The pharmacokinetics of capmatinib and its efficacy in non-small cell lung cancer treatment: a narrative review

Abstract

Background and Objective

Inhibitors of mesenchymal-epithelial transition (MET) receptor serve as significant therapeutic agents in MET-driven non-small cell lung cancer (NSCLC). Among these, capmatinib has demonstrated particularly notable efficacy and safety. However, the mechanisms responsible for its benefit remain unclear. This narrative review presents the pharmacokinetics (PK)-related evidence regarding the efficacy of MET inhibitors for NSCLC and examines the differences in capmatinib as compared to other type Ib MET inhibitors.

Methods

We conducted an exhaustive search of the English-language literature on MET inhibitors in NSCLC published or presented from June 2010 to February 2025 in the PubMed and Foreign Medical Literature Retrieval Service (FMRS; China) databases. It also included literature presented at various international meetings. The key literatures were identified from this search. Further, the clinical PK and clinical efficacy of type Ib MET inhibitors were analyzed.

Key Content and Findings

The review provides a comparison of the PK for type Ib MET inhibitors in clinical practice. Specifically, capmatinib is absorbed more quickly in humans and exhibits the highest level of exposure compared to other MET inhibitors. Capmatinib has greater efficacy as assessed via the ratio of half maximal inhibitory concentration, and there is no requirement for dosage adjustment based on any level of hepatic impairment. Capmatinib has a faster clearance time, minimizing the likelihood of accumulation and the occurrence of adverse events (AEs). Its exposure levels are minimally impacted by food intake and drug-drug interaction. Capmatinib has a good PK profile after combination with gefitinib, constituting a promising option for patients with epidermal growth factor receptor (EGFR)-mutated NSCLC. Moreover, capmatinib exerts marked effects for brain metastases (BMs) in patients with NSCLC due its lipophilicity and permeability. Furthermore, capmatinib and tepotinib demonstrate extraordinary efficacy for patients with NSCLC and MET exon 14 (METex14) skipping mutation, and the combination of capmatinib and gefitinib in particular can achieve remarkable therapeutic effects in patients with EGFR-mutated, MET-dysregulated (amplified/overexpressing) NSCLC.

Conclusions

MET inhibitors, especially capmatinib, are the preferred treatment choice for patients with NSCLC and METex14 mutation and BM. The administration of capmatinib can help mitigate potential food-intake and drug-drug interactions in clinical settings. This facilitates the optimization of long-term medication schedules, enhancing the clinical efficacy of the treatment.

Introduction

Mesenchymal-epithelial transition (MET) receptor tyrosine kinase activates a wide range of signaling pathways, including proliferation, motility, migration, and invasion. The gene amplification or mutation of MET can promote the development of several cancers, including non-small cell lung cancer (NSCLC) (1). MET dysregulation is recognized as a negative factor of NSCLC and was attributable to an estimated 1.8 million deaths in 2020 alone (2). Common types of MET dysregulations include MET exon 14 (METex14) skipping mutation, MET amplification, overexpression and fusion (1). Globally, several MET tyrosine kinase inhibitors (TKIs) have been approved for the treatment of NSCLC patients with MET dysregulations, including capmatinib, tepotinib, savolitinib, and gumarontinib. However, there is a lack of head-to-head clinical studies to support which MET TKI is the optimal choice. It’s definitely worth summarizing the differences in the pharmacology of the four MET TKIs, which may provide some insights for clinical experts.

Capmatinib (INC280) is an oral, adenosine triphosphate-competitive, reversible, highly selective inhibitor of the MET receptor tyrosine kinase (3) and especially effective in binding to the mutant variant produced by METex14 skipping (4). Capmatinib was first approved in the United States for the treatment of adults with metastatic NSCLC with tumors whose mutation results in METex14 skipping (4). Compared with other type Ib MET inhibitors, capmatinib has demonstrated the highest inhibitory effect on cancer cell growth driven by MET pathway activation in preclinical studies (3,5). Capmatinib is highly potent, with a half maximal inhibitory concentration (IC₅₀) of 0.6 nmol/L in the Ba/F3 cell line with METex14 mutations, and it has a 10,000-fold selectivity for c-met over a large panel of human kinase, including the blockage of c-met phosphorylation and the activation of epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor-3 (HER-3) pathways (3). In clinical studies, capmatinib has been well tolerated by patients, with only mild or moderate adverse events (AEs) (6-8). Antitumor activity has been observed in patients with NSCLC treated with capmatinib alone or in combination with gefitinib (7,8). In a study on treatment-naive patients with NSCLC and the METex14 skipping mutation, capmatinib demonstrated excellent therapeutic effects, with an overall response rate (ORR) of 68%, a median progression-free survival (mPFS) of 12.5 months, and a median overall survival (mOS) of 21.4 months (8). Brain metastasis (BM) in patients with NSCLC is associated with a poor prognosis and survival outcome (9); therefore, the ability to cross the blood-brain barrier (BBB) is a key trait for an effective MET inhibitor in treating these patients. In one study, the mean cerebrospinal fluid (CSF) capmatinib concentration in rats and monkeys was approximately 33.5% and 89.8%, respectively, and corresponded to the estimated free plasma concentration. Indeed, the activity of capmatinib in the brain is encouraging, with good intracranial responses observed in patients with NSCLC, BMs, and METex14 mutation (10). Based on initial ORR and duration of response demonstrated in the GEOMETRY mono-1 trial, capmatinib was granted accelerated approval by US Food and Drug Administration (FDA) for the treatment of adult patients with metastatic NSCLC and the METex14 mutation on May 6, 2020. On August 10, 2022, the FDA granted regular approval to it for the same indication.

The narrative review provides an overview of the pharmacokinetics (PK) related to the superior efficacy of capmatinib over other type Ib MET inhibitors in the treatment of NSCLC to better inform application in clinical practice. We present this article in accordance with the Narrative Review reporting checklist (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-700/rc).

Methods

We conducted an exhaustive search of the English-language literature on MET inhibitor in NSCLC published or presented from June 2010 to February 2025. This search encompassed both the PubMed and the Foreign Medical Retrieval System (FMRS) databases of China. It also included literature presented at various international meetings, including the European Lung Cancer Conference (ELCC), the American Association for Cancer Research (AACR), the American Society of Clinical Oncology (ASCO), the World Conference on Lung Cancer (WCLC), the European Society for Medical Oncology (ESMO), and the ESMO Asia meetings. The search terms included “mesenchymal-epithelial transition inhibitors”, “non-small cell lung cancer”, “pharmacokinetics”, “capmatinib”, “tepotinib”, “savolitinib”, “glumetinib”, “gumarontinib”, “brain metastases”, “gefitinib”, “efficacy”, “IC₅₀” and “safety”. We then screened the literature to identify key papers related to MET inhibitors, including capmatinib, for the treatment of NSCLC. The preclinical basic research data, results of clinical PK, and clinical efficacy of type Ib MET inhibitors were analyzed and discussed in this review. The specific search strategy is detailed in Table 1.

Table 1. Summary of the search strategy.

Items	Specification
Date of search	February 28, 2025
Databases and other sources searched	The PubMed and FMRS (China) databases and the ELCC, AACR, ASCO, WCLC, ESMO, and ESMO Asia meetings
Search terms used note	“Mesenchymal-epithelial transition inhibitors”, “non-small cell lung cancer”, “pharmacokinetics”, “capmatinib”, “tepotinib”, “savolitinib”, “glumetinib”, “gumarontinib”, “brain metastases”, “gefitinib”, “efficacy”, “IC50”, “safety”
Timeframe	Concentrated in June 2010–February 2025, with a small amount of literature published from 2000 and 2010
Inclusion criteria	Studies in the English language, type Ib MET inhibitors, and human PK
Selection process	B.B. performed literature selection, with J.Z., B.F., and W.F. contributing. S.L. reviewed the literature and made the final decision for inclusion
Any additional considerations	Primary focus on studies related to the METex14 mutation

AACR, the American Association for Cancer Research; ASCO, the American Society of Clinical Oncology; ELCC, European Lung Cancer Conference; ESMO, the European Society for Medical Oncology; FMRS, Foreign Medical Literature Retrieval Service; IC₅₀, half maximal inhibitory concentration; MET, mesenchymal-epithelial transition; METex14, MET exon 14 skipping; PK, pharmacokinetics; WCLC, the World Conference on Lung Cancer.

The characteristics of clinical PK

Absorption

In a dose-escalation study, the area under the curve (AUC) and peak concentration (C_max) in steady-state capmatinib were found to be generally dose proportional at a range of 100 to 600 mg twice a day (BID) (11). Meanwhile, the increase in dose proportionality of tepotinib exposure was reported for doses within 300 mg qd, with a lower increase at higher doses [400–1,400 mg once a day (QD)] (12). According to the supplementary data of savolitinib in a first-in-human phase I study (13), the AUC and C_max were dose proportional at the range from 100 to 1,000 mg QD. Unfortunately, we could not obtain the linear PK data of gumarontinib in patients with tumors to provide a more detailed analysis for a closer look at the PK of MET inhibitors. Table 2 provides a summary of the PK parameters of various MET inhibitors at their recommended phase II doses (RP2Ds). The absorption of capmatinib in the human body [time to maximum concentration (t_max) 1.09–1.87 hours] is faster than that of tepotinib (t_max 8.0 hours), savolitinib (t_max 2.0–4.0 hours), and gumarontinib (t_max 4.0 hours) (12-15), with the plasma concentration of tepotinib reaching its peak the latest. The systemic exposure of capmatinib is the highest, while that of tepotinib is relatively low after a single dose, with the others being relatively similar. Capmatinib is a highly potent MET inhibitor in many types of tumor cells, with an IC₅₀ of 0.3–1.1 nmol/L (3,16). In one study, the Ba/F3 cell line with METex4 skipping mutations was used to verify the efficacy of MET inhibitors (17). As shown in Table 3, the IC₅₀ with METex14 mutations of capmatinib, tepotinib, and savolitinib are 0.6, 3.0, and 2.1 nmol/L, respectively. By comparing IC₅₀ values, we found that capmatinib has considerably greater efficacy than do the other inhibitors. For MET chromosomal rearrangement [translocated promoter region (TPR)-MET], the IC₅₀ of capmatinib, tepotinib, and savolitinib are 2.2, 24, and 8.8 nmol/L, respectively. In another study employing METex14 mutations assays, gumarontinib was found to inhibit MET phosphorylation in BaF3/TPR-MET (IC₅₀ =2.45 nmol/L) (18). Based on the excellent absorption, capmatinib has shown particular high efficacy and controllable safety profile, especially in patients with the METex14 skipping mutation and BM (8).

Table 2. PK parameters of II type MET inhibitors.

MET inhibitor	Dose†	Patients	Treatment	Tmax (h)	t1/2 (h)	Cmax (ng/mL)	AUC0-t (ng·h/mL)	CL (L/h)	Racc	Reference
Capmatinib	400 mg (BID)	Patients (fasting) with MET-dysregulated advanced NSCLC	Single	1.87	NA	3,600	14,400	NA	–	(14)
			Multiple	1.09	6.54	4,780	20,200	NA	1.40
Tepotinib	500 mg (QD)	Patients (fed) with MET-dysregulated advanced NSCLC	Single	8.0	NA	461	7,637	NA	–	(12)
			Multiple	8.0	46‡	1,291	27,438	26.43	3.59
Savolitinib	600 mg (QD)	Patients (fasting) with locally advanced or metastatic solid tumors	Single	4.0	5.6	2,575.3	17,757.6	(32.95, 48.33)§	–	(13)
			Multiple	2.0	3.711	2,414.8	17,053.9	NA	0.96
Gumarontinib	300 mg (QD)	Healthy males (fasting)	Single	4.0	26.1	824.2	24,799.8	12.8	–	(15)
			Multiple	NA	NA	NA	NA	NA	–

^†, recommended phase II dose (RP2D); ^‡, average effective t_1/2 (an approximate value); ^§, range of value. The C_max, AUC_0–t, CL_, and t_1/2 values are expressed as the geometric mean, while T_max values are expressed as the median. AUC_0-t, area under the plasma concentration-time curve from time zero to the last detectable concentration; CL, total body clearance; C_max, maximum plasma concentration; MET, mesenchymal-epithelial transition; NA, not available; NSCLC, non-small cell lung cancer; PK, pharmacokinetics; Racc, accumulation ratio; T_max, rime to reach the C_max; t_1/2, terminal elimination half-life.

Table 3. IC₅₀ of II type MET inhibitors.

MET inhibitor	Cell line	IC50 (nmol/L)	Reference
Capmatinib	Ba/F3 cells harboring MET exon 14 mutations	0.6	(17)
Tepotinib	Ba/F3 cells harboring MET exon 14 mutations	3.0	(17)
Savolitinib	Ba/F3 cells harboring MET exon 14 mutations	2.1	(17)
Gumarontinib	Ba/F3 cells harboring TPR-MET mutations	2.45	(18)

IC₅₀, half maximal inhibitory concentration; MET, mesenchymal-epithelial transition.

Metabolism

MET inhibitors are predominantly metabolized via the liver. Previous study has found that capmatinib is metabolized via cytochrome P450 (CYP) 3A4, with aldehyde oxidase (19), tepotinib, savolitinib, and gumarontinib also primarily metabolized by this enzyme. Patients with hepatic impairment may experience higher exposure to capmatinib. To verify whether the metabolism of capmatinib is different in individuals with decreased liver function, a study was conducted to compare the PK changes in capmatinib in participants with hepatic impairment and those in a control group with healthy liver function. All patients received a single oral dose of 200 mg capmatinib (20). Compared to that in control group, the group with mild hepatic dysfunction had a 27.6% lower C_max, the moderate hepatic dysfunction group a 17.2% lower C_max, and the severe hepatic dysfunction had an unchanged C_max; meanwhile, the area under the curve from time zero to infinity (AUC_inf) was 23.3% lower, 8.6% lower, and 24% higher, respectively. The PK differences of capmatinib at all levels of hepatic dysfunction were not considered significantly different to those of the control group, suggesting that a dose adjustment of capmatinib is not required for patients with hepatic impairment. Capmatinib was also well tolerated in participants with mild, moderate, and severe hepatic dysfunction. It was also reported that total tepotinib exposure is similar among participants with mild or moderate hepatic impairment and normal function, but unbound tepotinib AUC_inf was 13% and 24% higher in patients with mild and moderate hepatic dysfunction, respectively (21). However, the C_max of unbound tepotinib and the total tepotinib exposure in participants with severe hepatic impairment are unknown. Thus far, there are no PK studies on savolitinib and gumarontinib PK in patients with hepatic impairment have been performed. Additionally, for patients with savolitinib treatment, the recommended starting dose is 600 mg for those with body weight ≥50 kg, and 400 mg for those with body weight <50 kg. This indicates that savolitinib’s PK may be influenced by body weight, necessitating weight-based dose adjustments to optimize efficacy and safety. In contrast, other MET TKIs exhibit stable pharmacokinetic profiles across varying body weights, allowing fixed initiation doses without the need for weight-based modifications.

Elimination

Under fasting conditions, capmatinib and savolitinib metabolize quite quickly, with the terminal elimination half-life (t_1/2) of 6.54 and 3.711 hours after multi-dosing, respectively (Table 2). In contrast, tepotinib and gumarontinib have a relatively long elimination t_1/2 of about 1 to 2 days. Absorbed capmatinib is eliminated mainly via metabolism and subsequent biliary/fecal and renal excretion, with the clearance of capmatinib being at a moderate-to-high range (30.0–121 L/h) (19). The clearance of tepotinib after multiple administrations is 26.43 L/h, while that of savolitinib and gumarontinib is 32.95–48.33 and 12.8 L/h after a single administration, respectively. These data also indicate that capmatinib and savolitinib are cleared faster in the human body, but no studies on the differences in TKIs clearance, for example, related to race, metabolic enzyme, gender, or body mass index have been conducted. At a steady state, the accumulation of capmatinib at 400 mg BID is low [accumulation ratio (Racc) =1.40], close to that of savolitinib (Racc =0.96), which is an indicator of benign long-term medication. Capmatinib has a short half-life, and theoretically, its dosing interval should be shorter than specified. However, due to its high therapeutic index, the maintenance time of the concentration can be extended by increasing the dosage. Based on the efficacy and toxicity data (6,7,17,22), BID is safe, effective, and convenient for clinical application. It is worth noting that there is a significant accumulation of tepotinib after continuous use of 500 mg QD (Racc =3.59), requiring a careful consideration of the risks of dose increase and individualized drug disposal in clinical practice. However, a recent case report showed the feasibility of using the standard dose of tepotinib (500 mg) in a patient with advanced METex14 skipping NSCLC with end-stage renal disease undergoing hemodialysis, who attained disease control without dose adjustment (23). However, further research on tepotinib with a greater sample size is necessary to confirm whether renal injury affects its elimination and accumulation (12). The above analysis on drug eliminations may serve as a reference for preventing AEs.

Impact of food intake

Food intake is likely to alter the PK of many antitumor drugs, and therefore, their safety. It is thus critical that novel drugs be evaluated in terms of the influence of food and lipid intake on their PK. One study (22) reported the PK profile and safety of capmatinib at 300 and 400 mg BID administered with food in patients with advanced solid tumors and MET mutation; moreover, compared with the steady-state T_max of 1.09 hours reported in the GEOMETRY mono-1 trial (14), the steady-state T_max for capmatinib at 400 mg BID with a high-fat meal was 4.0 hours longer. The accumulation of capmatinib at 400 mg BID administered with food was similar (Racc =1.29) to that under fasted conditions (Racc =1.39). The C_max and AUC_0–12h for capmatinib at 400 mg BID tablet after food intake were 36% and 20% lower than those under fasting, respectively. Therefore, it can be concluded that capmatinib administered with food does not significantly affect its exposure. In a first-in-man phase I trial that investigated the maximum tolerated dose (MTD) of tepotinib (12), the initial capsule formulation produced a highly variable AUC and C_max in fasting patients, so the formulation was optimized and administered with food. The FDA’s instructions for tepotinib (TEPMETKO) tablets (24) (initial US FDA approval in 2021) are based on prescribing information showing that the AUC_inf of tepotinib increases by 1.6-fold and that C_max increases by 2-fold following the administration of a high-fat, high-calorie meal. In one study, compared with those under a fasting condition, the C_max and AUC_inf of savolitinib with food were found to be 102.7% and 117.1%, respectively, with the T_max being markedly delayed (P=0.023) (25). In addition, increases of AUC_inf of gumarontinib of up to 100% after a high-fat or low-fat meals have been reported (15).

Drug interactions

Studies have shown a manageable safety and efficacy profile of capmatinib, both as monotherapy and in combination with other anticancer drugs in patients with solid tumors (11,26,27); however, the clarification of the PK profile regarding drug-drug interaction is still necessary to confirm whether capmatinib is stable during metabolic processes. The substrate reactions catabolized by CYP3A and CYP1A2 are inhibited by capmatinib (28). In one study, midazolam and caffeine were used to evaluate the effect of capmatinib on CYP3A and CYP1A2 metabolism, respectively (29), resulting in a nonsignificant 22% increase in the midazolam C_max and a 134% increase in the AUC of caffeine; this suggests that caution concerning drug toxicity is needed when CYP1A2 substrates are used with capmatinib. In vitro, p-glycoprotein (P-gp) and breast cancer resistant protein (BCRP) are obviously inhibited by capmatinib (30). One study (31) found that the combination of capmatinib and digoxin (the substrate of P-gp) in patients with MET-dysregulated advanced solid tumors increased the C_max and AUC_inf by 74% and 47%, respectively, while combination of capmatinib and rosuvastatin (the substrate of BCRP) increased the C_max and AUC_inf by 204% and 108%, respectively; no unexpected safety events were observed. In another study (32), tepotinib was found not to affect the PK of midazolam (the substrate of CYP3A) but increased the C_max and AUC_inf of dabigatran (the substrate of P-gp) by 38% and 51%, respectively.

The combination therapy of MET TKIs and EGFR TKIs has been proven to be an ideal approach for the MET-dysregulated and EGFR-mutated NSCLC patients (26), to avoid the resistance of EGFR TKIs (33). It’s reported that capmatinib at 400 mg BID demonstrated effective absorption in combination with EGFR TKI gefitinib at 250 mg QD, and the value of T_max fluctuated around 2 hours, which was similar to that of capmatinib monotherapy (19). The mean plasma exposures of capmatinib in the QD and BID regimens increased proportionally with the increase in dose, and the capmatinib tablet group had higher C_max and area under the curve from time zero to the last sample time 12th hour (AUC_0-12h) than did the capmatinib capsule groups with 200 or 400 mg BID. Compared with capmatinib monotherapy, combination therapy had a 30% higher C_max and AUC_0-12h. No significant drug interactions in the combination of capmatinib and gefitinib were observed, and thus this regimen may be a promising treatment option for patients with EGFR-mutated and MET-dysregulated NSCLC. In a single-arm study on tepotinib, gefitinib, as an extrinsic factor of intake, exerted no relevant effect on the PK of tepotinib (34), but no detailed research on this topic has been conducted thus far.

Application in patients with BMs

BMs occur in approximately 10–50% of patients with NSCLC during the course of the disease, which is associated with a considerably poor prognosis (35). Local therapies have been commonly used for BMs, including radiotherapy or surgery (36). However, a detailed understanding of the optimal strategy for NSCLC patients with BMs is lacking. In the treatment of these patients, an MET inhibitor should have the ability to cross the BBB. One study found that different MET inhibitors demonstrated a varying ability in brain penetration and distribution due to their differing lipophilicity (37). In a clinical study, crizotinib had poor activity in treating patients with NSCLC and BMs (38), whereas capmatinib had strong activity. Out of 160 patients categorized with METex14 NSCLC, 16 (57%) of the 28 patients with evaluable diagnoses experienced intracranial complete responses or partial responses (13 patients who had previously undergone intracranial radiotherapy and 15 patients who did not). Furthermore, 9 complete responses were recorded. The overall intracranial complete response lasted over 6 months in 5 patients, whereas in the remaining 4, it lasted less than 6 months. Additionally, of the 15 evaluable patients with no previous intracranial radiotherapy, 10 (67%) demonstrated complete or partial intracranial responses and 5 achieved complete response. The duration of overall intracranial response was over 6 months in 2 patients and less than 6 months in the other 3.

A preclinical study tested the brain permeability of MET inhibitors in a xenograft model of BMs (39). The key parameter of brain penetration in the study was unbound brain-to-plasma concentration ratio (K_p,uu), which was calculated as follows: K_p,uu = (C_brain × f_u,brain)/(C_plasma × f_u,plasma), where C_brain is the total concentration in brain, C_plasma is the total concentration in plasma, f_u,brain is the unbound fraction in brain, and f_u,plasma is the unbound fraction in plasma; meanwhile, total brain-to-plasma concentration ratio (K_p) was calculated as follows: K_p = C_brain/C_plasma (40). Capmatinib was found to penetrate the BBB of the models and induce significant tumor regression. A 4-week investigative study (41) reported that rat brain tissue capmatinib concentrations were about 9% of the corresponding blood concentrations and thus in the range of the maximum expected vascular contamination (8%). Similarly, in tissue distribution studies of capmatinib radiolabeled carbon-14 in rats (19), the Kp was slightly higher than the limit for vascular contamination. Hence, radiolabeled material reflecting compound and/or its metabolites passed the BBB to a minor extent with no major differences in most of the brain regions. The good brain penetration of capmatinib may be due to its lipophilicity, high binding to plasma protein, and passive permeability. Additionally, Type Ib MET inhibitors, such as capmatinib, designed to selectively target the “DFG-in” conformation of MET, bind strongly to residue Y1230 through π-π interactions, enhancing their efficacy in treating NSCLC with METex14 alterations, including BMs. Moreover, P-gp and BCRP are both distributed in the epithelial cells membrane of the BBB, where they can extrude numerous compounds (42). These computational and experimental models have demonstrated capmatinib’s superior BBB permeability. Therefore, improving the CSF concentration of capmatinib in brain tumors may be achieved effectively by inhibiting P-gp or BCRP, which is likely one of the mechanisms underlying capmatinib’s therapeutic effect on BM. Despite challenges posed by P-gp mediated efflux, capmatinib illustrates a promising profile due to its favorable PK characteristics and minimal susceptibility to P-gp efflux, highlighting the importance of molecular dynamics simulations in predicting drug efficacy and BBB penetration (43). Tepotinib was also confirmed to cross the BBB in animal models and induce antitumor activity (44). The total concentration of tepotinib is 2.87-fold greater in the brain than in plasma, which is significantly higher than that reported for capmatinib (0.09) in rats (4). However, the unbound concentration of tepotinib in the brain only accounts for 25% of that in plasma (K_p,uu =0.25), indicating its ability of excessive binding in the brain. In another study on brain permeability, the CSF concentration of tepotinib was over 49 nmol/L (45), which exceeded its IC₅₀ of 1.7 nmol/L for MET (12). Thus far, there are no reports of K_p,uu related to other MET inhibitors.

Efficacy and safety

In treatment-naive NSCLC patients with METex14 skipping mutation, capmatinib has demonstrated excellent therapeutic effects, with a median time to response of 1.4 months, an ORR of 68%, an mPFS of 12.5 months, and an mOS of 21.4 months of (8). According to the results from the VISION study, tepotinib also demonstrated outstanding therapeutic efficacy in treatment-naive patients with NSCLC and METex14 mutation, with an ORR of 57.3%, an mPFS of 12.6 months, and an mOS of 21.3 months (46). For patients with the METex14 mutation treated with first-line savolitinib, the ORR was 62.1%, the mPFS was 13.7 months, and the mOS was not reached (47). As for gumarontinib in patients with NSCLC and the METex14 mutation, the ORR was 71%, the mPFS was 11.7 months, and the mOS was not reached (48). Due to the current lack of head-to-head study evidence between different MET TKIs, a propensity score-weighting model was employed to balance the baseline characteristics of patients from the GEOMETRY mono-1 and GEOMETRY-C studies, ensuring they matched the average baseline characteristics observed in NCT02864992 (VISION), NCT02897479, and NCT04270591 (GLORY). The Matched Adjusted Indirect Comparison (MAIC) (49) results suggested a trend toward overall survival (OS) benefit for capmatinib compared to other MET TKIs as first-line therapy for patients with METex14 skipping mutation-positive advanced NSCLC. The OS hazard ratio (HR) for capmatinib versus savolitinib was 0.5316 [95% confidence interval (CI): 0.2645–1.608], and for capmatinib versus tepotinib, the OS HR was 0.8699 (95% CI: 0.5789–1.307).

MET amplification was a key resistance mechanism in up to 22% in pretreated EGFR-mutant NSCLC (50). Currently, clinical studies have been conducted on the combination of MET TKIs and EGFR TKIs for the MET-dysregulated NSCLC patients with resistance to EGFR TKIs. In one study, capmatinib in combination with gefitinib also showed promising efficacy in patients with EGFR-mutated and MET-dysregulated NSCLC, particularly MET-amplified disease. For patients with MET gene copy number (GCN) ≥6, the ORR was 47%, and the mPFS was 5.49 months in a capmatinib + gefitinib treatment group (26). Moreover, capmatinib plus nazartinib demonstrated excellent antitumor effects in patients with EGFR-TKI-resistant and EGFR-mutated NSCLC (51). The RP2D regimen is a combination therapy with capmatinib at 400 mg BID and nazartinib at 100 mg QD. The antitumor efficacy, indicated by ORR, varied across all groups in this phase 1b/II trial. In group 1 [fasted, EGFR-TKI resistant, 1–3 prior lines, EGFRL858R/exon 19 deletion (ex19del), any T790M/MET], the ORR was 28.8 %; in group 2 (fasted, EGFR-TKI-naïve, 0–2 prior lines, de novo T790M+, any MET) the ORR was 33.3%; in group 3 (fasted, treatment-naïve, EGFRL858R/ex19del, T790M-, any MET), the ORR was 61.7 %; and in group 4 (with food, 0–2 prior lines, EGFRL858R/ex19del, any T790M/MET), the ORR was 42.9%. In the MET + subgroup (n=24; 45.8% of whom were treated in the third/fourth line), the ORR was 45.8%, the disease control rate (DCR) was 66.7%, the mPFS was 8.0 months, and the mOS was 18.6 months. These observations were consistent with previous findings. There is currently no research data for the combination of the three other three MET inhibitors (tepotinib, savolitinib, and gumarontinib with nazartinib. Moreover, in a study on capmatinib/osimertinib treatment, the majority of patients with EGFR-mutant NSCLC after progression on osimertinib received clinical benefit (52). Among a group of 8 patients with BMs, 62.5% derived clinical benefit, the ORR was 50%, the DCR was 72%, the median duration of response was 15.7 months, the mPFS was 18.1 months, and the mOS was not reached at a median follow-up of 21 months. In another study, tepotinib plus osimertinib showed promising effects in patients with EGFR-mutated NSCLC and MET amplification as a mechanism of resistance to first-line osimertinib (53), with the ORR being 50.0%.

As it pertains to safety, in the GEOMETRY mono-1 study, the most common treatment-related AEs were peripheral edema (47%), nausea (35%), increased blood creatinine (21%), and vomiting (20%). Grade 3–4 AEs were reported in 41% of patients, with serious AEs occurring in 54% of patients. Treatment discontinuation due to AEs occurred in 18% of patients, while 12% discontinued due to treatment-related AEs (TRAEs) (8). Moreover, capmatinib could overcome tepotinib-induced intolerable peripheral edema in some cases (54). The differences in the metabolism of capmatinib and tepotinib may result in the differences of exposure in individual cases and thus influence AEs. In addition, in one case report, a patient with stage IV NSCLC and METex14 mutation experienced savolitinib-induced severe liver impairment even when the dosage was reduced to 200 mg per day (55). The MAIC study shows that capmatinib has a lower safety risk compared to other MET TKIs. After adjusted corrections, the risk of TRAEs incidence for capmatinib compared to savolitinib, tepotinib, and glesatinib is significantly reduced in the Asian population, with rates of 11.4%, 11.1%, and 12.6%, respectively, all with P<0.05 (49).

Conclusions

Highly potent selective MET TKIs offer the best treatment efficacy for MET-driven NSCLC. Capmatinib stands out for its particularly good PK profile, high therapeutic efficacy index and controllable safety, especially in patients with METex14 skipping mutation and BM. Studies have demonstrated that capmatinib exhibits outstanding BBB permeability and minimal susceptibility to P-glycoprotein efflux, thus becoming a promising candidate for treating central nervous system metastases. The above factors support the recommendation of capmatinib as a superior option among MET TKIs. This narrative review provides deeper insights into the PK of MET TKIs, highlighting their ability to avoid food-intake or drug-drug interactions, thus optimizing long-term clinical medication schedules. Drug exposure of MET TKIs in the central nervous system and their elimination under specific organ functions should be evaluated in future research to understand a full clinical potential.

Supplementary

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