and more research is being done on how to further improve the effectiveness of adagrasib. This is a promising new treatment for many patients with colorectal cancer.

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Conflict of interest statement

Kanika G. Nair has received honoraria from Taiho Oncology and advisory fees from Exelixis. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Figures

Figure 1.
Figure 1.
KRAS signaling pathway and possible therapeutic combinations to overcome resistance.
See this image and copyright information in PMC

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