Merck and Pfizer Receive US FDA Breakthrough Therapy Designation and Submit Application for BAVENCIO(R) for First-Line Maintenance Treatment of Locally Advanced or Metastatic Urothelial Carcinoma

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

-  Breakthrough Therapy Designation and Submission based on positive Phase III JAVELIN Bladder 100 study results

-  Supplemental Biologics License Application being reviewed under FDA Real-Time Oncology Review (RTOR) pilot program

-  JAVELIN Bladder 100 marks the first time any immunotherapy has demonstrated in Phase III an overall survival benefit vs standard of care in first-line locally advanced or metastatic urothelial carcinoma

DARMSTADT, Germany and NEW YORK, April 9, 2020 /PRNewswire/ -- Merck and Pfizer Inc. (NYSE: PFE) today announced completion of the submission of a supplemental Biologics License Application (sBLA) to the US Food and Drug Administration (FDA) for BAVENCIO^® (avelumab)* for first-line maintenance treatment of patients with locally advanced or metastatic urothelial carcinoma (UC). The FDA granted Breakthrough Therapy Designation to BAVENCIO for this indication, and the sBLA is being reviewed by the FDA under its Real-Time Oncology Review (RTOR) pilot program.

The application is based on positive results from an interim analysis of the Phase III JAVELIN Bladder 100 trial, which met its primary endpoint of overall survival (OS). In this study, BAVENCIO plus best supportive care (BSC) as first-line maintenance therapy significantly extended the survival of patients with previously untreated locally advanced or metastatic UC whose disease did not progress on induction chemotherapy, compared with BSC only. A statistically significant improvement was demonstrated in both co-primary populations: all randomized patients and patients with PD-L1–positive tumors. The safety profile for BAVENCIO in the trial was consistent with that in the JAVELIN monotherapy clinical development program. Detailed results from the JAVELIN Bladder 100 study will be presented at an upcoming medical congress.

"BAVENCIO is the first immunotherapy to demonstrate a statistically significant improvement in overall survival in a Phase III clinical trial in the first-line setting for patients with locally advanced or metastatic urothelial carcinoma," said Chris Boshoff, M.D., Ph.D., Chief Development Officer, Oncology, Pfizer Global Product Development. "Participation in the Real-Time Oncology Review program, coupled with the Breakthrough Therapy Designation, reflect the potential impact of BAVENCIO in this patient setting and provide the opportunity to work towards bringing this treatment option to patients as quickly as possible."

The RTOR program is intended to create a more efficient review process to bring safe and effective treatments to patients earlier, including drugs that are likely to demonstrate substantial improvements over currently available therapy. It allows the FDA to review clinical trial data from certain applications before the complete application is formally submitted. Review under the program does not guarantee or influence the approvability of the application.¹

Breakthrough Therapy Designation is a program created by the FDA to accelerate the development and review of medicines intended to treat serious or life-threatening diseases where the new treatment may be a substantial improvement over available therapy. In order to receive Breakthrough Therapy Designation, preliminary clinical evidence must indicate that the drug may demonstrate a significant improvement over available therapy on a clinically significant endpoint.²

"Given the poor prognosis for patients with advanced urothelial carcinoma, there is an urgent need for additional treatment options that improve overall survival," said Luciano Rossetti, Head of Global R&D for the Biopharma business of Merck. "Our data highlight the potential for a first-line maintenance treatment approach with BAVENCIO to advance the current standard of care for previously untreated patients, and we are working with urgency toward our goal of bringing this regimen to patients."

"For the past 30 years, chemotherapy has been the first-line standard of care for patients with advanced urothelial carcinoma. While this is an effective short-term option for many patients, most will ultimately experience disease progression, underscoring a need for additional treatment options," said Petros Grivas, M.D., Ph.D., one of the principal investigators in the JAVELIN Bladder 100 trial. "Based on the positive overall survival results from JAVELIN Bladder 100, I believe avelumab has the potential to be practice-changing."

In 2017, the FDA approved BAVENCIO 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. This indication is approved under accelerated approval based on tumor response and duration of response. JAVELIN Bladder 100 is the confirmatory study for the conversion to full approval.

*BAVENCIO is under clinical investigation for the first-line maintenance treatment of advanced UC. There is no guarantee that BAVENCIO will be approved for first-line maintenance treatment of advanced UC by any health authority worldwide.

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. A total of 700 patients whose disease had not progressed after platinum-based induction chemotherapy as per RECIST v1.1 were randomized to receive either BAVENCIO plus BSC or BSC alone. The study achieved its primary endpoint of OS in each of the co-primary populations of all randomized patients and patients with PD-L1-positive tumors. Secondary endpoints include progression-free survival, anti-tumor activity, safety, pharmacokinetics, immunogenicity, predictive biomarkers and patient-reported outcomes in the co-primary populations. The safety profile for BAVENCIO in the trial was consistent with that in the JAVELIN monotherapy clinical development program.

About Urothelial Carcinoma
Bladder cancer is the tenth most common cancer worldwide.³ In 2018, there were over half a million new cases of bladder cancer diagnosed, with around 200,000 deaths from the disease globally.³ UC accounts for about 90% of all bladder cancers.⁴ This subtype becomes harder to treat as it advances, spreading through the layers of the bladder wall.⁵ For patients with metastatic UC, the five-year relative survival rate is 5%.⁶ Combination chemotherapy is currently the first-line standard of care for patients with advanced disease, and while a majority of patients experience high initial response rates, most patients will ultimately experience disease progression within nine months after initiation of treatment.^7,8 Given the poor prognosis for patients with advanced bladder cancer whose disease progresses after first-line chemotherapy, there is an urgent need for additional treatment options that improve overall survival.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 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^®) 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.

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About Merck
Merck, a leading science and technology company, operates across healthcare, life science and performance materials. Around 57,000 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 – the company is everywhere. In 2019, Merck generated sales of € 16.2 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 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 April 9, 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 potential indication for first-line maintenance therapy for BAVENCIO for the treatment of patients with locally advanced or metastatic urothelial 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; 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 therapy for locally advanced or metastatic urothelial carcinoma in any jurisdictions outside the U.S. 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; 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

1. US Food and Drug Administration. Real-Time Oncology Review Pilot Program. https://www.fda.gov/about-fda/oncology-center-excellence/real-time-oncology-review-pilot-program. Accessed April 2020.
2. US Food and Drug Administration. Frequently Asked Questions: Breakthrough Therapies. https://www.fda.gov/regulatory-information/food-and-drug-administration-safety-and-innovation-act-fdasia/frequently-asked-questions-breakthrough-therapies. Accessed April 2020.
3. 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.   
4. Cancer.net. Bladder Cancer: Introduction. https://www.cancer.net/cancer-types/bladder-cancer/introduction. Accessed April 2020.
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9. Dietrich B, Srinivas S. Urothelial carcinoma: the evolving landscape of immunotherapy for patients with advanced disease. Res Rep Urol. 2018;10:7-16.
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