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

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.

Trial registration: ClinicalTrials.gov NCT03785249.

FIG 1.

Disposition of study patients. ^aScreen failures were not distinguished by phase.

FIG 2.

Mean (+SD) plasma adagrasib concentration–time profiles (PK profiles): (A) after a single 600-mg oral dose and (B) after a 600-mg twice-a-day regimen in the steady state under fasting conditions. PK, pharmacokinetics; SD, standard deviation.

FIG 3.

(A) Waterfall plot depicting the best tumor change from baseline. (B) Spider plot depicting the change in tumor measurement over time. Clinical activity evaluable population, n = 24; one patient (NSCLC, treated with 600 mg twice a day) was not included due to having no target lesion; therefore, change from baseline cannot be calculated. Data cutoff date: August 15, 2021. CRC, colorectal cancer; NSCLC, non–small-cell lung cancer; PD, progressive disease; PR, partial response; SD, stable disease.