Pharmacokinetics and safety of capmatinib with food in patients with MET-dysregulated advanced solid tumors.

Purpose: In the Phase II GEOMETRY mono-1 study, the potent and selective mesenchymal-epithelial transition (MET) inhibitor capmatinib exhibited considerable efficacy in MET exon 14 skipping (METex14)-mutated metastatic non-small cell lung cancer at a dose of 400 mg BID. The current recommended dose is 400 mg BID in tablet formulation, with or without food. This article reports the pharmacokinetic (PK) profile, safety, and tolerability of capmatinib 300 and 400 mg BID given with food in MET-dysregulated advanced solid tumors.
Methods: This multicenter, open-label, Phase I study enrolled adult patients with MET-dysregulated advanced solid tumors. In the dose escalation phase, capmatinib tablets were orally administered at a dose of 300 mg BID with food; if tolerated, the dose escalation cohort of 400 mg BID was to be opened to enrollment. In the expansion phase, patients were to be enrolled at the higher of the tolerated doses. Tablets were taken within 30 minutes of an unrestricted meal type, except on cycle 1 day 1 (C1D1) and cycle 1 day 7 (C1D7), when they were given with a high-fat meal. The primary objectives were to determine the higher of the tolerated study doses and assess PK variables, with a secondary objective of safety.
Findings: Overall, 35 patients (300 mg BID, n = 8; 400 mg BID, n = 27) with MET-dysregulated advanced solid tumors were enrolled; all patients had received prior antineoplastic therapy, and the most common primary site was lung (45.7%). Among PK-evaluable patients, the median T _max for capmatinib after administration with a high-fat meal (on C1D1/C1D7) was 4.0 to 5.6 hours across doses. At steady state (C1D7), capmatinib accumulation was low across dose levels (geometric mean of accumulation ratios, 1.29-1.69), with an increase in exposure (AUC _tau and C _max ) from 300 to 400 mg BID. There were no occurrences of dose-limiting toxicity. All patients experienced at least 1 adverse event, and treatment-related adverse events occurred in 28 patients (80%; 300 mg BID, n = 6; 400 mg BID, n = 22), the most frequent of which were fatigue (37.1%) and nausea (34.3%).
Implications: Capmatinib tablet formulation at a dose of up to 400 mg BID with food is well tolerated in patients with MET-dysregulated advanced solid tumors, with safety observations consistent with the existing profile under fasted conditions. These findings support the capmatinib dosing recommendation of 400 mg BID with or without food. ClinicalTrials.gov identifier: NCT02925104.
Competing Interests: DISCLOSURES Dr. Moreno has received personal fees (advisory board honoraria) from Bristol Myers Squibb, Bayer, Pieris, Janssen, Roche and Basilea, outside of the current work. Dr. Greil has received personal fees from AstraZeneca, Novartis, Amgen, Bristol Myers Squibb, Merck Sharp & Dohme, Sandoz, AbbVie, Gilead, Daiichi Sankyo, and Janssen, outside of the current work. Dr. Arkenau is employed by the Sarah Cannon Research Institute, UK (part of HCA Healthcare UK); and has received personal fees (advisory board honoraria) from Pierre Fabre, Servier, BeiGene, Bicycle, BioNTech, iOnctura, Roche, Guardant and Taiho, outside of the current work. Dr. Majem has received grant support and personal fees from Bristol Myers Squibb; personal fees and non-financial support from Merck Sharp & Dohme and Boehringer Ingelheim; personal fees, non-financial support, and other support from AstraZeneca and Roche; and personal fees from Kyowa Kirin and Pierre Fabre, all of which are outside of the current work. Dr. Wermke has received grant support (research funding) and personal fees (honoraria) from Novartis, outside of the current work. Dr. Basque, Kapoor, and Giovannini and Mr. Nidamarthy are full-time employees of Novartis. Dr. Cui is a full-time employee and shareholder of Novartis. The authors have indicated that they have no other conflicts of interest regarding the content of this article. Data were collected and analyzed by the sponsor (Novartis Pharmaceuticals Corporation) in conjunction with the authors.
(Copyright © 2021. Published by Elsevier Inc.)