Informations générales (source: ClinicalTrials.gov)
A Randomized Controlled Trial of Tepotinib vs Standard Treatment in Patients With Advanced MET Exon 14 Mutated Non-Small Cell Lung Cancer
Interventional
Phase 3
Intergroupe Francophone de Cancerologie Thoracique (Voir sur ClinicalTrials)
novembre 2025
juillet 2028
02 décembre 2025
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.
Etablissements
| Les établissements d'Île-de-France ayant mis à jour leurs données Origine et niveau de fiabilité des données | |||||
|---|---|---|---|---|---|
| CLCC INSTITUT GUSTAVE ROUSSY | Jordi REMON MASIP | 16/06/2026 07:45:07 | Contacter | ||
| Les établissements d'Île-de-France dont les données sont issues de ClinicalTrials.gov Origine et niveau de fiabilité des données | |||||
| AP-HP - Hôpital Bichat | Valérie Gounant, Dr | Contact (sur clinicalTrials) | |||
| AP-HP - Hôpital Cochin | Marie Wislez, Pr | Contact (sur clinicalTrials) | |||
| AP-HP - Hôpital Tenon | Vincent Fallet, Dr | Contact (sur clinicalTrials) | |||
| Les établissements hors Île-de-France dont les données sont issues de ClinicalTrials.gov Origine et niveau de fiabilité des données | |||||
| Besançon - CHU - Besançon 3033123 - France | Hamadi ALMOTLAK, Dr | Contact (sur clinicalTrials) | |||
| Centre Léon Bérard - 69373 - Lyon 2996944 - France | Aurélie SWALDUZ, Dr | Contact (sur clinicalTrials) | |||
| CH de Valence - Valence 2971053 - France | Julie MORACCHINI, Dr | Contact (sur clinicalTrials) | |||
| CHU Toulouse - Toulouse 2972315 - France | Julien MAZIERES, Pr | Contact (sur clinicalTrials) | |||
| Le Mans - CHG - Le Mans 3003603 - France | Dr Camille GUGUEN | Contact (sur clinicalTrials) | |||
| Montpellier - CHU - Montpellier 2992166 - France | Benoit ROCH | Contact (sur clinicalTrials) | |||
| Toulon - CHI - 83000 - Toulon 2972328 - France | Clarisse Audigier-Valette, Dr | Contact (sur clinicalTrials) | |||
| Les établissements sans correspondance certaine dans le répertoire FINESS dont les données sont issues de ClinicalTrials.gov Origine et niveau de fiabilité des données | |||||
| Bordeaux - CHU - Pessac 2987805 - France | Rémi VEILLON, Dr | Contact (sur clinicalTrials) | |||
| Bordeaux - Institut Bergonie - Bordeaux 3031582 - France | Sophie COUSIN, Dr | Contact (sur clinicalTrials) | |||
| Brest - CHU - Brest 3030300 - France | Jessica NGUYEN, Dr | Contact (sur clinicalTrials) | |||
| Caen - CRLCC - Caen 3029241 - France | Hubert CURCIO, Dr | Contact (sur clinicalTrials) | |||
| Centre Antoine Lacassagne - Nice 2990440 - France | Victoria FERRARI, MD | Contact (sur clinicalTrials) | |||
| Centre Hospitalier Général - Pau - 64000 - Pau 2988358 - France | Aldo RENAULT, Dr | Contact (sur clinicalTrials) | |||
| CHD Vendée - La Roche-sur-Yon 3006767 - France | Bastien SOUDET, Dr | Contact (sur clinicalTrials) | |||
| CHRU de Lille - Lille 2998324 - France | Alexis CORTOT, Pr | Contact (sur clinicalTrials) | |||
| CHRU de Tours - Tours 2972191 - France | Marion FERREIRA, Dr | Contact (sur clinicalTrials) | |||
| Dijon - Centre Georges-François Leclerc - 21000 - Dijon 3021372 - France | Coureche-Guillaume KADERBHAI, Dr | Contact (sur clinicalTrials) | |||
| Grenoble - CHU - Grenoble 3014728 - France | Denis MORO-SIBILOT, Pr | Contact (sur clinicalTrials) | |||
| Gustave Roussy - Villejuif 2968705 - France | Jordi REMON, Dr | Contact (sur clinicalTrials) | |||
| Institut de Cancérologie de l'Ouest - René Gauducheau - 44805 - Saint-Herblain 2979590 - France | Judith RAIMBOURG, Dr | Contact (sur clinicalTrials) | |||
| Institut Paoli Calmette - Marseille 2995469 - France | Anne MADROSZYK, Dr | Contact (sur clinicalTrials) | |||
| Marseille - APHM - Marseille 2995469 - France | Pascale TOMASINI | Contact (sur clinicalTrials) | |||
| Nancy - CHU - 54500 - Vandœuvre-lès-Nancy 2970797 - France | Bertrand MENNECIER, Dr | Contact (sur clinicalTrials) | |||
| Sens - CH - 89100 - Sens 2975050 - France | Huu Thanh LE, Dr | Contact (sur clinicalTrials) | |||
| Strasbourg - NHC - 63000 - Strasbourg 2973783 - France | Céline MASCAUX, Dr | Contact (sur clinicalTrials) | |||
Critères
Tous
1. 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.
2. Histologically proven advanced NSCLC.
3. 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.
4. 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.
5. Has received no more than 2 prior lines of treatment.
6. ECOG Performance Status 0-3.
7. Brain metastases are allowed. If immediate local treatment is required, inclusion is
possible once the latter is complete.
8. Stage IIIB or IIIC non irradiable or stage IV (8th classification TNM, UICC 2015)
9. Age ≥ 18 years.
10. Adequate biological function:
- Creatinine clearance ≥ 30 ml/min;
- Neutrophils ≥ 1500/mm3;
- Platelets ≥100,000/mm3;
- Haemoglobin ≥ 8 g/dL;
- Liver enzymes < 3x ULN except for patients with liver metastases (< 5x ULN);
- Total bilirubin ≤ 1.5 x ULN except for patients with proven Gilbert's syndrome
(≤ 5 x ULN) or patients with liver metastases (≤ 3.0 ULN).
11. Protected adults may participate in the study if they are capable of making
decisions regarding their medical treatment in accordance with the guardianship
judgment.
12. For women of childbearing potential (including women who have had a tubal ligation),
serum pregnancy test must be performed and documented as negative within 14 days
prior to C1D1.
13. Women of childbearing potential must remain abstinent (refrain from heterosexual
intercourse) or use contraceptive methods with a failure rate of < 1% per year
during the treatment period and for at least 6 months after the last dose of study
drugs. Women must refrain from donating eggs during this same period. A woman is
considered to be of childbearing potential if she is post-menarcheal, has not
reached a postmenopausal state (≥ 12 continuous months of amenorrhea with no
identified cause other than menopause), and has not undergone surgical sterilization
(removal of ovaries or uterus). Examples of contraceptive methods with a failure
rate of <1% per year include bilateral tubal ligation, male sterilization,
established proper use of hormonal contraceptives that inhibit ovulation,
hormone-releasing intrauterine devices, and copper intrauterine devices. Hormonal
contraceptive methods must be supplemented by a barrier method plus spermicide. The
reliability of sexual abstinence should be evaluated in relation to the duration of
the clinical study and the preferred and usual lifestyle of the patient. Periodic
abstinence (e.g. calendar, ovulation, symptothermal, or postovulation methods) and
withdrawal are not acceptable methods of contraception.
14. Men with female partners of childbearing potential or pregnant female partners, must
remain abstinent or use a condom during the treatment period and for at least 6
months after the last dose of study treatment to avoid exposing the embryo. Men must
refrain from donating sperm during this same period. The reliability of sexual
abstinence should be evaluated in relation to the duration of the clinical study and
the preferred and usual lifestyle of the patient. Periodic abstinence (e.g.
calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not
acceptable methods of contraception.
15. Patient covered by a national health insurance.
Exclusion Criteria:
1. Prior treatment with a MET inhibitor (including crizotinib).
2. Presence of another known driver oncogene alteration (including EGFR, HER2, KRAS,
BRAF mutations or ALK, ROS1, RET fusions). In case of detection of any other driver
alteration, inclusion should be discussed with the sponsor.
3. ECOG Performance Status 4.
4. Known hypersensitivity to tepotinib or its excipients.
5. History of cancer within 3 years or active cancer except those with a negligible
risk of metastasis or death, or those treated curatively. If a patient does not
fulfil this criterion but the investigator considers that the benefit/risk balance
is in favour of inclusion in the study, please contact IFCT.
6. Inability to comply with study or follow-up procedures.
7. Pregnant, lactating, or breastfeeding women.
8. 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.
9. 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.