Tepotinib Treatment in Patients With MET Exon 14–Skipping Non–Small Cell Lung Cancer

Abstract

ImportanceMET 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.ObjectiveTo 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.Design, Setting, and ParticipantsThe 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.InterventionPatients received tepotinib, 500 mg (450 mg active moiety), once daily.Main Outcomes and MeasuresThe 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.ResultsCohorts 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).Conclusions and RelevanceThe findings from cohort C in this nonrandomized clinical trial supported the results from original cohort A. Overall, the long-term outcomes of VISION demonstrated robust and durable clinical activity following treatment with tepotinib, particularly in the treatment-naive setting, in the largest known clinical trial of patients with METex14-skipping NSCLC, supporting the global approvals of tepotinib and enabling clinicians to implement this therapeutic approach for such patients.Trial RegistrationClinicalTrials.gov Identifier: NCT02864992"https://clinicaltrials.gov/ct2/show/NCT02864992"

Targeting MET in NSCLC: An Ever-Expanding Territory

“… 43 In contrast, tepotinib exhibited a comparable ORR (57.3% versus 45.0%), DCR (78.7% versus 73.8%), mPFS (12.6 versus 11.0 mo), and mOS (21.3 versus 19.3 mo) in treatment-naive and previously treated patients. 31 Gumarontinib yielded an ORR of 71% versus 60%, a DCR of 89% versus 77%, an mPFS of 11.7 versus 7.6 months, and an mOS of not reached versus 16.2 months in treatment-naive versus previously treated patients, respectively. 44 So does bozitinib (77.1% versus 70.6%).…”

“… 32 Among 15 patients with brain metastases, tepotinib was associated with an intracranial ORR of 66.7% (3 complete response, 5 PR; 12 patients had previously undergone brain radiotherapy). 31 Savolitinib and gumarontinib also exhibited intracranial activity. 44 , 46 Taken together, these results suggest that ensartinib, capmatinib, tepotinib, savolitinib, and gumarontinib can be effective in METex14 NSCLC with brain metastases.…”

“…The ORR in the overall population was 51.4%, and greater than 90% of tumors were regressed; the mPFS was 11.2 months, and the mOS was 19.6 months. 31 Among other type Ib MET TKIs, savolitinib was evaluated in a phase 3B study of 87 patients. The first-line treatment data revealed an ORR of 59.5%, a disease control rate (DCR) of 95.2%, and an mPFS of 12.6 months.…”

“… 5 , 28 A GCN of greater than or equal to 5.0 was defined as METamp in the TATTON trial and INSIGHT study. 29 , 30 However, a GCN of greater than or equal to 2.5 was used as the threshold in the VISION study, 31 and a GCN of greater than or equal to 10 were considered indicative of METamp in the GEOMETRY mono-1 trial. 32 Similarly, discrepancies in establishing a definitive threshold for MET overexpression through immunohistochemistry (IHC) have been identified across trials.…”

First-line tepotinib for a very elderly patient with metastatic NSCLC harboring MET exon 14 skipping mutation and high PD-L1 expression

“…Mesenchymal epithelial transition gene ( MET ) exon 14 ( MET ex14) skipping mutations occur in approximately 3-4% of non-small cell lung cancer (NSCLC) ( 1 ). In the VISION trial, a phase 2, non-randomized open-label study, the MET inhibitor tepotinib achieved a response rate of 51.4% and a median duration of response (DOR) of 18 months among 313 patients with MET ex14 mutant advanced/metastatic NSCLC, both treatmet-naïve (n = 164) and previously treated (n ;= ;149) patients ( 2 , 3 ). Based on these results, tepotinib was approved by the Food and Drug Administration for the treatment of patients with metastatic NSCLC harboring MET ex14 skipping mutation regardless of the line of therapy ( 4 ), whereas the European Medicines Agency (EMA) approved tepotinib only for patients previously treated with immunotherapy and/or platinum-based chemotherapy ( 5 ).…”