Brief Report: Combination Capmatinib and Trametinib in Metastatic MET-Driven NSCLC

Abstract

Introduction

MET tyrosine kinase inhibitor (TKI) therapy has improved outcomes in patients with NSCLC harboring MET alterations. Nevertheless, primary and acquired resistance ultimately limit the durability of response. This study evaluated the safety and efficacy of the MET inhibitor capmatinib with the MEK inhibitor trametinib in patients with metastatic MET-driven NSCLC who had progressed on prior treatment with at least one MET inhibitor.

Methods

A multicenter phase I study evaluated capmatinib in combination with trametinib in patients with advanced-stage NSCLC harboring activating MET alterations and prior exposure to at least one MET TKI. A three-plus-three dose-escalation design was used to assess the safety and tolerability of the combination.

Results

Three patients (N = 3) were enrolled in the study and completed a median of three cycles of therapy. Dose-limiting toxicities, including rash, edema, and nausea, necessitated dose reductions in the first two patients and the initiation of therapy in the third patient at a lower dose level. Ultimately, all patients discontinued therapy because of treatment-related adverse events (TRAEs). The study was terminated early because of poor accrual and TRAEs. No radiographic objective responses were observed.

Conclusions

In this phase I trial, capmatinib plus trametinib was associated with marked TRAEs, and treatment was discontinued in all participants. On the basis of these findings, further investigation of this combination of MET and MEK inhibitors at the tested dose levels is not recommended. Future studies, if pursued, should consider modified dosing strategies, alternative MET and MEK inhibitor combinations, and MET-altered tumors with evidence of MAPK-mediated resistance.

ClinicalTrials.gov Identifier

NCT05435846

Introduction

Alterations in MET occur in approximately 2% to 4% of NSCLC cases and are most frequently observed in lung adenocarcinoma. MET encodes a receptor tyrosine kinase that, on binding to its ligand, hepatocyte growth factor (HGF), undergoes dimerization and activates multiple downstream signaling pathways (such as RAS-MAPK and PI3K-AKT) that are critical for tumor growth, survival, and invasion.¹

Targeted inhibition of MET with tyrosine kinase inhibitors (TKIs), including capmatinib and tepotinib, has improved outcomes for patients with advanced NSCLC harboring MET alterations, as reported in clinical observations and the GEOMETRY mono-1 (Study of Oral cMET inhibitor INC280 in Patients with EGFR Wild-type [wt], Advanced Non-small Cell Lung Cancer [NSCLC]) and VISION (Tepotinib Phase II in NSCLC Harboring MET Alterations) trials.2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 Despite these advances, resistance to MET TKI therapy invariably occurs. Through comprehensive sequencing of circulating tumor DNA from 289 patients with MET exon 14 (METex14)–mutated NSCLC, we revealed a significantly higher prevalence of co-occurring alterations in RAS/MAPK pathway genes compared with tumors harboring EGFR mutations. Furthermore, in a preclinical METex14-mutated model, we found that NF1 downregulation or KRAS overexpression was associated with enhanced MAPK signaling and resistance to MET TKI therapy. This resistance was overcome by dual MET and MEK inhibitor therapy, suggesting that a combination therapeutic approach directed towards MET and MAPK pathway signaling warrants clinical investigation.¹⁴

Materials and Methods

This multi-institution, investigator-initiated, phase I/Ib trial, funded by Novartis Pharmaceuticals Corporation, evaluated capmatinib plus trametinib in patients with previously treated stage IV NSCLC with a METex14 skipping mutation. Eligibility required an archived or new tissue biopsy and a documented METex14 skipping mutation confirmed by tumor DNA sequencing or cell-free DNA testing performed in a Clinical Laboratory Improvement Amendments–approved laboratory. The study was approved by institutional review boards, and all patients provided written informed consent. A three-plus-three dose escalation scheme was employed with four prespecified dose levels. Dose level −2 consisted of capmatinib 200 mg twice daily plus trametinib 1.0 mg daily; dose level −1 consisted of capmatinib 300 mg twice daily plus trametinib 1.0 mg daily; dose level 1 consisted of capmatinib 300 mg twice daily plus trametinib 1.5 mg daily; and dose level 2 consisted of capmatinib 400 mg twice daily plus trametinib 1.5 mg daily (Supplementary Fig. 1). Dose-limiting toxicity (DLT) was defined as any of the following toxicities possibly related to study treatment occurring within the first cycle: grade 3 or greater clinically significant non-hematologic toxicity; grade 4 or greater neutropenia or thrombocytopenia lasting longer than 7 days; grade 3 or greater febrile neutropenia; any adverse event (AE) requiring a dose reduction in the DLT period was considered a DLT; or rash or diarrhea of grade 3 or greater lasting longer than 3 days attributed to study treatment despite optimal medical management. The primary endpoint of the study was to determine the safety and tolerability of the combination and to determine the recommended phase 2 dose. Pharmacokinetic assessments were planned but were not performed due to a lack of funding. For additional methods, see the Supplementary Appendix.

Results

A total of three patients were enrolled in this study (Supplementary Fig. 2). The baseline characteristics of the patients treated are summarized in Table 1. All three patients had never smoked and had stage IV NSCLC with METex14 skipping mutations. All patients had prior treatment with a MET inhibitor, and one patient received prior combination chemotherapy and immunotherapy. Testing after prior MET inhibitor exposure in patient 1 identified CDK4 and ERBB2 amplifications without an on-target MET resistance mutation. Testing for patients 2 and 3 preceded MET-inhibitor therapy and could not assess acquired resistance. Two patients initiated treatment at dose level 1. During cycle 1, one patient experienced a grade 2 rash requiring a dose hold of more than 7 days; this was deemed a DLT. The second patient experienced grade 2 nausea and grade 3 edema during cycle 2, requiring a 20-day treatment hold. Although the treatment-related AEs (TRAEs) occurred outside the DLT period, the principal investigator, in consultation with the co-investigators, classified these events as the cohort’s second DLT in the interest of patient safety. The patient restarted treatment at dose level −1, and the data safety monitoring committee was informed. Because of the frequency and severity of AEs observed in the first two patients at dose level 1, the third patient was initiated at dose level −1. Treatment-related AEs for the third patient included grade 1 facial rash and a serious AE of grade 3 pneumonitis, resulting in treatment discontinuation.

Table 1.

Baseline Characteristics of Patients

Characteristics	Patient 1	Patient 2	Patient 3
Baseline characteristics
Age, y	64	75	77
Sex	Female	Male	Female
Smoking history	Never	Never	Never
MET alteration	MET exon 14 deletion	MET exon 14 deletion	MET exon 14 deletion
Additional mutations	TP53, CDK4, ERBB2 amplificationa	Noneb	TP53, RB1b
Prior treatment history
Prior Lines of systemic therapy, n	2	1	2
Prior MET inhibitor	Crizotinib; Capmatinib	Capmatinib	Capmatinib
Duration of prior MET inhibitor, mo	31 mo, 4 mo	44 mo	7 mo
Best response to prior MET inhibitor	PR; PD	PR	PR

PD, progressive disease; PR, partial response.

^aMolecular findings were derived from specimens collected after progression on a MET inhibitor.

^bMolecular findings were derived from specimens collected before MET inhibitor treatment.

The most frequently observed AEs and TRAEs of any grade are listed in Table 2 and Supplementary Table 1 and include rash (n = 3; 100%), dyspnea (n = 2; 67%), edema (n = 2; 67%), nausea (n = 2; 67%), and ocular irritation (n = 2; 67%). The most common study-attributable grade 3 or higher AEs were edema (n = 2; 67%) and pneumonitis (n = 1; 33%). Two serious AEs were reported, including pneumonitis and chest pain. The median number of treatment cycles was three. All patients discontinued the study due to AEs. There were no treatment-related deaths.

Table 2.

Summary of Adverse Events Observed

Toxicity Observed	Grade 1 (%)	Grade 2 (%)	Grade 3 (%)	Total, Any Grade (%)
Rash	2 (67)	1 (33)		3 (100)
Ocular irritationa	2 (67)			2 (67)
Dyspnea	2 (67)			2 (67)
Edema			2 (67)	2 (67)
Nausea	1 (33)	1 (33)		2 (67)
Vomiting		1 (33)		1 (33)
Esophagitis		1 (33)		1 (33)
Pneumonitis			1 (33)	1 (33)
Rhinorrhea	1 (33)			1 (33)
Diarrhea	1 (33)			1 (33)
Vitreous detachment	1 (33)			1 (33)
Mouth sores	1 (33)			1 (33)
Chest pain			1 (33)	1 (33)
Shoulder pain	1 (33)			1 (33)
Dysuria	1 (33)			1 (33)
Urinary tract infection		1 (33)		1 (33)
Melena	1 (33)			1 (33)
Colon polyps		1 (33)		1 (33)
Pruritus	1 (33)			1 (33)

^aOcular irritation included conjunctival injection, xerophthalmia, and periorbital edema.

All patients experienced stable disease as their best response per Response Evaluation Criteria in Solid Tumors, version 1.1 criteria. The best percentage change in target lesion size ranged from −20% to +14% (Fig. 1). No patient experienced disease progression during study treatment. All patients discontinued the study before trial closure owing to AEs. The study was ultimately terminated before the evaluation of dose level −2 due to poor accrual and treatment-related toxicity. Median progression-free survival, overall survival, and median duration of response could not be estimated.

Figure 1.

Best percentage change from baseline in target lesions. Waterfall plots for best percentage change in target lesion size by RECIST 1.1 criteria by investigator assessment are reported for patients who received capatinib plus trametinib. ∗Indicates patients who received dose level 1 of capmatinib 300 mg PO twice daily plus trametinib 1.5 mg PO daily. ∗∗Indicates patients who received dose level −1 of capatinib 300 mg PO twice daily plus trametinib 1.0 mg PO daily. PO, per os; RECIST, Response Evaluation Criteria in Solid Tumors.

Discussion

This study sought to characterize the safety and efficacy of the combination of the MET inhibitor capmatinib with the MEK inhibitor trametinib in patients with MET-altered NSCLC who had progressive disease on prior MET inhibitor therapy. The primary finding of this study was the poor tolerability of the drug combination at dose level 1, with capmatinib 300 mg orally twice daily and trametinib 1.5 mg orally once daily. This resulted in dose reductions to dose level −1, using capmatinib 300 mg orally twice daily and trametinib 1.0 mg orally once daily. Although no treatment-related deaths occurred, dose-limiting toxicities and frequent drug-related AEs precluded dose escalation and ultimately led to treatment discontinuation in all patients. The anticipated AEs for MEK and MET inhibitor combination included fatigue, nausea, vomiting, diarrhea, rash, and peripheral edema. The known U.S. Food and Drug Administration AEs for capmatinib monotherapy included pneumonitis (4.5%), peripheral edema (53%), and rash (13%). Trametinib has Food and Drug Administration–reported AEs, namely pneumonitis (2%), peripheral edema (21%), and rash (32 %). All reported percentages represent all-grade AEs.

Edema is a common and challenging toxicity to manage in patients treated with MET inhibitors; in this study, two of three patients enrolled experienced grade 3 edema. Rash is a common AE associated with trametinib and limited patients’ ability to stay on the study, even at the lower dose of 1.0 mg daily. Finally, grade 3 pneumonitis was observed in one patient, raising significant safety concerns about continuing to study this combination. The observed toxicities in this study, including pneumonitis (n = 1; 33%), edema (n = 2; 67%), and rash (n = 3; 100%), may reflect additive toxicity from overlapping AE profiles of MET and MEK inhibition. Gastrointestinal toxicities, although common with both drugs, were grade 1. Chest pain was reported as a serious AE; nevertheless, this patient’s presentation was thought to be unrelated to the study drugs. Overall, capmatinib plus trametinib was not well tolerated at the tested dose levels, which is similar to the binimetinib and crizotinib combination in a phase I trial in colorectal cancer, in which no objective responses were observed.¹⁵ In that study, coadministration did not significantly alter the pharmacokinetics of either drug; whether a pharmacokinetic interaction contributed to the toxicities observed with capmatinib plus trametinib remains unknown. Overall, these findings suggest several clinical considerations. First, continuous capmatinib and trametinib at the tested dose levels were not tolerated, supporting the evaluation of lower doses or alternative schedules. Second, future trials could prioritize tumors with evidence of MAPK-mediated resistance. Third, pharmacokinetic and pharmacodynamic assessments may also help clarify toxicity and target inhibition. The lack of radiographic objective responses also suggests limited clinical benefit of this combination.

The limitations of this trial included the small sample size and early trial closure, precluding further dose evaluation or expansion and a full assessment of efficacy. In this cohort of three patients with a median treatment exposure of three cycles, the observed AEs may not fully represent the frequency and spectrum of toxicities associated with the combination.

In summary, while co-targeting MET and MEK remains a biologically rational strategy to overcome resistance to MET-targeted therapy, the combination of capmatinib and trametinib is poorly tolerated, with all patients discontinuing treatment because of AEs, including grade 3 edema (n = 2) and grade 3 pneumonitis (n = 1). These findings warrant caution in the further development of combined MET and MEK inhibition. If pursued, further investigations could consider alternative dosing or drug schedules, different MET or MEK inhibitor combinations, and selecting patients with evidence of MAPK-mediated resistance, with close safety monitoring and pharmacokinetic assessment.

CRediT Authorship Contribution Statement

Tyiesha Brown: Data curation, Formal analysis, Visualization, Writing - original draft, Writing - review & editing.

Matthew S. Lara: Conceptualization, Writing - original draft, Writing - review & editing.

Fei Jiang: Formal analysis, Writing - review & editing.

Edward B. Garon: Investigation, Writing - review & editing.

Jonathan W. Goldman: Investigation, Writing - review & editing.

Jonathan W. Riess: Conceptualization, Investigation, Writing - review & editing.

Collin M. Blakely: Conceptualization, Investigation, Data curation, Writing - review & editing, Supervision, Project administration, Funding acquisition.

Disclosure

Dr. Garon reports institutional grants from ABL-Bio, Arrivent, AstraZeneca, Bayer, BridgeBio, Bristol Myers Squibb, Daiichi Sankyo, Eli Lilly, EMD Serono, Genentech, Gilead, Iovance Biotherapeutics, Merck, Mirati, Prelude, Regeneron, Synthekine, and TILT Biotherapeutics; consulting fees from Abbvie, Arcus, AstraZeneca, Arrivent, Atreca, Bayer, Bicycle, Black Diamond Therapeutics, BridgeBio, Bristol Myers Squibb, Daiichi-Sankyo, Eli Lilly, Gilead, Glaxo Smith Kline, Hexagon, Hookipa, I-Mab, IO Biotech, iTeos, LianBio, Merck, Merus, Novartis, Nuvalent, Oxford Bio, Pfizer, Regeneron, Samsung, Sanofi, Seagen, Sumitomo, Strata, Summit, Servier, Synthekine, Transcode, and Verastem; pending patents from Motif Neoepitopes for Cancer Immunotherapy; support for attending meetings from Bristol Myers Squibb, Gilead, I-Mab, Merck, Novartis, and Regeneron; and participation on a data safety monitoring board. Dr. Goldman reports an institutional grant from Novartis; consulting fees from AbbVie, AstraZeneca, Genentech, Lilly, and Summit; support for attending meetings from Summit; and participation on a data safety monitoring board for AbbVie, AstraZeneca, and Summit. Dr. Riess reports institutional grants from ArriVent, Merck, AstraZeneca, Boehringer Ingelheim, Novartis, Revolution Medicines, IO Biotech, Summit Pharmaceuticals, Nuvalent, Pfizer, Blossom Hill, and Prelude Therapeutics; consulting fees from ArriVent, Daiichi Sankyo, AstraZeneca, Pfizer, Regeneron, Catalyst, Janssen, BMS, Genentech, Amgen, GSK, Replimmune, Oncohost, Bicycle Therapeutics, Nuvalent, Taiho, Verastem, Merck, Boehringer Ingelheim, Natera, and Revolution Medicines; support for attending meetings from Biotech; and being a board member for the Association of Northern California Oncologists. Dr. Blakely reports grants from AstraZeneca, Puma, Roche, and Mirati and consulting fees from Pfizer, BMS, Janssen, and Blossom Hill. The remaining authors declare no conflict of interest.