First-in-Human Phase I/IB Dose-Finding Study of Adagrasib (MRTX849) in Patients With Advanced KRASG12C Solid Tumors (KRYSTAL-1)

Author(s): Sai-Hong Ignatius Ou, MD, PhD1; Pasi A. Jänne, MD, PhD2; Ticiana A. Leal, MD3; Igor I. Rybkin, MD, PhD4; Joshua K. Sabari, MD, PhD5; Minal A. Barve, MD6
Source: DOI: 10.1200/JCO.21.02752 Journal of Clinical Oncology Published online February 15, 2022. PMID: 35167329
Original Article
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Dr. Lucio Gordan's Thoughts

This is an important progress for patients with KRASG12C mutation. Median PFS of 11 months is very encouraging for a previously “undruggable” molecular signature.

PURPOSE

Adagrasib (MRTX849) is an oral, highly selective, small-molecule, covalent inhibitor of KRASG12C. We report results from a phase I/IB study of adagrasib in non–small-cell lung cancer, colorectal cancer, and other solid tumors harboring the KRASG12C mutation.

MATERIALS AND METHODS

Patients with advanced KRASG12C-mutant solid tumors were treated with adagrasib 150 mg orally once daily, 300 mg once daily, 600 mg once daily, 1,200 mg once daily, or 600 mg orally twice a day using an accelerated titration design, which transitioned to a modified toxicity probability interval design when a predefined degree of toxicity was observed or target adagrasib exposure was achieved. Safety, pharmacokinetics, and clinical activity were evaluated.

RESULTS

Twenty-five patients were enrolled and received at least one dose of adagrasib. The recommended phase II dose (RP2D) was 600 mg twice a day on the basis of safety, tolerability, and observed pharmacokinetics properties. No maximum tolerated dose was formally defined. After a median follow-up of 19.6 months, eight of 15 patients (53.3%; 95% CI, 26.6 to 78.7) with RECIST-evaluable KRASG12C-mutant non–small-cell lung cancer treated at 600 mg twice a day achieved a confirmed partial response. The median duration of response was 16.4 months (95% CI, 3.1 to not estimable). The median progression-free survival was 11.1 months (95% CI, 2.6 to not estimable). One of two patients with KRASG12C-mutant colorectal cancer treated at 600 mg twice a day achieved a partial response (duration of response, 4.2 months). At the RP2D, the most common treatment-related adverse events (any grade) were nausea (80.0%), diarrhea (70.0%), vomiting (50.0%), and fatigue (45.0%). The most common grade 3-4 treatment-related adverse event was fatigue (15.0%).

CONCLUSION

Adagrasib 600 mg twice a day was well tolerated and exhibited antitumor activity in patients with advanced solid tumors harboring the KRASG12C mutation.

Author Affiliations

1University of California Irvine School of Medicine and Chao Family Comprehensive Cancer Center, Orange, CA 2Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 3University of Wisconsin Carbone Cancer Center, Madison, WI 4Henry Ford Cancer Institute, Detroit, MI 5Perlmutter Cancer Center New York University Langone Health, New York, NY 6Mary Crowley Cancer Center, Dallas, TX 7University of California San Diego, Moores Cancer Center, La Jolla, CA 8Sarah Cannon Research Institute, Tennessee Oncology, Nashville, TN 9Mirati Therapeutics, Inc, San Diego, CA 10START San Antonio, San Antonio, TX

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