FDA Approves BAVENCIO® (avelumab) plus Axitinib Combination for Patients with Advanced Renal Cell Carcinoma

DARMSTADT,Germany and NEW YORK,May 15,2019 --

Not intended for US,Canada and UK-based media

BAVENCIO is the first anti-PD-L1 in combination with axitinib approved by FDA for first-line treatment of patients with advanced renal cell carcinoma (RCC)

Phase III study showed combination significantly lowered risk of disease progression or death by 31% and extended progression-free survival by 5.4 months for patients with advanced RCC compared with sunitinib

Combination approved based on Phase III data in an overall population that included patients regardless of PD-L1 expression and across favorable,intermediate and poor prognostic groups

Additional regulatory reviews for BAVENCIO plus axitinib in advanced RCC are underway worldwide,including in the European Union and Japan

Merck and Pfizer Inc. (NYSE: PFE) today announced that the US Food and Drug Administration (FDA) has approved BAVENCIO® (avelumab) in combination with axitinibfor the first-line treatment of patients with advanced renal cell carcinoma (RCC). This is the first FDA approval for an anti-PD-L1 therapy as part of a combination regimen for patients with advanced RCC. The approval of BAVENCIO in combination with axitinibwas based on positive results from the Phase III JAVELIN Renal 101 study (NCT02684006),in which the combination significantly improved median progression-free survival (PFS) compared with sunitinib by more than five months in the intent-to-treat (ITT) patient population (HR: 0.69 [95% CI: 0.56–0.84]; 2-sided p-value=0.0002; median PFS for BAVENCIO in combination with axitinib: 13.8 months [95% CI: 11.1-NE]; sunitinib: 8.4 months [95% CI: 6.9-11.1]). The ITT population included patients regardless of PD-L1 expression and across IMDC (International Metastatic Renal Cell Carcinoma Database) prognostic risk groups (favorable 21%,intermediate 62% and poor 16%).1

"As we look to continue to improve outcomes for people with advanced RCC,new treatment approaches have the potential to benefit patients," said Robert J. Motzer,M.D.,Jack and Dorothy Byrne Chair in Clinical Oncology,Memorial Sloan Kettering Cancer Center,New York,US,and principal investigator for JAVELIN Renal 101. "With today's FDA approval of avelumab in combination with axitinib,we can now offer patients with advanced RCC a first-line treatment option that combines a PD-L1 immunotherapy with a well-known VEGFR TKI to provide a significant reduction in the risk of disease progression or death and doubling of the response rate compared with sunitinib."

RCC is a type of cancer where PD-L1 expression may contribute to inhibition of the immune response against the tumor.2 It is also a highly vascular tumor,in which vascular endothelial growth factor (VEGF) plays a key role.3

"A kidney cancer diagnosis is life-changing for both patients and their loved ones,and having a treatment strategy for their disease quickly becomes a priority,"said Dena Battle,President,KCCure. "The approval of new treatments such as BAVENCIO in combination with axitinibgives patients with advanced RCC much-needed options."

There is a significant unmet need for first-line treatments that delay progression and have an acceptable safety profile. 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.4,5 About half of patients living with advanced RCC do not go on to receive additional treatment after first-line therapy,6,7for reasons that may include poor performance status oradverse events from their initial treatment.6,8,9

"Today's approval of BAVENCIO in combination with axitinibbuilds on Pfizer's long heritage in bringing innovation to the RCC community with the hopes of making a significant and meaningful impact on the lives of patients," said Andy Schmeltz,Global President,Pfizer Oncology. "For more than 12 years,Pfizer has led the field in its commitment to developing new treatments for patients with advanced kidney cancer."

"With today's FDA approval of BAVENCIO in combination with axitinib,we feel privileged that we can offer patients with first-line advanced renal cell carcinoma a new treatment option," saidRehan Verjee,President of EMD Serono,Merck's Biopharma business in the US,and Global Head of Innovative Medicine Franchises,Merck.

In JAVELIN Renal 101,the objective response rate (ORR) was doubled in the ITT population with BAVENCIO in combination with axitinibversus sunitinib(51.4% [95% CI: 46.6-56.1] vs. 25.7% [95% CI: 21.7-30.0]). With a median overall survival (OS) follow-up of 19 months,data for the trial's other primary endpoint of OS were immature,with 27% of deaths in the ITT population,and the trial is continuing as planned.The most common adverse reactions (≥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 in combination with axitinib. The incidence of major adverse cardiovascular events (MACE) was higher with BAVENCIO in combination with axitinibversus sunitinib.1 Findings from the study have been published in The New England Journal of Medicine.10

The European Medicines Agency (EMA) validated the Type II variation application for BAVENCIO in combination with axitinibin advanced RCC in March 2019,and a supplemental application for BAVENCIO in combination with axitinibin unresectable or metastatic RCC was submitted inJapanin January 2019.The combination of BAVENCIO and axitinib is only approved for the first-line treatment of advanced RCC in the United States.

About Renal Cell Carcinoma

In 2019,an estimated 73,820 new cases of kidney cancer will be diagnosed in the US,and approximately 14,770 people will die from the disease.11 RCC is the most common form of kidney cancer,accounting for about 2% to 3% of all cancers in adults.12,13 Approximately 20% to 30% of patients with kidney cancer are first diagnosed at the advanced stage.4 The five-year survival rate for patients with metastatic RCC is approximately 12%.14

About the JAVELIN Renal 101 study

The Phase III JAVELIN Renal 101 study is a randomized (1:1),multicenter,open-label study of BAVENCIO in combination with axitinibin 886 patients with untreated advanced RCC regardless of tumor PD-L1 expression [intent-to-treat (ITT) population]. Patients with autoimmune disease or conditions requiring systemic immunosuppression were excluded. The major efficacy outcome measures were PFS as assessed by a Blinded Independent Central Review (BICR) using RECIST v1.1 and OS in patients with PD-L1-positive tumors using a clinical trial assay (PD-L1 expression level ≥1%). If PFS was statistically significant in patients with PD-L1-positive tumors,it was then tested in the ITT population. The hazard ratio for PFS in patients with PD-L1-positive tumors was HR 0.61 (95% CI: 0.48,0.79). PFS and OS in the ITT population,overall response 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 about 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® (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.15-17 BAVENCIO has also been shown to induce NK cell-mediated direct tumor cell lysis via antibody-dependent cell-mediated cytotoxicity (ADCC) in vitro.17-19 In November 2014,Merckand 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 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® (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 12months 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 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,diarrhea,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,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,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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Scientific exploration and responsible entrepreneurship have been key to Merck's technological and scientific advances. This is how Merck has thrived since its founding in 1668. The founding family remains the majority owner of the publicly listed company. Merck holds the global rights to the Merck name 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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Pfizer Disclosure Notice

The information contained in this release is as of May 14,2019. Pfizer assumes no obligation to update forward-looking statementscontained 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 new indication approved in the U.S. for BAVENCIO in combination with axitinib for the treatment of patients with advanced renal cell carcinoma,the alliance between Merckand 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 whenany 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

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

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Eggers H,Ivanyi P,Hornig M and Grünwald V. Predictive Factors for Second-Line Therapy in Metastatic Renal cell Carcinoma: A Retrospective Analysis.Journal of Kidney Cancer and VHL. 2017;4(1):8-15.

Motzer R,et al. Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma. The New England Journal of Medicine. 2018;378:1277-1290.

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Motzer R,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. Journal of Clinical Oncology. 2014;32:2765-2772.

Motzer R,et al. Avelumab plus Axitinib versus Sunitinib for Advanced Renal Cell Carcinoma. The New England Journal of Medicine. 2019;380:1103-1115.

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American Cancer Society: What is Kidney Cancer? Available from: https://www.cancer.org/cancer/kidney-cancer/about/what-is-kidney-cancer.html. Accessed May 2019.

Ljungberg B,et al. European Association of Urology Guidelines on Renal Cell Carcinoma: The 2019 Update. European Urology. 2019 Feb.

National Cancer Institute: SEER Cancer Stat Fact Sheets: Kidney and Renal Pelvis. Available from: https://seer.cancer.gov/statfacts/html/kidrp.html. Accessed May 2019.

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Dahan R,Sega E,Engelhardt J,Selby M,Korman AJ,Ravetch JV. FcγRs modulate the anti-tumor activity of antibodies targeting the PD-1/PD-L1 axis. Cancer Cell. 2015;28(3):285-295.

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