Merck Announces FDA Breakthrough Therapy Designation for Investigational Therapy Tepotinib in Patients with Metastatic NSCLC with METex14 Skipping Alterations

PR80467

DARMSTADT, Germany, Sept. 11, 2019 /PRNewswire=KYODO JBN/ --

- Investigational oral MET inhibitor has previously received SAKIGAKE

'fast-track' regulatory designation in Japan

- MET exon 14 skipping alterations and MET amplifications are present in 3-5%

of non-small cell lung cancer patients and correlate with poor prognosis

- The designation is based on data from the ongoing VISION study, which showed

preliminary clinical evidence for tepotinib in metastatic NSCLC harboring

METex14 skipping alterations

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    Merck, a leading science and technology company, today announced that 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.

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    "Tepotinib was associated with 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. "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."

    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]

    Discovered in-house at Merck, tepotinib is an investigational oral MET

kinase inhibitor that is designed to be highly potent and selective[5] and to

inhibit the oncogenic signaling caused by MET (gene) alterations, including

both MET exon 14 skipping alterations and MET amplifications, or MET protein

overexpression.

    In March 2018, tepotinib's potential was recognized by the Japanese

Ministry of Health, Labour and Welfare (MHLW), which granted SAKIGAKE

'fast-track' designation for tepotinib in advanced NSCLC harboring MET exon 14

skipping alterations. SAKIGAKE designation promotes research and development in

Japan, aiming at early practical application for innovative pharmaceutical

products, medical devices and regenerative medicines.

    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 having acquired resistance to prior EGFR TKI.

    The Breakthrough Therapy Designation is based on data from the ongoing

VISION study (NCT02864992), showing preliminary clinical evidence that

tepotinib may offer an improvement over available therapy in patients with

metastatic NSCLC harboring MET exon 14 skipping alterations detected by liquid

biopsy (LBx) or tissue biopsy (TBx) across different lines of treatment.

    Results from an interim analysis of the ongoing VISION study in 73

efficacy-evaluable patients with NSCLC with MET exon 14 skipping alterations

identified by LBx or TBx testing demonstrate overall objective response rate

(ORR) of 50.0% for LBx-identified patients as assessed by Independent Review

Committee (IRC), and 55.3% as assessed by investigators. The ORR for

TBx-identified patients was 45.1% and 54.9%, respectively. The overall median

duration of response (DOR) was 12.4 months and 17.1 months among LBx-identified

patients, as assessed by IRC and investigators, respectively, while among

TBx-identified patients, 15.7 and 14.3 months were observed, respectively.   

    Most treatment-related adverse events (TRAEs) were Grade 1 and 2. No Grade

4 or 5 TRAEs were observed. Any grade TRAEs reported by ≥10% of 87

patients evaluable for safety were peripheral edema (48.3%), nausea (23.0%)

diarrhea (20.7%) and increased blood creatinine (12.6%). Other relevant TRAEs

of any grade include increased lipase (4.6%), fatigue (3.4%) and vomiting

(3.4%). TRAEs led to permanent discontinuation in four patients (two patients

due to peripheral edema, one due to interstitial lung disease, one due to

diarrhea and nausea).

    Results from this study were presented in an oral presentation at the 2019

American Society of Clinical Oncology (ASCO) Annual Meeting.[6] The use of both

LBx and TBx to identify patients for the VISION study is intended to support

improved patient selection and is consistent with the company's focus on

patient-centric drug development.

    *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.

    About Breakthrough Therapy Designation

    Breakthrough Therapy Designation is designed to expedite the development

and review of drugs which are intended to treat a serious condition, and

preliminary clinical evidence indicates that the drug may demonstrate

substantial improvement over available therapy on a clinically significant

endpoint(s). The FDA's granting of the Breakthrough Therapy Designation for

advanced NSCLC does not alter the standard regulatory requirement to establish

the safety and effectiveness of a drug through adequate and well-controlled

studies to support approval.

    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.[1]

Alterations of the MET signaling pathway, including MET exon 14 skipping

alterations and MET amplifications, occur in 3-5% of NSCLC cases.[2],[3],[4]

    About Tepotinib

    Tepotinib, discovered in-house at Merck, is an investigational oral MET

inhibitor that is designed to inhibit the oncogenic MET receptor signaling

caused by MET (gene) alterations, including both MET exon 14 skipping

alterations and MET amplifications, or MET protein overexpression. It has been

designed to have a highly selective mechanism of action, with the potential to

improve outcomes in aggressive tumors that have a poor prognosis and harbor

these specific alterations.

    Tepotinib is currently being investigated in NSCLC and Merck is actively

assessing the potential of investigating tepotinib in combination with novel

therapies and in other tumor indications.

    References

     [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. https://doi.org/10.3322/caac.21492 PMID:30207593.

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

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

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

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

     [6]  Paik P, et al. J Clin Oncol 2019;37: (suppl; abstr 9005).

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