First-in-Human Phase I/IB Dose-Finding Study of Adagrasib (MRTX849) in Patients With Advanced <i>KRAS</i><sup><i>G12C</i></sup> Solid Tumors (KRYSTAL-1)
Sai‐Hong Ignatius Ou, Pasi A. Jänne, Ticiana Leal, Igor I. Rybkin, Joshua K. Sabari, Minal Barve, Lyudmila Bazhenova, Melissa L. Johnson, Karen Velastegui, Cornelius Cilliers, James G. Christensen, Xiaohong Yan, Richard C. Chao, Kyriakos P. Papadopoulos
Abstract
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.