Tepotinib vs Standard Treatment in Patients With Advanced MET Exon 14 Mutated Non-Small Cell Lung Cancer Previously Treated
COMET
A Randomized Controlled Trial of Tepotinib vs Standard Treatment in Patients With Advanced MET Exon 14 Mutated Non-Small Cell Lung Cancer
2 other identifiers
interventional
133
1 country
29
Brief Summary
The hypothesize is that tepotinib is more effective than the investigator's choice of treatment in patients with MET-mutated NSCLC who have progressed after at least one first-line treatment. The main benefit concerns patient access to tepotinib. There is currently no access to a new-generation MET TKI in France for METex14 patients, due to lack of comparative data. There are no phase III RCTs underway anywhere in the world. This study is the only opportunity, perhaps the last, to generate comparative data which, if positive, will enable the drug to be reimbursed. With this in mind, the methodology of this study was discussed with the HAS on several occasions beforehand, to ensure that it met their expectations. With a response rate of around 50% and a median progression-free survival of 11 months in previously-treated subjects based on clinical trials data, tepotinib is a key drug for METex14 NSCLC patients, who are generally elderly and frail, and for whom therapeutic options are limited. The investigators expect to observe a benefit for patients treated with tepotinib compared to the control arm in terms of PFS, quality of life, objective response rate and duration of response. The overall survival benefit may be compromised by allowing patients in the control arm to cross over to tepotinib once they have progressed. However, the investigators have decided to maintain this crossover and consequently use PFS as the primary endpoint, as there is no clinical equipoise regarding the efficacy of tepotinib in METex14 NSCLC patients. The EMA has already approved tepotinib based on efficacy and safety data from clinical trials, and patients and investigators already consider this treatment as an important therapeutic option. Indeed, both ESMO and ASCO guidelines recommend the use of MET TKIs in these patients. In France, although neither tepotinib nor capmatinib are available, crizotinib, a multi-target TKI also active on MET, can be used off-label. If cross-over to tepotinib was not allowed in this trial, most patients would still benefit from cross-over to a MET TKI by receiving off-label crizotinib, which would in any case lead to a misinterpretation of the OS data. Therefore, the investigators believe it is preferable to control for cross-over and expose progressive patients in the control arm to tepotinib and use PFS as the primary endpoint. Toxicity of MET TKIs is considered as manageable. In the VISION trial, of 313 patients treated with tepotinib (median age: 72 years), 109 (34.8%) experienced grade ≥3 treatment-related adverse events, leading to discontinuation in 46 patients (14.7%). Rates of adverse events (AE) were broadly consistent irrespective of prior therapies. Edema, the most common adverse event of clinical interest (AECI), was reported in 67.1% (grade ≥ 3, 11.2%). Median time to first edema onset was 7.9 weeks (range: 0.1-58.3). Edema was manageable with supportive measures, dose reduction (18.8%), and/or treatment interruption (23.1%), and rarely prompted discontinuation (4.3%). Other AECIs were also manageable and predominantly mild/moderate: hypoalbuminemia, 23.6% (grade ≥ 3, 3.5%); creatinine increase, 22.0% (grade ≥ 3, 1.0%); nausea, 23.3% (grade ≥ 3, 0.6%), diarrhea, 22.4% (grade ≥ 3, 0.3%), decreased appetite (grade ≥ 3, 0.3%), and ALT increase, 14.1% (grade ≥ 3, 2.2%). GI AEs typically occurred early and resolved in the first weeks10,13. Given the efficacy of tepotinib, the manageable safety profile, and the oral administration of tepotinib, the investigators anticipate that treatment with tepotinib will be associated with improved quality of life. Treatments offered in the control group correspond to standard treatments for advanced NSCLC in second line or beyond. In terms of prior lines of treatment, the eligibility criteria of the trial are aligned with the EMA label of tepotinib: "indicated for the treatment of adult patients with advanced non-small cell lung cancer (NSCLC) harboring alterations leading to MET gene exon 14 (METex14) skipping, who require systemic therapy following prior treatment with immunotherapy and/or platinum-based chemotherapy". The investigators have not included platinum-based chemotherapy as a treatment option in the control arm, considering that patients who are eligible to platinum-based chemotherapy should have received this regimen in first-line, as per ESMO guidelines14. Given the low efficacy of immunotherapy in patients with oncogene addiction, it is unlikely that some patients would receive immunotherapy alone as first-line treatment. Thus, the absence of platinum-based chemotherapy as a treatment choice in the control arm seems reasonable and will reduce the heterogeneity of this arm.
Trial Health
Trial Health Score
Automated assessment based on enrollment pace, timeline, and geographic reach
participants targeted
Target at P25-P50 for phase_3
Started Dec 2025
Typical duration for phase_3
29 active sites
Health score is calculated from publicly available data and should be used for screening purposes only.
Trial Relationships
Click on a node to explore related trials.
Study Timeline
Key milestones and dates
First Submitted
Initial submission to the registry
March 27, 2025
CompletedFirst Posted
Study publicly available on registry
April 3, 2025
CompletedStudy Start
First participant enrolled
December 9, 2025
CompletedPrimary Completion
Last participant's last visit for primary outcome
March 15, 2028
ExpectedStudy Completion
Last participant's last visit for all outcomes
July 15, 2028
December 17, 2025
December 1, 2025
2.3 years
March 27, 2025
December 9, 2025
Conditions
Keywords
Outcome Measures
Primary Outcomes (1)
Progression-Free Survival (PFS)
Progression-free survival is calculated from the date of randomization until progression as defined by independent review comity according to RECIST 1.1 or death (whichever occurs first).
About 36 months
Secondary Outcomes (9)
Global Health Status Quality of life
6 weeks after randomization
Overall Survival
About 36 months
Second Progression-Free Survival (PFS2)
About 36 months
Time to next treatment or death (TNT-D)
About 36 months
Objective Response Rate (ORR)
About 36 months
- +4 more secondary outcomes
Study Arms (2)
Investigator choice treatment
ACTIVE COMPARATORInvestigator's choice treatment among: * Monochemotherapy (including pemetrexed, docetaxel, paclitaxel with or without bevacizumab, gemcitabine, vinorelbine), * Anti-PD(L)1 agent (including pembrolizumab, nivolumab or atezolizumab), * Best supportive care - available only for patients with i) ECOG PS 3 or ii) contraindication to propose a systemic treatment based on an oncogeriatric assessment or confirmed by the local multidisciplinary tumor board. The treatment chosen cannot be a treatment already received.
Tepotinib
EXPERIMENTALInterventions
Tepotinib will be given orally once daily at the dose of 500mg of tepotinib hydrochloride hydrate.
90 mg/m² D1, D8, D15 every 4 weeks If bevacizumab added: 10 mg/kg D1, D15 every 4 weeks
Eligibility Criteria
You may qualify if:
- Informed, written and signed consent:
- Patients must have signed and dated the written informed consent form approved by the ethics committee in accordance with the legal and institutional framework.
- It must have been signed before protocol-related procedures that are not part of normal patient management are performed. Patients should be willing and able to adhere to the schedule of visits, treatment and laboratory tests.
- Histologically proven advanced NSCLC.
- Presence of a METex14 mutation (based on local testing). Detection of METex14 mutation should be performed on a tissue sample if available. In case no tissue sample is available, detection of METex14 on a liquid biopsy is authorized. The sponsor should be consulted if there is any doubt about the nature of the mutation.
- Evidence of disease progression after at least one prior line of treatment including either a platinum-based chemotherapy or an anti-PD(L)1 agent or both.
- Has received no more than 2 prior lines of treatment.
- ECOG Performance Status 0-3.
- Stage IIIB or IIIC non irradiable or stage IV (8th classification TNM, UICC 2015)
- Age ≥ 18 years.
- Adequate biological function:
- Creatinine clearance ≥ 30 ml/min;
- Neutrophils ≥ 1500/mm3;
- Platelets ≥100,000/mm3;
- Haemoglobin ≥ 8 g/dL;
- +7 more criteria
You may not qualify if:
- Prior treatment with a MET inhibitor (including crizotinib).
- ECOG Performance Status 4.
- Known hypersensitivity to tepotinib or its excipients.
- Inability to comply with study or follow-up procedures.
- Pregnant, lactating, or breastfeeding women.
- Any disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug, that may affect the interpretation of the results, or that may render the patient at high risk from treatment complications.
- History of idiopathic pulmonary fibrosis or active pneumonitis on chest computed tomography (CT) scan at screening. History of radiation pneumonitis in the radiation field (fibrosis) is permitted.
Contact the study team to confirm eligibility.
Sponsors & Collaborators
Study Sites (29)
Besançon - CHU
Besançon, France
Bordeaux - Institut Bergonie
Bordeaux, France
Brest - CHU
Brest, France
Caen - CRLCC
Caen, France
Centre Hospitalier Intercommunal de Créteil
Créteil, 94000, France
Dijon - Centre Georges-François Leclerc
Dijon, 21000, France
Grenoble - CHU
Grenoble, France
CHD Vendée
La Roche-sur-Yon, France
Le Mans - CHG
Le Mans, France
CHRU de Lille
Lille, France
Centre Léon Bérard
Lyon, 69373, France
Institut Paoli Calmette
Marseille, France
Marseille - APHM
Marseille, France
Montpellier - CHU
Montpellier, France
Centre Antoine Lacassagne
Nice, France
AP-HP Hôpital Cochin
Paris, 75014, France
AP-HP Hôpital Tenon
Paris, 75970, France
Paris - APHP Bichat
Paris, France
Centre Hospitalier Général - Pau
Pau, 64000, France
Bordeaux - CHU
Pessac, France
Institut de Cancérologie de l'Ouest - René Gauducheau
Saint-Herblain, 44805, France
Sens - CH
Sens, 89100, France
Strasbourg - NHC
Strasbourg, 63000, France
Toulon - CHI
Toulon, 83000, France
CHU Toulouse
Toulouse, France
CHRU de Tours
Tours, France
CH de Valence
Valence, France
Nancy - CHU
Vandœuvre-lès-Nancy, 54500, France
Gustave Roussy
Villejuif, France
Related Links
MeSH Terms
Conditions
Interventions
Condition Hierarchy (Ancestors)
Intervention Hierarchy (Ancestors)
Central Study Contacts
Study Design
- Study Type
- interventional
- Phase
- phase 3
- Allocation
- RANDOMIZED
- Masking
- NONE
- Purpose
- TREATMENT
- Intervention Model
- PARALLEL
- Sponsor Type
- OTHER
- Responsible Party
- SPONSOR
Study Record Dates
First Submitted
March 27, 2025
First Posted
April 3, 2025
Study Start
December 9, 2025
Primary Completion (Estimated)
March 15, 2028
Study Completion (Estimated)
July 15, 2028
Last Updated
December 17, 2025
Record last verified: 2025-12
Data Sharing
- IPD Sharing
- Will share
The individual participant data underlying the results reported in this article, as well as the study protocol and statistical analysis plan, will be made available after deidentification immediately following publication and for three years. Researchers who provide a methodologically sound proposal for any purpose may direct proposals to contact@ifct.fr. To gain access, data requestors will need to sign a data access agreement that requires approval by the French Cooperative Thoracic Intergroup.