FDA Approves BAVENCIO as First-Line Maintenance Treatment for Patients with Locally Advanced or Metastatic Urothelial Carcinoma

DARMSTADT,Germany and NEW YORK,July 1,2020 -- Merck and Pfizer Inc. (NYSE: PFE) today announced that the US Food and Drug Administration (FDA) has approved the supplemental Biologics License Application (sBLA) for BAVENCIO® (avelumab) for the maintenance treatment of patients with locally advanced or metastatic urothelial carcinoma (UC) that has not progressed with first-line platinum-containing chemotherapy.

The approval is based on results from the Phase III JAVELIN Bladder 100 study,which demonstrated a significant 7.1-month improvement in median overall survival (OS) with BAVENCIO as first-line maintenance plus best supportive care (BSC) compared with BSC alone: 21.4 months (95% CI: 18.9 to 26.1) vs. 14.3 months (95% CI: 12.9 to 17.9).1 This statistically significant improvement in OS represents a 31% reduction in the risk of death in the overall population (HR 0.69; 95% CI: 0.56 to 0.86; 2-sided P=0.001).1 OS was measured from the time of randomization,after patients were treated with four to six cycles of gemcitabine plus cisplatin or carboplatin over a period of approximately four months.2 The JAVELIN Bladder 100 results were presented at the ASCO 2020 Virtual Scientific Meeting.

"As the first immunotherapy to demonstrate a statistically significant improvement in overall survival in the first-line setting in locally advanced or metastatic urothelial carcinoma,the FDA approval of avelumab is one of the most significant advances in the treatment paradigm in this setting in 30 years," said Petros Grivas,M.D.,Ph.D.,one of the principal investigators in the JAVELIN Bladder 100 trial. "With median overall survival of more than 21 months,measured from randomization,the longest overall survival in a PhaseIII trial in advanced urothelial carcinoma,the JAVELIN Bladder 100 regimen with avelumab as a first-line switch maintenance treatment has the potential to become a new standard of care based on its proven ability to reinforce the benefit (response or stable disease) of induction chemotherapy and extend the lives of patients with this devastating disease."

Platinum-based chemotherapy is currently the first-line standard of care for eligible patients with advanced disease based on high initial response rates. However,most patients will ultimately experience disease progression within nine months of initiation of treatment,3,4 and only 5% of patients with metastatic disease at diagnosis will live longer than five years.5

"Many patients newly diagnosed with advanced urothelial carcinoma receive benefit from initial chemotherapy,but we still need treatment options that can help patients live longer," said Andrea Maddox-Smith,CEO of the Bladder Cancer Advocacy Network."We wholeheartedly support the development of new and promising treatments like BAVENCIO that can offer patients and their loved ones hope."

For patients that do not progress on platinum-containing chemotherapy,BAVENCIO is administered as a first-line maintenance treatment until disease progression or unacceptable toxicity.

The FDA previously approved BAVENCIO under the accelerated approval program in 2017 for the treatment of patients with locally advanced or metastatic UC who have disease progression during or following platinum-containing chemotherapy,or who have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy,based on tumor response rate and duration of response. Continued approval was contingent upon verification of clinical benefit,which was demonstrated in JAVELIN Bladder 100. The FDA has now converted the accelerated approval to full approval.

"Today's approval of BAVENCIO in the most common type of advanced bladder cancer underscores our commitment to advancing scientific innovation and transforming outcomes for people with genitourinary cancers," said Andy Schmeltz,Global President,Pfizer Oncology.

"With this approval for BAVENCIO,we have the opportunity to fundamentally shift the standard of care in the first-line setting of advanced bladder cancer. Our focus now is to work closely with the GU community to ensure that this novel and potentially life-changing treatment paradigm is rapidly integrated into clinical practice," said Rehan Verjee,President of North America and Global Head of Innovative Medicine Franchises for the Biopharma business of Merck.

About JAVELIN Bladder 100

JAVELIN Bladder 100 (NCT02603432) is a Phase III,multicenter,multinational,randomized,open-label,parallel-arm study investigating first-line maintenance treatment with BAVENCIO plus BSC versus BSC alone in patients with locally advanced or metastatic UC that did not progress with first-line platinum-containing chemotherapy as per RECIST v1.1. A total of 700 patients were randomly assigned to receive either BAVENCIO (10mg/kg intravenous infusion every 2weeks) plus BSC (n=350) or BSC alone (n=350). The primary endpoint was OS in the two primary populations of all randomized patients and patients with PD-L1+ tumors defined by the Ventana SP263 assay. Secondary endpoints included progression-free survival,anti-tumor activity,safety,pharmacokinetics,immunogenicity,predictive biomarkers and patient-reported outcomes in the two primary populations. All primary and secondary endpoints are measured from the time of randomization,after completion of four to six cycles of chemotherapy. Patients with autoimmune disease or a medical condition that required immunosuppression were excluded.

In PD-L1+ patients (n=358,51%),the risk of death was reduced by 44% in the BAVENCIO arm versus the control arm (HR 0.56; 95% CI: 0.40 to 0.79; 2-sided p-value <0.001). Consistent results were observed across the pre-specified subgroups of complete or partial response versus stable disease to first-line chemotherapy.1 In an exploratory analysis of patients with PD L1 negative tumors (n=271,39%),the OS hazard ratio was 0.85 (95% CI: 0.62,1.18).

A fatal adverse reaction (sepsis) occurred in one (0.3%) patient receiving BAVENCIO plus BSC. Serious adverse reactions occurred in 28% of patients receiving BAVENCIO plus BSC. Serious adverse reactions in ≥1% of patients included urinary tract infection (including kidney infection,pyelonephritis,and urosepsis) (6.1%),pain (including abdominal,back,bone,flank,extremity,and pelvic pain)(3.2%),acute kidney injury (1.7%),hematuria (1.5%),sepsis (1.2%),and infusion-related reaction (1.2%). The most common adverse reactions (≥20%) in patients receiving BAVENCIO plus BSC were fatigue,musculoskeletal pain,urinary tract infection,and rash.1

About Urothelial Carcinoma

Bladder cancer is the tenth most common cancer worldwide and the sixth most common cancer in the US.5,6 In 2018,there were over half a million new cases of bladder cancer diagnosed,with around 200,000 deaths from the disease globally.6 In the US,an estimated 80,470 cases of bladder cancer were diagnosed in 2019,with around 12,500 locally advanced or metastatic cases presented annually.5,7 UC accounts for about 90% of all bladder cancers.8 UC becomes harder to treat as it advances,spreading through the layers of the bladder wall.9

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.10-12 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® (avelumab) is indicated for the maintenance treatment of patients with locally advanced or metastatic urothelial carcinoma (UC) that has not progressed with first-line platinum-containing chemotherapy. BAVENCIO is also indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma 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.

BAVENCIO in combination with axitinib is indicated in the US 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®)for the treatment of adults and pediatric patients 12 years and older with metastatic Merkel cell carcinoma (MCC). This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

BAVENCIOis 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 Profilefrom 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,dysphonia,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.

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About Merck

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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 ofJune30,2020. 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 in the U.S. for the maintenance treatment of patients with locally advanced or metastatic urothelial carcinoma that has not progressed with first-line platinum-containing chemotherapy,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; 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 for first-line maintenance treatment for locally advanced or metastatic urothelial carcinoma in any other jurisdictions or in any jurisdictions for any other potential indications for BAVENCIO or combination therapies; whether and when regulatory authorities in any jurisdictions where any applications are pending or may be submitted for BAVENCIO or combination therapies,including BAVENCIO for locally advanced or metastatic urothelial carcinoma 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,including BAVENCIO for locally advanced or metastatic urothelial carcinoma; the impact of COVID-19 on Pfizer's business,operations and financial results; 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 31,2019,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.; 2020.

Powles T,et al. "Maintenance avelumab + best supportive care (BSC) versus BSC alone after platinum-based first-line chemotherapy in advanced urothelial carcinoma: JAVELIN Bladder 100 phase III results." 2020 ASCO Annual Meeting,31 May 2020,virtual. Conference Presentation.

Bukhari N,et al. Update on the treatment of metastatic urothelial carcinoma. ScientificWorldJournal. 2018;2018:5682078.

Von der Maase H,et al. Long-term survival results of a randomized trial comparing gemcitabine plus cisplatin,with methotrexate,vinblastine,doxorubicin,plus cisplatin in patients with bladder cancer. Journal of Clinical Oncology. 2005;23(21):4602-4608.

SEER. Cancer stat facts: bladder cancer. https://seer.cancer.gov/statfacts/html/urinb.html. Accessed June 2020.

Bray F,et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: A Cancer Journal. 2018;68(6):394-424.

Galsky M,et al. Cisplatin ineligibility for patients with metastatic urothelial carcinoma: a survey of clinical practice perspectives among US oncologists. Bladder Cancer. 2019;5:281-288.

Cancer.net. Bladder cancer: introduction. https://www.cancer.net/cancer-types/bladder-cancer/introduction. Accessed June 2020.

American Cancer Society. What is bladder cancer? https://www.cancer.org/cancer/bladder-cancer/about/what-is-bladder-cancer.html. Accessed June 2020.

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.

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