The US Food and Drug Administration (FDA) has granted Breakthrough Therapy Designation for the investigational targeted therapy tepotinib* in patients with metastatic non-small cell lung cancer (NSCLC) harboring MET exon 14 skipping alterations who progressed following platinum-based cancer therapy.

Tepotinib, is a highly selective, investigational oral MET inhibitor, was discovered in-house at Merck KGaA, Darmstadt, Germany. In clinical trials, tepotinib was associated with a partial response in approximately half the patients with advanced non-small-cell lung cancer (NSCLC) with a confirmed MET exon 14 skipping mutation.

“Tepotinib [demonstrated a] robust objective responses with durability that has not previously been seen in patients with metastatic NSCLC harboring MET exon 14 skipping alterations, selected by either tissue or liquid biopsy approaches,” said Luciano Rossetti, Global Head of Research & Development for the Biopharma business of Merck KGaA, Darmstadt, Germany.

“This breakthrough therapy designation further underscores the potential of tepotinib, and we aim to advance this program and deliver this medicine as quickly as possible to NSCLC patients who may benefit,” Rossetti added.

Lung cancer
Lung cancer is the most common type of cancer worldwide, with 2 million cases diagnosed annually.[1] Alterations of the MET signaling pathway are found in various cancer types, including 3-5% of NSCLC cases, and correlate with aggressive tumor behavior and poor clinical prognosis.[2][3][4][5][6]

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Trial design
In the trial, tepotinib was administered at a dose of 500 mg once daily. As of January 1, 2020, 152 patients had received tepotinib and 99 patients have been followed for at least 9 months.

The response rate by independent review was 46% (95% confidence interval [CI] 36 to 57), with a median duration of response of 11.1 months (95% CI, 7.2 to could not be estimated) in the combined biopsy group.

The response rate was 48% (95% CI 36 to 61) among 66 patients in the liquid biopsy group and 50% (95% CI 37 to 63) among 60 patients in the tissue biopsy group; 27 patients had positive results according to both methods.

The investigator-assessed response rate was 56% (95% CI 45 to 66) and was similar regardless of the previous therapy received for advanced or metastatic disease.

A molecular response, as measured in circulating free DNA, was observed in 67% of the patients with matched liquid biopsy samples at baseline and during treatment.

Adverse events
In the vision study, peripheral edema was, with 7%, the main side effect of grade 3 or higher directly associated with treatment with tepotinib. Overall, grade 3 or higher side effects that were considered related to tepotinib were reported in 28% of the patients,

Proactive monitoring for peripheral edema is recommended and can be managed with temporary discontinuation of tepotinib or dose reduction. Side effects led to permanent discontinuation of tepotinib in 11% of the patients. The patients’ quality of life was maintained during tepotinib treatment.

Paul K. Paik, M.D., is a medical oncologist focusing on lung cancer at Memorial Sloan Kettering Cancer Center. Photo courtesy: 2020 Memorial Sloan Kettering Cancer Center.

New England Journal of Medicine
The results of the Vision study where published by Paul K. Paik, MD, a medical oncologist at Memorial Sloan Kettering Cancer Center in New York, NY, and colleagues in the September 3, 2020 issue of The New England Journal of Medicine (NEJM). [7]

In the article, Paik and his colleagues explain that MET alterations are primary oncogenic drivers that occur in 3-4% of patients with NSCLC and can be detected in liquid biopsy or tissue biopsy samples. These tumors typically do not contain other known oncogenic drivers. NSCLC patients with MET exon 14 skipping mutations are typically 70 years of age or older.

The Vision team conducted the multicohort, open-label, phase II study to evaluate the efficacy and side effect profile of tepotinib in patients with advanced NSCLC with MET alterations. In their article, published in the NEJM, they reported the results in patients with MET exon 14 skipping mutations.

The study primary endpoint was the objective response by independent review among patients who had undergone at least 9 months of follow-up. The response was also analyzed according to whether the presence of a MET exon 14 skipping mutation was detected on liquid biopsy or tissue biopsy.

Paik et al concluded that their results show that the selective MET inhibitor tepotinib has durable clinical activity in patients with NSCLC with MET mutations associated with exon 14 skipping. Furthermore, results from the Vision study have led to regulatory approval of tepotinib and its companion diagnostic assay for the detection of MET alterations, ArcherMET CDx, in March 2020 in Japan.

The findings from the Vision study validate MET exon 14 skipping mutation as a therapeutic target and emphasize the importance of routine testing for these MET alterations by liquid or tissue biopsy.

The study was funded by Merck (Darmstadt, Germany).

* Tepotinib is the recommended International Nonproprietary Name (INN) for the MET kinase inhibitor (MSC2156119J). Tepotinib is currently under clinical investigation and not approved for any use anywhere in the world.

Clinical trials
Tepotinib Phase II in Non-small Cell Lung Cancer (NSCLC) Harboring MET Alterations (VISION) – NCT02864992

[1] Bray F, et al. CA Cancer J Clin. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. 2018;68(6):394–424. PMID:30207593
[2] Reungwetwattana T, Liang Y, Zhu V, Ou SI. The race to target MET exon 14 skipping alterations in non-small cell lung cancer: The Why, the How, the Who, the Unknown, and the Inevitable. Lung Cancer. 2017;103:27-37. doi:10.1016/j.lungcan.2016.11.011
[3] Mo HN, Liu P. Targeting MET in cancer therapy. Chronic Dis Transl Med. 2017;3(3):148-153. Published 2017 Jul 19. doi:10.1016/j.cdtm.2017.06.002
[4] Lutterbach B, Zeng Q, Davis LJ, et al. Lung cancer cell lines harboring MET gene amplification are dependent on Met for growth and survival [published correction appears in Cancer Res. 2007 Apr 15;67(8):3987]. Cancer Res. 2007;67(5):2081-2088. doi:10.1158/0008-5472.CAN-06-3495
[5] Bladt F, Faden B, Friese-Hamim M, et al. EMD 1214063 and EMD 1204831 constitute a new class of potent and highly selective c-Met inhibitors. Clin Cancer Res. 2013;19(11):2941-2951. doi:10.1158/1078-0432.CCR-12-3247
[6] Paik PK, Veillon R, Cortot AB, Felip E, Sakai H, Mazieres J, Griesinger F, et al. Phase II study of tepotinib in NSCLC patients with METex14 mutations. J Clin Oncol 2019;37: (suppl; abstr 9005).
[7] 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;383:931-43. DOI: 10.1056/NEJMoa2004407.

Featured image: Woman with lung cancer during a medical visit. Photo courtesy: © 2016 – 2020 Fotolia. Used with permission

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