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

- 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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Darmstadt, Germany (ots/PRNewswire) - 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.

"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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