Merck Data at ASCO 2019 Showcase Multiple Innovative Molecules with Potential to Impact Unmet Needs in Cancer Care

PR78769

DARMSTADT, Germany, May 16, 2019, /PRNewswire=KYODO JBN/--

Not intended for UK- , Canada- or US-based media

ASCO Abstract #

Bintrafusp alfa (bifunctional fusion protein): TPS9114; Tepotinib (MET kinase

inhibitor): 9005; Discovery: 2567; ERBITUX(R) (cetuximab): 3580; BAVENCIO(R)

(avelumab): 9569; 101; 4552; 4072

- New biomarker analyses for BAVENCIO(R)* (avelumab) in combination with

axitinib in first-line renal cell carcinoma (RCC)

- Data presented across several modalities and mechanisms showcase the

scientific innovation and diversity of the company's pipeline, which includes

bintrafusp alfa~ (M7824) and tepotinib^

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

across several modalities and mechanisms targeting difficult-to-treat cancers

will be presented at the 2019 American Society of Clinical Oncology (ASCO)

Annual Meeting, May 31–June 4, Chicago, IL, US. New data will be presented for

BAVENCIO(R)* (avelumab) and ERBITUX(R) (cetuximab), including rational

combinations with chemotherapy, radiation therapy and other targeted agents to

try to identify new ways to improve patient outcomes. This includes an oral

presentation of data defining biomarkers that differentiate therapy-specific

outcomes in patients with advanced renal cell carcinoma (RCC), and who have

been treated first-line with BAVENCIO(R) (avelumab) in combination with

axitinib. Abstracts also showcase the scientific innovation and diversity of

Merck's pipeline, with results from a number of high-priority clinical

development programs, including tepotinib^, bintrafusp alfa~ (M7824) and the

company's comprehensive DNA Damage Response (DDR) portfolio.

"At this year's ASCO meeting we continue to demonstrate the breadth and depth

of our oncology and immuno-oncology portfolio. We will present examples of the

latest precision medicine and biomarker research and some of the most exciting

mechanisms being investigated today, including tepotinib and our first-in-class

bifunctional fusion protein immunotherapy, bintrafusp alfa," said Luciano

Rossetti, Global Head of Research & Development for the Biopharma business of

Merck. "Merck's oncology pipeline has significant promise in the near term

through our late-stage priority programs, and our early pipeline includes

several potentially groundbreaking modalities. We look forward to sharing the

latest science with the global oncology community."

For BAVENCIO(R) (avelumab), Merck will share data from five studies across

tumor types including Merkel cell carcinoma, RCC, hepatocellular carcinoma and

urothelial carcinoma. This includes an oral presentation of biomarker analyses

of baseline tumor samples from the Phase III JAVELIN Renal 101 trial in

previously untreated patients with advanced RCC. The trial indicated that PD-L1

expression (equal-to-or-less-than 1% immune cells) was associated with the

longest progression-free survival (PFS) in the avelumab plus axitinib arm and

the shortest PFS in the sunitinib arm (HR, 0.63; 95% CI, 0.49, 0.81). An

analysis of relevant gene expression signatures (GES) indicated that in the

avelumab plus axitinib arm, PFS was enhanced in immune GES–positive patients vs

those in the negative group (HR, 0.63; 95% CI, 0.46, 0.86; 2-sided p=0.004),

and vs those in an independent dataset (JAVELIN Renal 100; Choueiri, Lancet

Oncol, 2018) (HR, 0.46; 95% CI, 0.20, 1.05; 2-sided p=0.064). The combination

demonstrated a safety and tolerability profile consistent with the known safety

profiles of each drug alone. The most common adverse reactions

(equal-to-or-less-than 20%) were diarrhea, fatigue, hypertension,

musculoskeletal pain, nausea, mucositis, palmar-plantar erythrodysesthesia,

dysphonia, decreased appetite, hypothyroidism, rash, hepatotoxicity, cough,

dyspnea, abdominal pain, and headache. Serious adverse reactions occurred in

35% of patients receiving BAVENCIO(R) (avelumab) in combination with axitinib.

The incidence of major adverse cardiovascular events (MACE) was higher with

BAVENCIO(R) (avelumab) in combination with axitinib vs sunitinib.

ERBITUX(R) (cetuximab) data from a retrospective analysis of overall survival

by subsequent therapy in patients with RAS wild-type metastatic colorectal

cancer from the Phase III EPIC study will be presented, to evaluate the effect

of post-study therapies (with ERBITUX(R) without ERBITUX(R), or no subsequent

therapy) on OS.

A number of the molecules to be featured were discovered in-house at Merck.

This includes tepotinib, an oral MET inhibitor designed to inhibit the

oncogenic MET receptor signaling caused by MET (gene) alterations, and

bintrafusp alfa, a bifunctional fusion protein designed to simultaneously

target two immuno-suppressive pathways. Merck's partnership with GSK to jointly

develop and commercialize bintrafusp alfa, announced in February 2019, is part

of the company's strategic approach to oncology R&D. Together, Merck and GSK

aim to rapidly and efficiently progress this molecule, which represents a

potential step change in the treatment of cancer.

For tepotinib, promising updated results from the ongoing Phase II VISION study

in 85 patients with non-small cell lung cancer (NSCLC) with MET exon 14

skipping mutations (identified by liquid biopsy [LBx] or tumor biopsy [TBx])

will be shared. Results show an overall response rate (ORR) of 51.4% for LBx

patients (independent review committee [IRC]-assessed) or 63.9%

(investigator-assessed). The ORR for TBx patients was 41.5% (IRC-assessed) or

58.5% (investigator-assessed). Median duration of response was 9.8

(IRC-assessed) or 17.1 months (investigator-assessed) for LBx patients and 12.4

(IRC-assessed) or 14.3 months (investigator-assessed) for TBx patients. Any

grade treatment-related adverse events (TRAEs) reported by

equal-to-or-less-than 10% of 69 patients evaluable for safety were peripheral

edema (47.8%), diarrhea (18.8%), nausea (15.9%) and asthenia (10.1%). No Grade

4 or 5 TRAEs were observed. TRAEs led to permanent discontinuation in two

(2.9%) patients (one interstitial lung disease, one diarrhea and nausea). These

data continue to mature, and an updated data cut from the VISION study will be

given as an oral presentation at the ASCO meeting on Monday, June 3.

For bintrafusp alfa, a trial-in-progress poster will be shared on the

open-label study of bintrafusp alfa vs pembrolizumab as a first-line treatment

in patients with PD-L1-expressing advanced NSCLC.

Merck takes a personalized approach to R&D, and precision medicine has long

been a priority. Abstracts being presented at ASCO also include biomarker

research programs that aim to help identify the patients most likely to benefit

from specific treatments so they can achieve the best possible medical outcomes.

*The combination of BAVENCIO and axitinib is approved for the first-line

treatment of advanced RCC only in the United States. There is no guarantee that

avelumab in combination with axitinib will be approved for RCC by any other

health authority worldwide.

^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.

~Bintrafusp alfa is the proposed International Nonproprietary Name (INN) for

the bifunctional immunotherapy M7824. Bintrafusp alfa is currently under

clinical investigation and not approved for any use anywhere in the world.

Notes to Editors

Key Merck-supported abstracts slated for presentation are listed below. In

addition, a number of investigator-sponsored studies have been accepted (not

listed).

Biomarker analyses from

JAVELIN Renal 101:

avelumab + axitinib

(A+Ax) vs sunitinib (S)

in advanced renal cell

carcinoma (aRCC)

T.K. Choueiri

101

Sat, Jun 1, 8:00

AM – 9:30 AM

(8:12 AM – 8:24

AM lecture time)

Hall D1

Poster Sessions

5-factor prognostic

model for survival of

patients with metastatic

urothelial carcinoma

receiving 3 different

post-platinum PD-L1

inhibitors

G. Sonpavde

4552

Mon, Jun 3, 1:15

PM – 4:15 PM

Hall A

First-line avelumab +

axitinib in patients with

advanced hepatocellular

carcinoma: results from

a phase 1b trial (VEGF

Liver 100)

M. Kudo

4072

Mon, Jun 3, 8:00

AM – 11:00 AM

Hall A

Integrative molecular

analysis of metastatic

Merkel cell carcinoma to

identify predictive

biomarkers of response

to avelumab

S. Georges

9569

Mon, Jun 3, 1:15

PM – 4:15 PM

Hall A

Bintrafusp Alfa

Poster Session

Randomized open-label

study of M7824 vs

pembrolizumab as first-

line (1L) treatment in

patients with PD-L1

expressing advanced

non-small cell lung

cancer (NSCLC)

L. Paz-Ares

TPS9114

Sun, Jun 2, 8:00

AM – 11:00 AM

Hall A

Discovery

Poster Session

Understanding

contribution and

independence of multiple

biomarkers for

predicting response to

atezolizumab

P.K. Shah

2567

Sat, Jun 1, 8:00

AM – 11:00 AM

Hall A

ERBITUX(R) (cetuximab)

Poster Session

Retrospective Analysis of

Overall Survival (OS) by

Subsequent Therapy in

Patients With RAS-Wild-

type (wt) Metastatic

Colorectal Cancer

(mCRC) Receiving

Cetuximab ± Irinotecan

A. Sobrero

3580

Mon, Jun 3, 8:00

AM – 11:00 AM

Hall A

Tepotinib

Oral Session

Phase II study of

tepotinib in

NSCLC patients with

METex14 mutations

P.K. Paik

9005

Mon, Jun 3, 8:00 AM –

11:00 AM (9:24

AM – 9:36 AM

lecture time)

Hall B1

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 mutations

add 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 other tumor indications.

About Bintrafusp Alfa (M7824)

Bintrafusp alfa is an investigational bifunctional immunotherapy that is

designed to combine a TGF-BETA trap with the anti-PD-L1 mechanism in one fusion

protein. Bintrafusp alfa is designed to combine co-localized blocking of the

two immuno-suppressive pathways – targeting both pathways aims to control tumor

growth by potentially restoring and enhancing anti-tumor responses. Bintrafusp

alfa is currently in Phase I studies for solid tumors, as well as a randomized

Phase II trial to investigate bintrafusp alfa compared with pembrolizumab as a

first-line treatment in patients with PD-L1 expressing advanced NSCLC. The

multicenter, randomized, open-label, controlled study is evaluating the safety

and efficacy of bintrafusp alfa versus pembrolizumab as a monotherapy

treatment.

To date, nearly 700 patients have been treated with bintrafusp alfa across more

than 10 tumor types in Phase I studies. Encouraging data from the ongoing Phase

I studies indicates bintrafusp alfa's potential safety and clinical anti-tumor

activity across multiple types of difficult-to-treat cancers, including

advanced NSCLC, human papillomavirus-associated cancers, biliary tract cancer

and gastric cancer. In addition, in pre-clinical studies bintrafusp alfa

demonstrated superior anti-tumor activity, compared with anti-PD-L1 alone or

with anti-PD-L1 and TGF-BETA trap when co-administered. In total, eight

high-priority immuno-oncology clinical development studies are ongoing or

expected to commence in 2019, including studies in non-small cell lung and

biliary tract cancers.

About BAVENCIO(R) (avelumab)

BAVENCIO is a human anti-programmed death ligand-1 (PD-L1) antibody. BAVENCIO

has been shown in preclinical models to engage both the adaptive and innate

immune functions. By blocking the interaction of PD-L1 with PD-1 receptors,

BAVENCIO has been shown to release the suppression of the T cell-mediated

antitumor immune response in preclinical models.1-3 BAVENCIO has also been

shown to induce NK cell-mediated direct tumor cell lysis via antibody-dependent

cell-mediated cytotoxicity (ADCC) in vitro.3-5 In November 2014, Merck and

Pfizer announced a strategic alliance to co-develop and co-commercialize

BAVENCIO.

The clinical development program for avelumab, known as JAVELIN, involves at

least 30 clinical programs and about 10,000 patients evaluated across more than

15 different tumor types. These tumor types include RCC,

gastric/gastro-esophageal junction cancer, head and neck cancer, Merkel cell

carcinoma, non-small cell lung cancer, and urothelial carcinoma.

BAVENCIO approved Indications

In September 2017, the European Commission granted conditional marketing

authorization for BAVENCIO as a monotherapy for the treatment of adult patients

with metastatic Merkel cell carcinoma (MCC). BAVENCIO is currently approved for

patients with MCC in more than 45 countries globally, with the majority of

these approvals in a broad indication that is not limited to a specific line of

treatment.

BAVENCIO(R) (avelumab) in combination with axitinib is indicated in the US for

the first-line treatment of patients with advanced renal cell carcinoma (RCC).

In the US, the FDA granted accelerated approval for BAVENCIO for the treatment

of (i) adults and pediatric patients 12 years and older with metastatic Merkel

cell carcinoma (mMCC) and (ii) patients with locally advanced or metastatic

urothelial carcinoma (mUC) who have disease progression during or following

platinum-containing chemotherapy, or have disease progression within 12 months

of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.

These indications are approved under accelerated approval based on tumor

response rate and duration of response. Continued approval for these

indications may be contingent upon verification and description of clinical

benefit in confirmatory trials.

BAVENCIO(R) Safety Profile from the EU Summary of Product Characteristics (SmPC)

The special warnings and precautions for use for BAVENCIO include

infusion-related reactions and immune-related adverse reactions (such as

pneumonitis, hepatitis, colitis, endocrinopathies, nephritis and renal

dysfunction, and other adverse reactions).

The SmPC list of the most common adverse reactions in patients with solid

tumors includes fatigue, nausea, diarrhea, decreased appetite, constipation,

infusion-related reactions, and weight loss and vomiting.

Axitinib Important Safety Information from the US FDA Approved Label

In the study of advanced RCC after failure of one prior systemic therapy, the

warnings and precautions for axitinib include hypertension, including

hypertensive crisis, arterial and venous thrombotic events, hemorrhagic events,

cardiac failure, gastrointestinal perforation and fistula, hypothyroidism,

wound healing complications, reversible posterior leukoencephalopathy syndrome

(RPLS), proteinuria, liver enzyme elevation, hepatic impairment, and fetal harm

during pregnancy.

Common adverse events (reported in at least 20% of patients) in patients

receiving axitinib were diarrhea, hypertension, fatigue, decreased appetite,

nausea, dysphonia, hand-foot syndrome, weight decreased, vomiting, asthenia,

and constipation.

About ERBITUX(R) (cetuximab)

Erbitux(R) is an IgG1 monoclonal antibody targeting the epidermal growth factor

receptor (EGFR). As a monoclonal antibody, the mode of action of Erbitux(R) is

distinct from standard non-selective chemotherapy treatments in that it

specifically targets and binds to the EGFR. This binding inhibits the

activation of the receptor and the subsequent signal-transduction pathway,

which results in reducing both the invasion of normal tissues by tumor cells

and the spread of tumors to new sites. It is also believed to inhibit the

ability of tumor cells to repair the damage caused by chemotherapy and

radiotherapy and to inhibit the formation of new blood vessels inside tumors,

which appears to lead to an overall suppression of tumor growth. Based on in

vitro evidence, Erbitux(R) also targets cytotoxic immune effector cells towards

EGFR-expressing tumor cells (antibody-dependent cell-mediated cytotoxicity

[ADCC]).

Very commonly reported side effects with Erbitux(R) include acne-like skin

rash, mild to moderate infusion-related reactions and hypomagnesemia.

Erbitux(R) has already obtained market authorization in 114 countries worldwide

for the treatment of RAS wild-type metastatic colorectal cancer and for the

treatment of squamous cell carcinoma of the head and neck. Merck licensed the

right to market Erbitux(R), a registered trademark of ImClone LLC, outside the

U.S. and Canada from ImClone LLC, a wholly owned subsidiary of Eli Lilly and

Company, in 1998.

References

1. Dolan DE, et al. Cancer Control 2014;21:231–7.

2. Dahan R, et al. Cancer Cell 2015;28:285–95.

3. Boyerinas B, et al. Cancer Immunol Res 2015;3:1148–57.

4. Kohrt HE, et al. Immunotherapy 2012;4:511–27.

5. Hamilton G, et al. Expert Opin Biol Ther 2017;17:515–23.

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About Merck

Merck, a leading science and technology company, operates across healthcare,

life science and performance materials. Around 52,000 employees work to make a

positive difference to millions of people's lives every day by creating more

joyful and sustainable ways to live. From advancing gene editing technologies

and discovering unique ways to treat the most challenging diseases to enabling

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sales of EUR 14.8 billion in 66 countries.

Scientific exploration and responsible entrepreneurship have been key to

Merck's technological and scientific advances. This is how Merck has thrived

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