Not intended for US, Canada and UK-based media -- EU approval based on JAVELIN Renal 101 trial results demonstrating significant improvement in progression-free survival with BAVENCIO in combination with axitinib compared with sunitinib -- Combination regimen approved across all IMDC prognostic risk groups and irrespective of PD-L1 expression Merck and Pfizer Inc. (NYSE: PFE) today announced that the European Commission (EC) has approved BAVENCIO(R) (avelumab) in combination with axitinib for the first-line treatment of adult patients with advanced renal cell carcinoma (RCC). The approval was based on positive interim results from the Phase III JAVELIN Renal 101 study, which demonstrated that BAVENCIO in combination with axitinib significantly lowered risk of disease progression or death by 31% (HR: 0.69 [95% CI: 0.574-0.825; p less than 0.0001]) and nearly doubled objective response rate (ORR; 52.5% [95% CI: 47.7-57.2] vs. 27.3% [95% CI: 23.2-31.6]) compared with sunitinib in patients with advanced RCC regardless of PD-L1 status. The study included patients across International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) prognostic risk groups. Improvement in progression-free survival (PFS) was observed across pre-specified subgroups in patients receiving the treatment combination.1 Merck and Pfizer have a global strategic alliance to jointly develop and commercialize BAVENCIO. "There is a high incidence of kidney cancer in Europe, and for the most common type, renal cell carcinoma, we continue to need additional treatment options, particularly for patients with advanced disease, where outcomes are poorest," said Professor James Larkin, Consultant Medical Oncologist at The Royal Marsden NHS Foundation Trust and Professor at the Institute of Cancer Research (ICR). "We've seen a demonstrated efficacy benefit and safety and tolerability profile for avelumab in combination with axitinib across all prognostic risk groups in patients with advanced renal cell carcinoma, so today's approval in Europe brings an important option that can help healthcare professionals optimize treatment strategies across risk stratification." 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 Many patients living with advanced RCC do not go on to receive additional treatment after first-line therapy,3,4 for reasons that may include poor performance status or adverse events from their initial treatment.3,5,6 The five-year survival rate for patients with advanced RCC is approximately 12%.7 "This first European approval of an anti-PD-L1 as part of a combination treatment for advanced renal cell carcinoma builds on our commitment to bringing innovative treatment options to patients with hard-to-treat cancers through our extensive JAVELIN clinical trial program," said Rehan Verjee, Global Head of Innovative Medicine Franchises for the Biopharma business of Merck. "RCC is the most common form of kidney cancer, accounting for 90% of diagnoses. We are now working to make BAVENCIO in combination with axitinib available for patients with advanced renal cell carcinoma as quickly as possible." "The European Commission approval of BAVENCIO in combination with axitinib has the potential to bring even more patients with advanced renal cell carcinoma a new first-line treatment, and it allows us to continue to deliver on our more than decade-long passion to do more for patients with kidney cancer," said Andy Schmeltz, Global President, Pfizer Oncology. "We thank all of the researchers, doctors, advocates, patients and their families who helped get us here today, and we will continue in our fight against this advanced cancer." The EC's decision follows the U.S. Food and Drug Administration (FDA) approval of BAVENCIO in combination with axitinib for the first-line treatment of patients with advanced RCC in May 2019. A supplemental application for BAVENCIO in combination with axitinib in unresectable or metastatic RCC was submitted in Japan in January 2019. Additionally, with this approval, the posology section of the Summary of Product Characteristics for BAVENCIO has been updated. The recommended dose of BAVENCIO as monotherapy is 800 mg administered intravenously over 60 minutes every 2 weeks. Administration of BAVENCIO should continue according to the recommended schedule until disease progression or unacceptable toxicity. The recommended dose of BAVENCIO in combination with axitinib is 800 mg administered intravenously over 60 minutes every 2 weeks and axitinib 5 mg orally taken twice daily (12 hours apart) with or without food until disease progression or unacceptable toxicity.1 Data from JAVELIN Renal 101 Study Supporting Approval This approval was based on interim data from the Phase III JAVELIN Renal 101 study, a randomized, multicenter, open-label study of BAVENCIO in combination with axitinib in 886 patients with untreated advanced or metastatic RCC with a clear cell component. The study included patients across risk groups (International Metastatic Renal Cell Carcinoma Database Consortium [IMDC]: 21% favorable, 62% intermediate and 16% poor; Memorial Sloan Kettering Cancer Center [MSKCC]: 22% favorable, 65% intermediate and 11% poor). The primary efficacy endpoints were progression-free survival (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 greater than equal to 1%). PFS based on BICR assessment per RECIST v1.1 and OS irrespective of PD‑L1 expression, objective response (OR), time to response (TTR), duration of response (DOR) and safety are included as secondary endpoints. The study is continuing for OS. In the analysis, BAVENCIO in combination with axitinib significantly improved median PFS compared with sunitinib by more than five months in patients irrespective of PD-L1 expression (13.3 months [95% CI: 11.1–15.3] vs. 8.0 months [95% CI: 6.7–9.8]). With a median follow-up for OS of 19 months, data for the trial's other endpoint of OS were immature, with 27% of deaths, and the trial is continuing as planned. The hazard ratio for OS in patients treated with BAVENCIO in combination with axitinib compared with sunitinib was 0.80 (95% CI: 0.616, 1.027) at the interim analysis. The most common adverse reactions were diarrhea (62.8%), hypertension (49.3%), fatigue (42.9%), nausea (33.5%), dysphonia (32.7%), decreased appetite (26.0%), hypothyroidism (25.2%), cough (23.7%), headache (21.3%), dyspnea (20.9%), and arthralgia (20.9%). 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.8-10 In November 2014, Merck and Pfizer announced a strategic alliance to co-develop and co-commercialize BAVENCIO. BAVENCIO Approved Indications The European Commission has authorized the use of BAVENCIO in combination with axitinib for the first-line treatment of adult patients with advanced renal cell carcinoma (RCC). 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). 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 Food and Drug Administration (FDA) granted accelerated approval for avelumab (BAVENCIO(R)) 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 is currently approved for patients with MCC in 50 countries globally, with the majority of these approvals in a broad indication that is not limited to a specific line of treatment. BAVENCIO Safety Profile from the EU Summary of Product Characteristics (SmPC) The special warnings and precautions for use for BAVENCIO monotherapy include infusion-related reactions, as well as immune-related adverse reactions that include pneumonitis and hepatitis (including fatal cases), colitis, pancreatitis (including fatal cases), myocarditis (including fatal cases), endocrinopathies, nephritis and renal dysfunction, and other immune-related adverse reactions. The special warnings and precautions for use for BAVENCIO in combination with axitinib include hepatotoxicity. The SmPC list of the most common adverse reactions with BAVENCIO monotherapy in patients with solid tumors includes fatigue, nausea, diarrhea, decreased appetite, constipation, infusion-related reactions, weight decreased and vomiting. The list of most common adverse reactions with BAVENCIO in combination with axitinib includes diarrhea, hypertension, fatigue, nausea, dysphonia, decreased appetite, hypothyroidism, cough, headache, dyspnea, and arthralgia. 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. All Merck Press Releases are distributed by e-mail at the same time they become available on the Merck Website. Please go to www.merckgroup.com/subscribe to register online, change your selection or discontinue this service. About Merck Merck, a leading science and technology company, operates across healthcare, life science and performance materials. Around 56,000 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 the intelligence of devices – Merck is everywhere. In 2018, Merck generated sales of 14.8 billion Euros in 66 countries. 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. Pfizer Inc.: Breakthroughs that change patients' lives At Pfizer, we apply science and our global resources to bring therapies to people that extend and significantly improve their lives. We strive to set the standard for quality, safety and value in the discovery, development and manufacture of health care products, including innovative medicines and vaccines. Every day, Pfizer colleagues work across developed and emerging markets to advance wellness, prevention, treatments and cures that challenge the most feared diseases of our time. Consistent with our responsibility as one of the world's premier innovative biopharmaceutical companies, we collaborate with health care providers, governments and local communities to support and expand access to reliable, affordable health care around the world. For more than 150 years, we have worked to make a difference for all who rely on us. We routinely post information that may be important to investors on our website at www.pfizer.com. In addition, to learn more, please visit us on www.pfizer.com and follow us on Twitter at @Pfizer and @Pfizer_News, LinkedIn, YouTube and like us on Facebook at Facebook.com/Pfizer. Pfizer Disclosure Notice The information contained in this release is as of October 28, 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 new indication approved 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; 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 application in 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(R) (avelumab) EU SmPC. Available from: http://www.ema.europa.eu/ema/. Accessed October 2019. 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. 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. Motzer R, et al. Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma. The New England Journal of Medicine. 2018;378:1277-1290. 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. 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. Ridge C, Pua B, Madoff D. Epidemiology and staging of renal cell carcinoma. Semin Intervent Radiol. 2014;31(1):3-8. Dolan DE, Gupta S. PD-1 pathway inhibitors: changing the landscape of cancer immunotherapy. Cancer Control. 2014;21(3):231-237. 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. 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. Your Contacts Merck Media Relations: +49 151 1454 6328 friederike.segeberg@merckgroup.com Investor Relations: +49 6151 72 3321 investor.relations@merckgroup.com Pfizer Media Relations: +1 212 733 6213 jessica.m.smith@pfizer.com +44 7929 339 560 lisa.o'neill@pfizer.com Investor Relations: +1 212 733 8160 ryan.crowe@pfizer.com Source: Merck