First-in-Human Phase I/IB Dose-Finding Study of Adagrasib (MRTX849) in Patients With Advanced KRAS(G12C) Solid Tumors (KRYSTAL-1)
Recommended Citation
Ou SI, Jänne PA, Leal TA, Rybkin, II, Sabari JK, Barve MA, Bazhenova LA, Johnson ML, Velastegui KL, Cilliers C, Christensen JG, Yan X, Chao RC, and Papadopoulos KP. First-in-Human Phase I/IB Dose-Finding Study of Adagrasib (MRTX849) in Patients With Advanced KRAS(G12C) Solid Tumors (KRYSTAL-1). J Clin Oncol 2022.
Document Type
Article
Publication Date
2-15-2022
Publication Title
Journal of clinical oncology
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.
PubMed ID
35167329
ePublication
ePub ahead of print
First Page
2102752
Last Page
2102752
