Tepotinib Approved in Europe for METex14-Altered Advanced NSCLC

The European Commission has approved tepotinib for use as a single agent in adult patients with advanced non–small cell lung cancer harboring METex14 skipping alterations who require systemic therapy after prior treatment with immunotherapy and/or platinum-based chemotherapy.

The European Commission has approved tepotinib (Tepmetko) for use as a single agent in adult patients with advanced non–small cell lung cancer (NSCLC) harboring METex14 skipping alterations who require systemic therapy after prior treatment with immunotherapy and/or platinum-based chemotherapy.1

The regulatory decision is supported by findings from the phase 2 VISION trial (NCT02864992), which showed that the agent elicited an objective response rate (ORR) of 46% (95% CI, 36%-57%) by independent review among 99 patients evaluable for efficacy.2 All responders experienced partial responses (PRs) to treatment. Notably, patients achieved similar responses to tepotinib, irrespective of baseline characteristics and the number of prior lines of therapy.

“The approval of [tepotinib] in Europe helps to address the need for targeted treatment options for people with lung cancer who have received prior treatment and whose tumors harbor METex14 skipping alterations,” Anne-Marie Baird, BSc, PhD, president of Lung Cancer Europe, stated in a press release. “It is vital that biomarker testing is made consistently available and utilized across Europe to ensure people with advanced lung cancer receive an accurate diagnosis and optimal treatment.”

The multicenter, multicohort, single-arm, open-label trial enrolled patients with histologically or cytologically confirmed, locally advanced or metastatic NSCLC with MET exon 14 skipping mutations, who are at least 18 years of age, had measurable disease per RECIST v1.1 criteria, and an ECOG performance status of 0 or 1.

Patients were able to have received up to 2 courses of prior treatment for advanced or metastatic disease. Notably, those with stable central nervous system metastases whose glucocorticoid dose was being tapered, were able to participate.

The trial is comprised of 3 cohorts; those in cohort A had MET exon 14 skipping mutations and those in cohort B had MET-amplified disease without METex14 skipping mutations. Cohort C is enrolling patients with MET exon 14 skipping mutations for a confirmatory analysis of cohort A.

Study participants received oral tepotinib at a once-daily dose of 500 mg until disease progression, withdrawn consent, or toxicities leading to treatment discontinuation.

The primary end point of the trial was confirmed ORR per RECIST v1.1 criteria, and key secondary end points included investigator-assessed objective response, duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Investigators also evaluated patient-reported outcomes.

Among those in cohort A who were determined to be evaluable for efficacy, the median age was 74 years, 46% had a history of smoking, and 97% had metastatic disease at the time of study entry. Three patients were noted to have tumors that had sarcomatoid features. Notably, 56 of the 99 evaluable patients previously received treatment; 29 of these patients had received prior immunotherapy.

Patients received tepotinib for a median of 6.9 months (range, <0.1 to 36.7). The median follow-up in the efficacy population was 17.4 months. Additional data showed that the investigator-assessed response rate with tepotinib was 56% (95% CI, 45%-66%). Per this assessment, 2 patients were noted to have achieved a complete response, and 53 experienced a PR.

Per independent review, 89% of patients experienced tumor shrinkage; per investigator assessment, this rate was 88%.

The median DOR with tepotinib was 11.1 months (95% CI, 7.2–not estimable [NE]) per independent review in the 99 patients with a combined biopsy. The median DOR was 9.9 months (95% CI, 7.2-NE) in the group who only had a liquid biopsy (n = 66); in those who only had a tissue biopsy (n = 60), the median DOR was 15.7 months (95% CI, 9.7-NE).

In the combined-biopsy group, the median duration of PFS per independent review was 8.5 months (95% CI, 6.7-11.0); this was 8.5 months (95% CI, 5.1-11.0) in the liquid-biopsy group and 8.5 months (95% CI, 5.7-17.1) in the tissue-biopsy group. Similar findings were observed per investigator assessment. Although the data were not yet mature, the median duration of OS was 17.1 months (95% CI, 12.0-26.8).

Among 11 patients with brain metastases, tepotinib resulted in a response rate of 55% (95% CI, 23%-83%) per independent review, and the median DOR was 9.5 months (95% CI, 6.6-NE) and the median PFS was 10.9 months (95% CI, 8.0-NE).

In the safety population (n = 152), 98% were reported to have experienced a toxicity of any cause, with 89% experiencing events that were determined by investigators to be associated with tepotinib. Grade 3 or higher toxicities occurred in 28% of patients, with the most common being peripheral edema (7%). Although increased levels of amylase were frequently observed, these cases were noted to range from mild to moderate in severity.

Fifteen percent of patients experienced serious toxicities determined to be related to tepotinib. Treatment-related adverse effects (TRAEs) that resulted in dose reduction was observed in 33% of patients; 11% of patients discontinued treatment permanently because of TRAEs. Reductions and discontinuations were mostly associated with peripheral edema, pleural effusion, or dyspnea.

Notably, peripheral edema was the most frequently reported TRAE and resulted in a dose reduction or interruption for 16% and 18% of patients, respectively. Only 5% of patients discontinued treatment with tepotinib because of this toxicity.

Twenty-one patients experienced AEs that resulted in death, with 1 death considered by investigators to be associated with the study drug.

“With the European Commission’s approval of [tepotinib], we are now able to bring this important medicine to more patients with this hard-to-treat and aggressive form of lung cancer,” Andrew Paterson, chief marketing officer for the healthcare business of Merck KGaA, Darmstadt, Germany, added in the release. “As pioneers in the targeting of the MET signaling pathway, we will now be working on ways to bring this medicine to patients in Europe who may benefit.”

In February 2021, the FDA granted an accelerated approval to tepotinib for the treatment of adult patients with metastatic NSCLC harboring MET exon 14 skipping mutations based on findings from VISION.3


  1. European Commission approves TEPMETKO (tepotinib) for patients with advanced NSCLC with METex14 skipping alterations. News release. EMD Serono; February 18, 2022. Accessed February 21, 2022. https://bwnews.pr/3LRDTrR
  2. Paik PK, Felip E, Veillon R, et al. Tepotinib in non-small-cell lung cancer with MET exon 14 skipping mutations. N Engl J Med. 2020;383(10):931-943. doi:10.1056/NEJMoa2004407
  3. FDA grants accelerated approval to tepotinib for metastatic non-small cell lung cancer. News release. FDA; February 3, 2021. Accessed February 22, 2022. http://bit.ly/3az71Cj