The era of precision medicine has identified several genomic alterations that can be targeted with novel therapies. In lung adenocarcinomas, a histology structure that accounts for nearly 50% of all cases of lung cancer, a number of genomic targets have been linked with effective targeted therapies. Comprehensive genomic testing is now the standard of care in advanced-stage lung adenocarcinomas; for patients that have specific driver molecular alterations, targeted therapies have resulted in substantial improvement in efficacy without excessive toxicity.
Introducing Tepotinib (Tepmetko)
In November 2021, the Health Sciences Authority (HSA) Singapore granted approval to Tepotinib (Tepmetko) for the treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) harbouring mesenchymal-epithelial transition factor gene (MET)exon 14 (METex14) skipping alterations. Aberrant oncogenic activation of MET signalling is associated with aggressive cancer phenotypes and poor prognosis. The incidence of the splice mutation in patients with NSCLC is reported to be approximately 3% and is observed most frequently in elderly patients, above the age of 70. Tepotinib is an oral tyrosine kinase inhibitor (TKI) that inhibits MET phosphorylation and MET-dependent downstream signalling pathways leading to suppression of tumour cell proliferation and growth.
Efficacy and Safety of Tepotinib: Phase II VISION
Its local regulatory approval was based on data from one pivotal Phase II VISION trial, a single-arm, open-label study of Tepotinib in adult patients with advanced NSCLC harbouring METex14 skipping alterations or MET amplification. METex14 was mainly identified centrally, either by cell-free DNA from the liquid biopsy with the Guardant360 NGS panel or by RNA from tissue biopsy with the Oncomine Focus Assay. The study included 3 cohorts of which Cohort A provided direct evidence in support of its approved indication i.e. patients with METex14 skipping alterations.
The primary efficacy endpoint was the objective response rate (ORR) assessed by the Independent Central Review (ICR), defined as confirmed complete response (CR) or partial response (PR) determined according to the Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1. Key secondary efficacy endpoints were duration of response (DOR), progression-free survival (PFS) and overall survival (OS).
A summary of the trial’s key efficacy and safety outcomes is presented in the table below.
| Population | Intervention | Efficacy
(data derived from Cohort A) |
Safety
(Data derived from Cohort A, Cohort C, and a pooled dataset of patients from several studies treated with Tepotinib 450mg once daily monotherapy for other malignancies) |
N=151 (intent-to-treat population)
|
All patients in Cohort A received Tepotinib 450mg orally once daily during each 21-day cycle until disease progression, death, withdrawal of consent or adverse event (AE) leading to discontinuation | At data cut-off date 1 Jul 2020:
The primary endpoint demonstrated an ORR of:
Secondary endpoints:
|
At the data cut-off date: the median duration of exposure in Cohorts A and C was 22.3 weeks, while the median duration of exposure in the pooled dataset was 16.9 weeks
|
Notably, meaningful conclusions regarding survival benefits on time-to-event endpoints are limited in the absence of a comparator in the single-arm VISION study. However, the observed ORR with Tepotinib could be considered promising in this patient population characterised by the rare, aggressive cancer phenotype and poor prognosis. In separate studies, the median overall survival (OS) of Stage IV METex14 NSCLC patients in the absence of MET inhibitor treatment was reported to be 6.7 months (n=18) in a study by Gow et al., and 8.1 months (n=34) in a study by Awad et al.
From a safety perspective, the risks associated with Tepotinib are related to the pharmacological class of the product and have also been reported for other TKIs and MET inhibitors. Regulatory bodies have considered the safety profile to be acceptable in the target patient population.
Implications to the treatment landscape
In the first-line setting of Stage IV NSCLC and METex14 skipping mutations, guidelines today recommend the use of MET-targeted therapy or standard treatment based on non-driver mutation guidelines (i.e. pembrolizumab monotherapy, platinum-based chemotherapy monotherapy, or pembrolizumab in combination with chemotherapy).
To date, Tepotinib and Capmatinib (Tabrecta) are locally approved targeted therapies available for patients with NSCLC who are positive for the METex14 oncogenic driver. Notably, Tepotinib and Capmatinib have not been compared in head-to-head trials precluding a clearly superior option. Both MET inhibitors were individually studied in prospective clinical trials that enrolled no control group, VISION and GEOMETRY, respectively. In these single-arm studies of previously-treated NSCLC patients and those without prior therapy, response rates suggest that MET inhibitors may be superior to chemotherapy in the first-line setting. However, the presently low quality of evidence has precluded guidelines from conclusively recommending MET inhibitors as the predominant first-line option.
Cohort C of the VISION study involving additional NSCLC patients harbouring the METex14 skipping alteration is ongoing and expected to augment existing clinical data from the results of Cohort A. Merck is expected to submit VISION’s final results to confirm the clinical benefit of Tepotinib for the treatment of metastatic NSCLC in the target patient population.
The rapidly developing treatment paradigm is predicted to become increasingly complex, with ongoing clinical trials in different development stages and more targeted drugs expected to be available for NSCLC patients with METex14 skipping mutations in the future.
