Tepotinib vs Standard Treatment in Patients With Advanced MET Exon 14 Mutated Non-Small Cell Lung Cancer Previously Treated

Sponsor
Intergroupe Francophone de Cancerologie Thoracique
Study ID
NCT06908993
Phase
PHASE3
Status
Recruiting
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Conditions

  • Advanced Non Small Cell Lung Cancer
  • MET Exon 14 Mutation

Eligibility Criteria

Sex
ALL
Age
18 Years - N/A
Healthy Volunteers
Not accepted

Interventions

  • Tepotinib — DRUG
    Tepotinib will be given orally once daily at the dose of 500mg of tepotinib hydrochloride hydrate.
  • Pemetrexed (Alimta) — DRUG
    500 mg/m² every 3 weeks
  • Vinorelbine — DRUG
    25-30 mg/m² D1, D8, every 3 weeks
  • Gemcitabine alone — DRUG
    1250 mg/m² D1, D8, every 3 weeks
  • Docetaxel — DRUG
    75 mg/m² every 3 weeks
  • Paclitaxel — DRUG
    90 mg/m² D1, D8, D15 every 4 weeks If bevacizumab added: 10 mg/kg D1, D15 every 4 weeks
  • Pembrolizumab — DRUG
    200 mg every 3 weeks
  • Nivolumab — DRUG
    240 mg every 2 weeks
  • Atezolizumab — DRUG
    1200 mg every 3 weeks

Study Details

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.

Key Dates

Start date
Dec 9, 2025
Status verified
Dec 2025
Primary completion
Mar 15, 2028
Completion
Jul 15, 2028

Study Design

Enrollment
133 participants (estimated)
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT

Arms

  • Active Comparator: Investigator choice treatment
    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.
  • Experimental: Tepotinib

Primary Outcome Measure

Progression-Free Survival (PFS) [ Time Frame: About 36 months ]

Central Contacts

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