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

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 KRAS^G12C. 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 KRAS^G12C mutation.

MATERIALS AND METHODS

Patients with advanced KRAS^G12C-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 KRAS^G12C-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 KRAS^G12C-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 KRAS^G12C 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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