A Phase 3 interventional study of Tepotinib and Pemetrexed (Alimta) in Advanced Non Small Cell Lung Cancer and MET Exon 14 Mutation, sponsored by Intergroupe Francophone de Cancerologie Thoracique. Recruiting at 29 sites in France. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2025-12-17.
Sponsored by Intergroupe Francophone de Cancerologie Thoracique · Phase 3, Interventional, and Treatment
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.
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This study's planned enrollment of 133 is above the median of 62 across 5,213 interventional studies indexed under Carcinoma, Non-Small-Cell Lung.
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Informed, written and signed consent:
Adequate biological function:
Exclusion Criteria:
Investigator'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.
Drug: Pemetrexed (Alimta) · Drug: Vinorelbine · Drug: Gemcitabine alone · Drug: Docetaxel · Drug: Paclitaxel · Drug: Pembrolizumab · Drug: Nivolumab · Drug: Atezolizumab
Drug: Tepotinib
Tepotinib will be given orally once daily at the dose of 500mg of tepotinib hydrochloride hydrate.
500 mg/m² every 3 weeks
25-30 mg/m² D1, D8, every 3 weeks
1250 mg/m² D1, D8, every 3 weeks
75 mg/m² every 3 weeks
90 mg/m² D1, D8, D15 every 4 weeks If bevacizumab added: 10 mg/kg D1, D15 every 4 weeks
200 mg every 3 weeks
240 mg every 2 weeks
1200 mg every 3 weeks
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).
Time frame: About 36 months
Global Health Status Quality of life
Quality of life will be assessed using the EORTC (European Organisation for Research and Treatment of Cancer) Quality of Life Questionnaire C30 with lung cancer module LC29 at baseline and week 6. A linear transformation will be applied to standardise the raw score to a 0-100 range (100=best possible QoL). A 10-point change will be considered clinically meaningful.
Time frame: 6 weeks after randomization
Overall Survival
Overall survival is calculated from the date of randomization until death (for whatever reason).
Time frame: About 36 months
Second Progression-Free Survival (PFS2)
PFS2 is defined as the time from randomization to the date of progression of disease on first subsequent systemic anti-cancer therapy (as defined by the RECIST criteria v.1.1) (second progression), or death from any cause, whichever occurs first.
Time frame: About 36 months
Time to next treatment or death (TNT-D)
TNT-D is defined as the time from randomization to the date of first subsequent systemic anti-cancer therapy (as defined by the RECIST criteria v.1.1), or death from any cause, whichever occurs first.
Time frame: About 36 months
Objective Response Rate (ORR)
ORR is defined as the proportion of patients who have achieved a best overall response of complete response (CR) or partial response (PR) as determined by investigator review of radiographic disease assessments per RECIST v1.1.
Time frame: About 36 months
Duration of response (DOR)
DOR is defined as the time from the date of the first documented response (CR or PR) to the earliest date of disease progression, as determined by Investigator review of radiographic disease assessments per RECIST v1.1, or death due to any cause.
Time frame: About 36 months
Quality of life of patient
Quality of life will be assessed using the EORTC (European Organisation for Research and Treatment of Cancer) C30 with lung cancer module LC29 at baseline and week 6. For each scale in QLQ-C30 LC29, a linear transformation will be applied to standardise the raw score to a 0-100 range (100=best possible function or QoL for functional scales and highest symptom burden for symptom scales and symptom items). A 10-point change in an item or domain will be considered clinically meaningful. QoL will be defined as improved when a ≥10-point increase will be recorded for functioning scales and ≥10-point reduction for symptom domains.
Time frame: About 36 months
Observance of treatments
The number of cycles will be reported for each arm. The number of dose interruptions and dose modifications will be reported on the safety population.
Time frame: About 36 months
Safety and tolerability of treatments
Safety is measured by the frequency and the severity of adverse events, serious or not, at each patient visit and at each post treatment follow-up visit using the CTCAE Version 5.0.
Time frame: About 36 months
Plan to share: Yes — 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.
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Carcinoma, Non-Small-Cell Lung→
Intergroupe Francophone de Cancerologie Thoracique