Abstract
Background
Adagrasib, an oral small-molecule inhibitor of mutant KRAS G12C protein, has shown objective enactment successful pretreated patients with respective tumor types, including colorectal cancer. Preclinical studies suggest that combining a KRAS G12C inhibitor with an epidermal maturation origin receptor antibody could beryllium an effectual objective strategy.
Methods
In this signifier 1–2, open-label, nonrandomized objective trial, we assigned heavy pretreated patients with metastatic colorectal crab with mutant KRAS G12C to person adagrasib monotherapy (600 mg orally doubly daily) oregon adagrasib (at the aforesaid dose) successful operation with intravenous cetuximab erstwhile a week (with an archetypal loading dose of 400 mg per quadrate metre of body-surface area, followed by a dose of 250 mg per quadrate meter) oregon each 2 weeks (with a dose of 500 mg per quadrate meter). The superior extremity points were nonsubjective effect (complete oregon partial response) and safety.
Results
As of June 16, 2022, a full of 44 patients had received adagrasib, and 32 had received operation therapy with adagrasib and cetuximab, with a median follow-up of 20.1 months and 17.5 months, respectively. In the monotherapy radical (43 evaluable patients), a effect was reported successful 19% of the patients (95% assurance interval [CI], 8 to 33). The median effect duration was 4.3 months (95% CI, 2.3 to 8.3), and the median progression-free endurance was 5.6 months (95% CI, 4.1 to 8.3). In the combination-therapy radical (28 evaluable patients), the effect was 46% (95% CI, 28 to 66). The median effect duration was 7.6 months (95% CI, 5.7 to not estimable), and the median progression-free endurance was 6.9 months (95% CI, 5.4 to 8.1). The percent of people 3 oregon 4 treatment-related adverse events was 34% successful the monotherapy radical and 16% successful the combination-therapy group. No people 5 adverse events were observed.
Conclusions
Adagrasib had antitumor enactment successful heavy pretreated patients with metastatic colorectal crab with mutant KRAS G12C, some arsenic oral monotherapy and successful operation with cetuximab. The median effect duration was much than 6 months successful the combination-therapy group. Reversible adverse events were communal successful the 2 groups. (Funded by Mirati Therapeutics; KRYSTAL-1 ClinicalTrials.gov number, NCT03785249.)
Funding and Disclosures
Supported by Mirati Therapeutics and by a assistance (P30 CA 008748) to the Memorial Sloan Kettering Cancer Center from the National Cancer Institute.
Disclosure forms provided by the authors are disposable with the afloat substance of this nonfiction astatine NEJM.org.
This nonfiction was published connected December 21, 2022, astatine NEJM.org.
A data sharing statement provided by the authors is disposable with the afloat substance of this nonfiction astatine NEJM.org.
We convey the patients and their families and caregivers; the proceedings squad members astatine each site; Rachel Verdon of Ashfield MedComms for penning enactment with a erstwhile mentation of the manuscript; and Linh Alejandro and Aditya Shetty of Mirati Therapeutics for contributions to the improvement of the manuscript.
Author Affiliations
From the Department of Medicine, Memorial Sloan Kettering Cancer Center, New York (R.Y.); Lineberger Comprehensive Cancer Center, University of North Carolina astatine 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.) — some successful 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.) — each successful 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.) — some successful Boston.
Dr. Klempner tin beryllium contacted astatine [email protected] oregon astatine the Department of Medicine, Division of Hematology–Oncology, Massachusetts General Hospital, Boston, MA 02114. Dr. Yaeger tin beryllium contacted astatine [email protected] oregon astatine the Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065.
A implicit database of the KRYSTAL-1 proceedings investigators is provided successful the Supplementary Appendix, disposable astatine NEJM.org.
English (US)