CHMP Adopts Positive Opinion for BAVENCIO(R)(avelumab) Plus Axitinib for First-Line Treatment of Patients with Advanced Renal Cell Carcinoma

PR80661

DARMSTADT, Germany and NEW YORK, September 20, 2019 /PRNewswire=KYODO JBN / --

Not intended for US, Canada and UK-based media

- Opinion based on Phase III data showing combination lowered risk of disease

progression or death by 31% and improved objective response rate compared with

sunitinib [1]  

- Decision by the European Commission anticipated in fourth quarter of 2019  

Merck and Pfizer Inc. (NYSE: PFE) today announced that the Committee for

Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA)

adopted a positive opinion recommending approval of BAVENCIO(R)(avelumab) in

combination with axitinib for the first-line treatment of adult patients with

advanced renal cell carcinoma (RCC). The opinion was based on positive findings

from the Phase III JAVELIN Renal 101 study, which demonstrated a significant

extension in median progression-free survival (PFS) and a clinically meaningful

improvement in objective response rate (ORR) for the combination across all

prognostic risk groups compared with sunitinib.1 The CHMP positive opinion will

be reviewed by the European Commission (EC), with a decision anticipated in the

fourth quarter of this year. Merck and Pfizer have a global strategic alliance

to jointly develop and commercialize BAVENCIO.

"Today's positive CHMP opinion is a significant step toward potentially

transforming the treatment landscape and bringing much needed options to people

living with advanced renal cell carcinoma in Europe. We believe that the

combination of BAVENCIO plus axitinib has the potential to help address a

significant need for patients with advanced renal cell carcinoma for first-line

treatments with a benefit across all prognostic risk groups, and we look

forward to a decision from the European Commission," said Luciano Rossetti,

M.D., Executive Vice President, Head of Global Research & Development at the

Biopharma business of Merck.

In 2018, an estimated 136,500 new cases of kidney cancer were diagnosed in

Europe, and approximately 54,700 people died from the disease.2 RCC is the most

common form of kidney cancer, accounting for about 3% of all cancers in

adults.2 Approximately 20% to 30% of patients are first diagnosed with RCC at

the advanced stage, and 30% of patients treated for an earlier stage go on to

develop metastases.3,4 About half of patients living with advanced RCC do not

go on to receive additional treatment after first-line therapy,5,6 for reasons

that may include poor performance status or adverse events from their initial

treatment.5,7,8 The five-year survival rate for patients with metastatic RCC is

approximately 12%.9

"Kidney cancer represents a significant burden in Europe, where incidence rates

are among the highest in the world," said Chris Boshoff, M.D., Ph.D., Chief

Development Officer, Oncology, Pfizer Global Product Development. "Pfizer has

been a leader in the development of kidney cancer treatments for more than a

decade, and it is a privilege to continue our efforts to bring a new treatment

option to this community."

The U.S. Food and Drug Administration (FDA) approved BAVENCIO in combination

with axitinib for the first-line treatment of patients with advanced RCC in May

2019.10 A supplemental application for BAVENCIO in combination with axitinib in

unresectable or metastatic RCC was submitted in Japan in January 2019.

About the JAVELIN Renal 101 Study

The Phase III JAVELIN Renal 101 study is a randomized, multicenter, open-label

study of BAVENCIO in combination with axitinib in 886 patients with untreated

advanced or metastatic RCC. The major efficacy outcome measures were PFS as

assessed by a Blinded Independent Central Review (BICR) using RECIST v1.1 and

overall survival (OS) in the first-line treatment of patients with advanced RCC

who have PD-L1-positive tumors (PD-L1 expression level >or =1%). If PFS

was statistically significant in patients with PD-L1-positive tumors, it was

then tested in all patients irrespective of PD-L1 expression. PFS based on BICR

assessment per RECIST v1.1 and OS irrespective of PD-L1 expression,

objective response, time to response (TTR), duration of response (DOR) and

safety are included as secondary endpoints. The study is continuing for OS.

About the JAVELIN Clinical Development Program

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

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

than 15 different tumor types. In addition to RCC, these tumor types include

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

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

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.11-13 BAVENCIO has also been

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

cell-mediated cytotoxicity (ADCC) in vitro.13-15 In November 2014, Merck and

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

BAVENCIO.

BAVENCIO Approved Indications

In September 2017, the European Commission granted conditional marketing

authorization for BAVENCIO(R)(avelumab) 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.16

In the US, BAVENCIO in combination with axitinib is indicated for the

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

Additionally, the US 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.10

Avelumab Important Safety Information from the US FDA-Approved Label

The warnings and precautions for avelumab (BAVENCIO®) include immune-mediated

adverse reactions (such as pneumonitis and hepatitis, colitis,

endocrinopathies, nephritis and renal dysfunction and other adverse reactions),

infusion-related reactions, hepatotoxicity, major adverse cardiovascular events

(MACE), and embryo-fetal toxicity.

The most common adverse reactions (all grades, ≥ 20%) in patients with

metastatic Merkel cell carcinoma (MCC) were fatigue (50%), musculoskeletal pain

(32%), diarrhea (23%), nausea (22%), infusion-related reaction (22%), rash

(22%), decreased appetite (20%), and peripheral edema (20%).

Selected treatment-emergent laboratory abnormalities (all grades, ≥ 20%)

in patients with metastatic MCC were lymphopenia (49%), anemia (35%), increased

aspartate aminotransferase (34%), thrombocytopenia (27%), and increased alanine

aminotransferase (20%).

The most common adverse reactions (all grades, ≥ 20%) in patients with

locally advanced or metastatic urothelial carcinoma (UC) were fatigue (41%),

infusion-related reaction (30%), musculoskeletal pain (25%), nausea (24%),

decreased appetite/hypophagia (21%), and urinary tract infection (21%).

Selected laboratory abnormalities (Grades 3-4, ≥ 3%) in patients with

locally advanced or metastatic UC were hyponatremia (16%), increased

gamma-glutamyltransferase (12%), lymphopenia (11%), hyperglycemia (9%),

increased alkaline phosphatase (7%), anemia (6%), increased lipase (6%),

hyperkalemia (3%), and increased aspartate aminotransferase (3%).

Fatal adverse reactions in patients occurred in 1.8% of patients with advanced

renal cell carcinoma (RCC) receiving BAVENCIO in combination with axitinib.

These included sudden cardiac death (1.2%), stroke (0.2%), myocarditis (0.2%),

and necrotizing pancreatitis (0.2%).

The most common adverse reactions (all grades, ≥20%) in patients with

advanced RCC receiving BAVENCIO in combination with axitinib (vs sunitinib)

were diarrhea (62% vs 48%), fatigue (53% vs 54%), hypertension (50% vs 36%),

musculoskeletal pain (40% vs 33%), nausea (34% vs 39%), mucositis (34% vs 35%),

palmar-plantar erythrodysesthesia (33% vs 34%), dysphonia (31% vs 3.2%),

decreased appetite (26% vs 29%), hypothyroidism (25% vs 14%), rash (25% vs

16%), hepatotoxicity (24% vs 18%), cough (23% vs 19%), dyspnea (23% vs 16%),

abdominal pain (22% vs 19%), and headache (21% vs 16%).

Selected laboratory abnormalities (all grades, ≥20%) worsening from

baseline in patients with advanced RCC receiving BAVENCIO in combination with

axitinib (vs sunitinib) were blood triglycerides increased (71% vs 48%), blood

creatinine increased (62% vs 68%), blood cholesterol increased (57% vs 22%),

alanine aminotransferase increased (ALT) (50% vs 46%), aspartate

aminotransferase increased (AST) (47% vs 57%), blood sodium decreased (38% vs

37%), lipase increased (37% vs 25%), blood potassium increased (35% vs 28%),

platelet count decreased (27% vs 80%), blood bilirubin increased (21% vs 23%),

and hemoglobin decreased (21% vs 65%).

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 Merck-Pfizer Alliance

Immuno-oncology is a top priority for Merck and Pfizer. The global strategic

alliance between Merck and Pfizer enables the companies to benefit from each

other's strengths and capabilities and further explore the therapeutic

potential of BAVENCIO, an anti-PD-L1 antibody initially discovered and

developed by Merck. The immuno-oncology alliance is jointly developing and

commercializing BAVENCIO. The alliance is focused on developing high-priority

international clinical programs to investigate BAVENCIO as a monotherapy as

well as combination regimens, and is striving to find new ways to treat cancer.

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

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sales of € 14.8 billion in 66 countries.

Scientific exploration and responsible entrepreneurship have been key to

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and brand. The only exceptions are the United States and Canada, where the

business sectors of Merck operate as EMD Serono in healthcare, MilliporeSigma

in life science, and EMD Performance Materials.

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At Pfizer, we apply science and our global resources to bring therapies to

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Pfizer Disclosure Notice

The information contained in this release is as of September 20, 2019. Pfizer

assumes no obligation to update forward-looking statements contained in this

release as the result of new information or future events or developments.

This release contains forward-looking information about BAVENCIO (avelumab),

including a potential new indication in the European Union for BAVENCIO in

combination with axitinib for the treatment of patients with advanced renal

cell carcinoma, the alliance between Merck and Pfizer involving BAVENCIO and

clinical development plans, including their potential benefits, that involves

substantial risks and uncertainties that could cause actual results to differ

materially from those expressed or implied by such statements. Risks and

uncertainties include, among other things, uncertainties regarding the

commercial success of BAVENCIO and axitinib; the uncertainties inherent in

research and development, including the ability to meet anticipated clinical

endpoints, commencement and/or completion dates for our clinical trials,

regulatory submission dates, regulatory approval dates and/or launch dates, as

well as the possibility of unfavorable new clinical data and further analyses

of existing clinical data and uncertainties regarding whether the other primary

endpoint of JAVELIN Renal 101 will be met; risks associated with interim data;

the risk that clinical trial data are subject to differing interpretations and

assessments by regulatory authorities; whether regulatory authorities will be

satisfied with the design of and results from our clinical studies; whether and

when any drug applications may be filed for BAVENCIO in combination with

axitinib in any other jurisdictions or in any jurisdictions for any other

potential indications for BAVENCIO or combination therapies; whether and when

the pending applications in the European Union and Japan for BAVENCIO in

combination with axitinib may be approved and whether and when regulatory

authorities in any jurisdictions where any other applications are pending or

may be submitted for BAVENCIO or combination therapies, including BAVENCIO in

combination with axitinib may approve any such applications, which will depend

on myriad factors, including making a determination as to whether the product's

benefits outweigh its known risks and determination of the product's efficacy,

and, if approved, whether they will be commercially successful; decisions by

regulatory authorities impacting labeling, manufacturing processes, safety

and/or other matters that could affect the availability or commercial potential

of BAVENCIO or combination therapies, including BAVENCIO in combination with

axitinib; and competitive developments.

A further description of risks and uncertainties can be found in Pfizer's

Annual Report on Form 10-K for the fiscal year ended December 31, 2018, and in

its subsequent reports on Form 10-Q, including in the sections thereof

captioned "Risk Factors" and "Forward-Looking Information and Factors That May

Affect Future Results", as well as in its subsequent reports on Form 8-K, all

of which are filed with the U.S. Securities and Exchange Commission and

available at www.sec.gov and www.pfizer.com.

References

1. Motzer R, et al. Avelumab plus Axitinib versus Sunitinib for Advanced Renal

Cell Carcinoma. The New England Journal of Medicine. 2019;380:1103-1115.

2. Ferlay J, Colombet M, Soerjomataram I, et al. Cancer incidence and mortality

patterns in Europe: Estimates for 40 countries and 25 major cancers in 2018.

Eur J Cancer. 2018;103:356-387.

3. Ljungberg B, Campbell S, Cho H. The epidemiology of renal cell carcinoma.

Eur Urol. 2011;60:615-621.

4. Klatte T, Rossi SH, Stewart GD. Prognostic factors and prognostic models for

renal cell carcinoma: a literature review. World J Urol. 2018;36(12):1943-1952.

5. Eggers H, Ivanyi P, Hornig M, Grünwald V. Predictive factors for second-line

therapy in metastatic renal cell carcinoma: a retrospective analysis. J Kidney

Cancer VHL. 2017;4(1):8-15.

6. Motzer R, et al. Nivolumab plus Ipilimumab versus Sunitinib in Advanced

Renal-Cell Carcinoma. The New England Journal of Medicine. 2018;378:1277-1290.

7. Eichelberg C, Vervenne WL, De Santis M, et al. SWITCH: A randomised,

sequential, open-label study to evaluate the efficacy and safety of

sorafenib-sunitinib versus sunitinib-sorafenib in the treatment of metastatic

renal cell cancer. Eur Urol. 2015;68;837-847.

8. Motzer RJ, Barrios CH, Kim TM, et al. Phase II randomized trial comparing

sequential first-line everolimus and second-line sunitinib versus first-line

sunitinib and second-line everolimus in patients with metastatic renal cell

carcinoma. J Clin Oncol. 2014;32:2765-2772.

9. Ridge C, Pua B, Madoff D. Epidemiology and staging of renal cell carcinoma.

Semin Intervent Radiol. 2014;31(1):3-8.

10. BAVENCIO Prescribing Information. Rockland, MA: EMD Serono Inc.; 2019.

11. Dolan DE, Gupta S. PD-1 pathway inhibitors: changing the landscape of

cancer immunotherapy. Cancer Control. 2014;21(3):231-237.

12. Dahan R, Sega E, Engelhardt J, et al. FcγRs modulate the anti-tumor

activity of antibodies targeting the PD-1/PD-L1 axis. Cancer Cell.

2015;28(3):285-295.

13. Boyerinas B, Jochems C, Fantini M, et al. Antibody-dependent cellular

cytotoxicity activity of a novel anti-PD-L1 antibody avelumab (MSB0010718C) on

human tumor cells. Cancer Immunol Res. 2015;3(10):1148-1157.

14. Kohrt HE, Houot R, Marabelle A, et al. Combination strategies to enhance

antitumor ADCC. Immunotherapy. 2012;4(5):511-527.

15. Hamilton G, Rath B. Avelumab: combining immune checkpoint inhibition and

antibody-dependent cytotoxicity. Expert Opin Biol Ther. 2017;17(4):515-523.

16. BAVENCIO(R)(avelumab) EU SmPC. Available from:

http://www.ema.europa.eu/ema/. Accessed September 2019.

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Source: Merck