tepotinib
Sources réglementaires consultées
Indications approuvées
- Chez l’adulte atteint d’un cancer bronchique non à petites cellules métastatique présentant des altérations entraînant le saut de l’exon 14 de MET.
Mises en garde cliniques
- Mise en garde majeure · La pneumopathie interstitielle ou pneumonite peut être fatale. Surveiller toute dyspnée, toux ou fièvre nouvelle ou aggravée ; suspendre immédiatement en cas de suspicion et arrêter définitivement si elle est confirmée. — DailyMed, TEPMETKO set_id 80a0f1b9-071a-47f5-9e67-32d638a669dc
- Mise en garde majeure · Contrôler ALT, AST et bilirubine avant le traitement, toutes les 2 semaines pendant les 3 premiers mois puis chaque mois. Une insuffisance hépatique fatale est survenue. — DailyMed, TEPMETKO set_id 80a0f1b9-071a-47f5-9e67-32d638a669dc
- Mise en garde majeure · Contrôler amylase et lipase au départ et régulièrement ; suspendre, réduire ou arrêter selon la gravité. — DailyMed, TEPMETKO set_id 80a0f1b9-071a-47f5-9e67-32d638a669dc
Interactions médicamenteuses
- SévèreSubstrats de la P-gp à marge thérapeutique étroite
Mécanisme: Le tépotinib inhibe la P-gp et peut augmenter leur concentration et leur toxicité.
Recommandation: Éviter l’association si de faibles variations peuvent provoquer une toxicité grave ou fatale ; si elle est indispensable, coordonner la réduction et la surveillance du substrat.
DailyMed, TEPMETKO set_id 80a0f1b9-071a-47f5-9e67-32d638a669dchttps://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=80a0f1b9-071a-47f5-9e67-32d638a669dc
Effets indésirables
Communs (≥1%)
œdème · nausées · fatigue · douleur musculosquelettique · diarrhée · dyspnée · diminution de l’appétit · éruption cutanée
Rares mais graves
insuffisance hépatique fatale · pneumonite fatale
Grossesse et allaitement
Peut provoquer une toxicité embryofœtale. Vérifier la grossesse avant de commencer. Les femmes et les hommes ayant une partenaire susceptible d’être enceinte doivent utiliser une contraception efficace pendant le traitement et pendant 1 semaine après. Ne pas allaiter pendant le traitement ni pendant 1 semaine après.
Bibliographie récente (PubMed)
Targeted therapies have revolutionized the treatment and improved the outcome for oncogene-driven NSCLC and an increasing number of oncogenic driver therapies have become available. For MET-dysregulated NSCLC (especially MET exon 14 skipping mutations and MET-amplifications, which is one of the most common bypass mechanisms of resistance in oncogene-addicted NSCLC), several anti-MET-targeted therapies have been approved recently (MET exon 14 skipping mutation) and multiple others are in development. In this narrative review, we summarize the role of MET as an oncogenic driver in NSCLC, discuss the different testing methods for exon 14 skipping mutations, gene amplification, and protein overexpression, and review the existing data and ongoing clinical trials regarding targeted therapies in MET-altered NSCLC. As immunotherapy with or without chemotherapy has become the standard of care for advanced NSCLC, immunotherapy data for MET-dysregulated NSCLC are put into perspective. Finally, we discuss future challenges in this rapidly evolving landscape.
MET inhibitors have recently demonstrated clinical activity in patients with MET exon 14 (METex14)-skipping non-small cell lung cancer (NSCLC); however, data with longer follow-up and in larger populations are needed to further optimize therapeutic approaches. To assess the long-term efficacy and safety of tepotinib, a potent and highly selective MET inhibitor, in patients with METex14-skipping NSCLC in the VISION study. The VISION phase 2 nonrandomized clinical trial was a multicohort, open-label, multicenter study that enrolled patients with METex14-skipping advanced/metastatic NSCLC (cohorts A and C) from September 2016 to May 2021. Cohort C (>18 months' follow-up) was an independent cohort, designed to confirm findings from cohort A (>35 months' follow-up). Data cutoff was November 20, 2022. Patients received tepotinib, 500 mg (450 mg active moiety), once daily. The primary end point was objective response by independent review committee (RECIST v1.1). Secondary end points included duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. Cohorts A and C included 313 patients (50.8% female, 33.9% Asian; median [range] age, 72 [41-94] years). The objective response rate (ORR) was 51.4% (95% CI, 45.8%-57.1%) with a median (m)DOR of 18.0 (95% CI, 12.4-46.4) months. In cohort C (n = 161), an ORR of 55.9% (95% CI, 47.9%-63.7%) with an mDOR of 20.8 (95% CI, 12.6-not estimable [NE]) months was reported across treatment lines, comparable to cohort A (n = 152). In treatment-naive patients (cohorts A and C; n = 164), ORR was 57.3% (95% CI, 49.4%-65.0%) and mDOR was 46.4 (95% CI, 13.8-NE) months. In previously treated patients (n = 149), ORR was 45.0% (95% CI, 36.8%-53.3%) and mDOR was 12.6 (95% CI, 9.5-18.5) months. Peripheral edema, the most common treatment-related adverse event, occurred in 210 patients (67.1%) (35 [11.2%] experienced grade ≥3 events). The findings from cohort C in this nonrandomized clinical trial supported the re
The complex therapeutic strategy of non-small cell lung cancer (NSCLC) has changed significantly in recent years. Disease-free survival increased significantly with immunotherapy and chemotherapy registered in perioperative treatments, as well as adjuvant registered immunotherapy and targeted therapy (osimertinib) in case of EGFR mutation. In oncogenic-addictive metastatic NSCLC, primarily in adenocarcinoma, the range of targeted therapies is expanding, with which the expected overall survival increases significantly, measured in years. By 2021, the FDA and EMA have approved targeted agents to inhibit EGFR activating mutations, T790 M resistance mutation, BRAF V600E mutation, ALK, ROS1, NTRK and RET fusion. In 2022, the range of authorized target therapies was expanded. With therapies that inhibit KRASG12C, EGFR exon 20, HER2 and MET. Until now, there was no registered targeted therapy for the KRAS mutations, which affect 30% of adenocarcinomas. Thus, the greatest expectation surrounded the inhibition of the KRAS G12C mutation, which occurs in ∼15% of NSCLC, mainly in smokers and is characterized by a poor prognosis. Sotorasib and adagrasib are approved as second-line agents after at least one prior course of chemotherapy and/or immunotherapy. Adagrasib in first-line combination with pembrolizumab immunotherapy proved more beneficial, especially in patients with high expression of PD-L1. In EGFR exon 20 insertion mutation of lung adenocarcinoma, amivantanab was registered for progression after platinum-based chemotherapy. Lung adenocarcinoma carries an EGFR exon 20, HER2 insertion mutation in 2%, for which the first targeted therapy is trastuzumab deruxtecan, in patients already treated with platinum-based chemotherapy. Two orally administered selective c-MET inhibitors, capmatinib and tepotinib, were also approved after chemotherapy in adenocarcinoma carrying MET exon 14 skipping mutations of about 3%. Incorporating reflex testing with next-generation sequencing (N
Patients with EGFR-mutated non-small-cell lung cancer (NSCLC) and MET amplification as a mechanism of resistance to first-line osimertinib have few treatment options. Here, we report the primary analysis of the phase 2 INSIGHT 2 study evaluating tepotinib, a highly selective MET inhibitor, combined with osimertinib in this population. This open-label, phase 2 study was conducted at 179 academic centres and community clinics in 17 countries. Eligible patients were aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0 or 1 and advanced or metastatic EGFR-mutated NSCLC of any histology, with MET amplification by tissue biopsy fluorescence in-situ hybridisation (FISH; MET gene copy number of ≥5 or MET-to-CEP7 ratio of ≥2) or liquid biopsy next-generation sequencing (MET plasma gene copy number of ≥2·3), following progression on first-line osimertinib. Patients received oral tepotinib 500 mg plus oral osimertinib 80 mg once daily. The primary endpoint was independently assessed objective response in patients with MET amplification by central FISH treated with tepotinib plus osimertinib with at least 9 months of follow-up. Safety was analysed in patients who received at least one study drug dose. This study is registered with ClinicalTrials.gov, NCT03940703 (enrolment complete). Between Feb 13, 2020, and Nov 4, 2022, 128 patients (74 [58%] female, 54 [42%] male) were enrolled and initiated tepotinib plus osimertinib. The primary activity analysis population included 98 patients with MET amplification confirmed by central FISH, previous first-line osimertinib and at least 9 months of follow-up (median 12·7 months [IQR 9·9-20·3]). The confirmed objective response rate was 50·0% (95% CI 39·7-60·3; 49 of 98 patients). The most common treatment-related grade 3 or worse adverse events were peripheral oedema (six [5%] of 128 patients), decreased appetite (five [4%]), prolonged electrocardiogram QT interval (five [4%]), and pneumonitis (four [3