TEPMETKO® (Tepotinib) Approved in Japan for Advanced NSCLC with METex14 Skipping Alterations

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- TEPMETKO is the first and only therapy in Japan to be approved for line-agnostic treatment of advanced non-small cell lung cancer with METexon 14 (METex14) skipping alterations

- In Phase II VISION study METex14 skipping alterations were identified by liquid or tissue biopsy

- TEPMETKO has been approved in Japan on the basis of demonstrating meaningful benefit in objective response across different lines of treatment,and is administered as a once-daily oral dose

DARMSTADT,Germany,March 25,2020 --Merck,a leading science and technology company,today announced that the Japanese Ministry of Health,Labour and Welfare (MHLW) has approved TEPMETKO®* (tepotinib) for the treatment of patients with unresectable,advanced or recurrent non-small cell lung cancer (NSCLC) with METexon 14 (METex14)skipping alterations.TEPMETKO is administered 500 mg once daily as two 250 mg tablets. This is the first regulatory approval globally for an oral MET inhibitor indicated for the treatment of advanced NSCLC harboring MET gene alterations. TEPMETKO was previously granted SAKIGAKE 'fast-track' designation and orphan drug designation by the MHLW.

"With TEPMETKO,we are pleased to offer the first approved MET inhibitor in Japan,and a new option that can change the course of treatment for non-small cell lung cancer harboring METex14 skipping alterations," said Belén Garijo,CEO Healthcare and Member of the Executive Board of Merck. "With a focus on identifying these alterations in NSCLC patients with flexibility and precision,the companion diagnostic to TEPMETKO offers both liquid and tissue biopsy testing capabilities to best support the delivery of this targeted therapy to the patients who may benefit."

The approval of TEPMETKO (tepotinib) in Japan is supported by data from 99 patients (including 15 Japanese patients) with NSCLC withMETex14 skipping alterations enrolled in the ongoing single-arm Phase II VISION study.1The primary endpoint,objective response rate as assessed by an Independent Review Committee (IRC),was 42.4% (95% CI: 32.5,52.8) in patients identified by liquid biopsy (LBx) or tissue biopsy (TBx). The median duration of response based on independent assessment was 12.4 months for both LBx-identified (95% CI: 8.4 months,not evaluable) and TBx-identified patients (95% CI: 9.7 months,NE). In a safety analysis of 130 patients,tepotinib was well-tolerated; the most frequent treatment-related adverse events (TRAEs) of any grade were peripheral edema (53.8%),nausea (23.8%) and diarrhea (20.8%). TRAEs led to permanent discontinuation in 11 patients (8.5%).

"Identifying oncogenic drivers in order to guide the course of treatment for lung cancer patients is a clinical best practice; however,there previously was no approved therapy that specifically targeted MET alterations in metastatic NSCLC," said Hiroshi Sakai,M.D.,Director,Division of Thoracic Oncology,Saitama Cancer Center,Saitama,Japan. "With the approval of TEPMETKO,we now have a new treatment option that addresses this need,offering clinical benefit and duration of response with convenient once-daily oral dosing,representing real progress for patients with this aggressive type of lung cancer."

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

Merck has a strategic partnership with ArcherDX to develop a companion diagnostic featuring both liquid and tissue biopsy capabilities to identify METex14 skipping alterations among patients with NSCLCwith high precision and accuracyprior to treatment. The companion diagnostic received approval by MHLW in March 2020,and it is the first and only companion diagnostic to be approved for the detection of MET gene alterations.ArcherDXis a genomic analysis company dedicated to democratizing precision oncology through a suite of products and services that are accurate,personal,actionable and easy to use in local settings.

Discovered in-house at Merck,tepotinib is an oral MET inhibitor that is designed to inhibit the oncogenic MET receptor signaling caused by MET (gene) alterations,including both METex14 skipping alterations and MET amplifications,or MET protein overexpression.

In September 2019,the US Food and Drug Administration (FDA) granted Breakthrough Therapy Designation for tepotinib in patients with metastatic NSCLC harboringMETex14 skipping alterations who progressed following platinum-based cancer therapy.Merck plans to file tepotinib for regulatory review with the FDA in 2020. Tepotinib is also being investigated in the INSIGHT 2 study (NCT03940703) in combination with the tyrosine kinase inhibitor (TKI) osimertinib in epidermal growth factor receptor (EGFR)-mutated,MET amplified,locally advanced or metastatic NSCLC that has acquired resistance to prior EGFR TKI.

*The brand name TEPMETKO® is not approved for use outside of Japan.

About Non-Small Cell Lung Cancer

With 2 million cases diagnosed annually,lung cancer (including trachea,bronchus and lung) is the most common type of cancer worldwide and the leading cause of cancer-related death,with 1.7 million mortality cases worldwide. Alterations of the MET signaling pathway,including MET exon 14 (METex14) skipping alterations and MET amplifications,occur in 3% to 5% of NSCLC cases.

About TEPMETKO®

TEPMETKO® (tepotinib) is approved in Japan for the treatment of unresectable,advanced or recurrent non-small cell lung cancer (NSCLC) with MET exon 14 (METex14)skipping alterations. Tepotinib is an oral MET inhibitor that is designed to inhibit the oncogenic MET receptor signaling caused by MET (gene) alterations,or MET protein overexpression. Discovered in-house at Merck,it has been designed to have a highly selective mechanism of action,7 with the potential to improve outcomes in aggressive tumors that have a poor prognosis and harbor these specific alterations.Tepotinibis currently under clinical investigation in NSCLC and not yet approved in any markets outside of Japan.Merck is actively assessing the potential of investigating tepotinib in combination with novel therapies and in other tumor indications.

References

Merck data on file.

Bray F,et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68(6):394–424. https://doi.org/10.3322/caac.21492 PMID:30207593.

Ferlay J,et al (2018). Global Cancer Observatory: Cancer Today. Lyon,France: International Agency for Research on Cancer. Available from: https://gco.iarc.fr/today. Accessed 20 March 2020.

Reungwetwattana T,et al. Lung Cancer 2017;103:27-37.

Mo HN,et al. Chronic Dis Transl Med 2017; 3(3):148-153.

Lutterbach B,et al. Cancer Res 2007;67:2081–8.

Bladt F,et al. Clin Cancer Res 2013;19:2941-2951.

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