Moreno, Victor, Greil, Richard, Yachnin, Jeffrey, Majem, Margarita, Wermke, Martin, Arkenau, Hendrik-Tobias, Basque, Jean-Rene, Nidamarthy, Prasanna, Kapoor, Shruti, Cui, Xiaoming and Giovannini, Monica (2021) Pharmacokinetics and safety of capmatinib with food in patients with MET-dysregulated advanced solid tumors. Clinical Therapeutics, 43 (6). p. 1092.

Abstract

Abstract
Purpose: In GEOMETRY mono-1, the potent and selective MET inhibitor capmatinib had considerable activity in METex14-mutated metastatic non–small cell lung cancer at a dose of 400 mg twice daily (bid). The current recommended dose is 400 mg bid in tablet formulation, with or without food. Herein, we report the pharmacokinetics (PK), 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 1 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 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, 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 time to peak plasma concentration (Tmax) for capmatinib after administration with a high-fat meal (on C1D1/C1D7) was 4.0‒5.6 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 from 300 to 400 mg bid (AUClast geometric mean 8660 vs 16800 ng*h/mL; Cmax geometric mean 1550 vs 3050 ng/mL). There were no occurrences of dose-limiting toxicity. All patients experienced at least one adverse event (AE) and treatment-related AEs 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.

Item Type:	Article
Keywords:	capmatinib, MET, phase 1, pharmacokinetics, food
Date Deposited:	11 May 2022 00:45
Last Modified:	11 May 2022 00:45
URI:	https://oak.novartis.com/id/eprint/43814