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Adagrasib with or without Cetuximab in Colorectal Cancer with Mutated KRAS G12C
Rona Yaeger1, Jared Weiss1, Meredith S Pelster1
1From the Department of Medicine, Memorial Sloan Kettering Cancer Center, New York (R.Y.); Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill (J.W.); Sarah Cannon Research Institute, Tennessee Oncology, Nashville (M.S.P.); Virginia Cancer Specialists, NEXT Oncology-Virginia, Fairfax (A.I.S.); US Oncology Research, the Woodlands (A.I.S.), and Mary Crowley Cancer Research, Dallas (M.B.) - both in Texas; the University of California Irvine School of Medicine, Chao Family Comprehensive Cancer Center, Orange (S.-H.I.O.), and Mirati Therapeutics, San Diego (J.G.C., K.V., T.K., H.D.-T.) - all in California; the Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta (T.A.L.); Medical Oncology, Mayo Clinic, Phoenix, Arizona (T.S.B.-S.); Belfer Center for Applied Cancer Science and the Department of Medical Oncology, Dana-Farber Cancer Institute (C.P.P., G.A.H.), and the Department of Medicine, Division of Hematology-Oncology, Massachusetts General Hospital (S.J.K.) - both in Boston.
Background:
Adagrasib, an oral small-molecule inhibitor of mutant KRAS G12C protein, has shown clinical activity in pretreated patients with several tumor types, including colorectal cancer. Preclinical studies suggest that combining a KRAS G12C inhibitor with an epidermal growth factor receptor antibody could be an effective clinical strategy.
Methods:
In this phase 1-2, open-label, nonrandomized clinical trial, we assigned heavily pretreated patients with metastatic colorectal cancer with mutant KRAS G12C to receive adagrasib monotherapy (600 mg orally twice daily) or adagrasib (at the same dose) in combination with intravenous cetuximab once a week (with an initial loading dose of 400 mg per square meter of body-surface area, followed by a dose of 250 mg per square meter) or every 2 weeks (with a dose of 500 mg per square meter). The primary end points were objective response (complete or partial response) and safety.
Results:
As of June 16, 2022, a total of 44 patients had received adagrasib, and 32 had received combination therapy with adagrasib and cetuximab, with a median follow-up of 20.1 months and 17.5 months, respectively. In the monotherapy group (43 evaluable patients), a response was reported in 19% of the patients (95% confidence interval [CI], 8 to 33). 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). In the combination-therapy group (28 evaluable patients), the response was 46% (95% CI, 28 to 66). 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). The percentage of grade 3 or 4 treatment-related adverse events was 34% in the monotherapy group and 16% in the combination-therapy group. No grade 5 adverse events were observed.
Conclusions:
Adagrasib had antitumor activity in heavily pretreated patients with metastatic colorectal cancer with mutant KRAS G12C, both as oral monotherapy and in combination with cetuximab. The median response duration was more than 6 months in the combination-therapy group. Reversible adverse events were common in the two groups. (Funded by Mirati Therapeutics; KRYSTAL-1 ClinicalTrials.gov number, NCT03785249.).
Insights
Adagrasib showed antitumor activity in patients with metastatic colorectal cancer harboring KRAS G12C mutations. Combining adagrasib with cetuximab improved response rates and duration compared to adagrasib alone.
Area of Science:
- Oncology
- Medical Research
- Clinical Trials
Background:
- Adagrasib, an oral small-molecule inhibitor targeting mutant KRAS G12C, demonstrates clinical activity in pretreated patients with various cancers, including colorectal cancer.
- Preclinical data suggest that combining KRAS G12C inhibitors with epidermal growth factor receptor antibodies may enhance clinical efficacy.
Purpose of the Study:
- To evaluate the safety and efficacy of adagrasib monotherapy versus adagrasib in combination with cetuximab in patients with heavily pretreated metastatic colorectal cancer with KRAS G12C mutation.
Main Methods:
- A phase 1-2, open-label, nonrandomized clinical trial assigned patients to receive adagrasib monotherapy or adagrasib plus intravenous cetuximab.
- Primary endpoints included objective response rate (complete or partial response) and safety assessment.
Main Results:
- In the adagrasib monotherapy group (43 evaluable patients), the objective response rate was 19%, with a median progression-free survival of 5.6 months.
- In the combination therapy group (28 evaluable patients), the objective response rate was 46%, with a median progression-free survival of 6.9 months and a median response duration exceeding 6 months.
- Grade 3 or 4 treatment-related adverse events were observed in 34% of the monotherapy group and 16% of the combination therapy group, with no grade 5 events.
Conclusions:
- Adagrasib exhibits antitumor activity in heavily pretreated patients with KRAS G12C-mutant metastatic colorectal cancer, both as monotherapy and in combination with cetuximab.
- Combination therapy with adagrasib and cetuximab demonstrated a higher response rate and longer response duration compared to adagrasib monotherapy.
- Reversible adverse events were common, and the combination regimen was generally well-tolerated.
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