Merck and Pfizer Inc. (NYSE: PFE) today announced that the Phase III JAVELIN Ovarian 200 trial evaluating avelumab* alone or in combination with pegylated liposomal doxorubicin (PLD), a type of chemotherapy, compared with PLD did not meet the prespecified primary endpoints of overall survival (OS) or progression-free survival (PFS) in patients with platinum-resistant or -refractory ovarian cancer. Signals were observed in the combination arm relative to PLD, and further analyses of the trial are warranted (HR for the primary PFS endpoint for avelumab + PLD vs PLD alone: 0.78 [repeated confidence interval (RCI): 0.587, 1.244; one-sided p-value: 0.0301]; HR for the primary OS endpoint for avelumab + PLD vs PLD alone: 0.89 [RCI: 0.744, 1.241; one-sided p-value: 0.2082]; HR for the primary PFS endpoint for avelumab alone vs PLD alone: 1.68 [RCI: 1.320, 2.601; one-sided p-value: >0.99]; HR for the primary OS endpoint for avelumab alone vs PLD alone: 1.14 [RCI: 0.948, 1.580; one-sided p-value: 0.8253]; objective response, a secondary endpoint: 13.3% [95% CI 8.8, 19.0] for avelumab + PLD; 3.7% [95% CI 1.5, 7.5] for avelumab alone; and 4.2% [95% CI 1.8, 8.1] for PLD alone). No new safety signals were observed for avelumab alone or in combination, and the safety profile for avelumab in this trial was consistent with that observed in the overall JAVELIN clinical development program. The data are currently being analyzed, and detailed results will be shared with the scientific community.

"JAVELIN Ovarian 200 enrolled a high proportion of patients with aggressive, refractory disease that had no response to prior platinum-based chemotherapy, a population known to have disease that is challenging to treat; as such, this group of patients is typically not included in Phase III ovarian cancer trials," said Chris Boshoff, M.D., Ph.D., Senior Vice President and Head of Immuno-Oncology, Early Development and Translational Oncology, Pfizer Global Product Development. "We initiated the JAVELIN Ovarian 200 trial as the first Phase III study of a checkpoint inhibitor in the platinum-resistant or -refractory setting recognizing these patients have the most pressing need for new treatment options. The results speak to the significant challenges these women face."

"Although OS and PFS did not reach statistical significance, study results indicate potential clinical activity of the combination of avelumab and chemotherapy which will be analyzed further," said Luciano Rossetti, M.D., Executive Vice President, Global Head of Research & Development at the Biopharma business of Merck. "We thank the patients, their families and the investigators who participated in the JAVELIN Ovarian 200 trial, and wish to underscore that the alliance remains committed to driving advances in ovarian cancer, a commitment that includes two ongoing Phase III trials in previously untreated patients testing avelumab in combination with chemotherapy and, separately, one in combination with chemotherapy followed by maintenance treatment of avelumab in combination with a PARP inhibitor."

"Effective management of platinum-resistant or -refractory ovarian cancer remains the biggest unmet medical need facing women with recurrent ovarian cancer today. The current treatment options have only limited and short-lived efficacy for the majority of women, as evidenced by an average life expectancy that does not exceed one year for this group," said Eric Pujade-Lauraine, M.D., Ph.D., head of the Women Cancers and Clinical Research Department at Hôpitaux Universitaires Paris Centre, site Hôtel-Dieu. "As a researcher and clinician, I know how important it is to continue to improve the outlook for women with advanced ovarian cancer and look forward to the results of more trials exploring the role of avelumab in delaying recurrence in platinum-sensitive patients and earlier lines of therapy."

Four out of five patients with ovarian cancer are diagnosed at advanced stages. The disease often has no symptoms early on, when it is much more treatable.(1) Approximately 70% of patients with ovarian cancer who receive standard-of-care, frontline, platinum-based chemotherapy will relapse in the first three years.(2) At first relapse, approximately 20% to 25% of ovarian cancer patients have platinum-resistant or -refractory disease, and eventually almost all patients will become platinum-resistant.(3-6)

JAVELIN Ovarian 200 is a Phase III, multicenter, randomized study investigating the efficacy and safety of avelumab alone or in combination with PLD versus PLD alone in 566 women with ovarian cancer that is resistant or refractory to platinum chemotherapy. The primary objectives were to demonstrate superior OS or PFS for one or both avelumab-based treatment regimens compared with PLD.

In addition to JAVELIN Ovarian 200, the avelumab ovarian cancer clinical development program includes several ongoing clinical trials investigating avelumab in combination with other therapies. JAVELIN Ovarian 100 is an open-label, international, multicenter, randomized Phase III study of avelumab in combination with and/or as follow-on (maintenance) treatment to platinum-based chemotherapy in previously untreated patients with locally advanced or metastatic (Stage III or Stage IV) epithelial ovarian cancer. JAVELIN Ovarian 100 is the first Phase III study to evaluate the addition of an immunotherapy to the standard of care in frontline treatment for this aggressive disease. JAVELIN Ovarian PARP 100 is a randomized, open-label, multicenter Phase III study of avelumab plus chemotherapy followed by maintenance therapy of avelumab in combination with a PARP inhibitor or chemotherapy followed by maintenance therapy with a PARP inhibitor, in patients with previously untreated advanced ovarian cancer. Avelumab is also undergoing investigation in combination with other therapies for gynecologic cancers.

* Avelumab is under clinical investigation for treatment of ovarian cancer and has not been demonstrated to be safe and effective for this indication. There is no guarantee that avelumab will be approved for ovarian cancer by any health authority worldwide.

About the JAVELIN Clinical Trial Program

The clinical development program for avelumab, known as JAVELIN, involves at least 30 clinical programs and more than 9,000 patients evaluated across more than 15 different tumor types. In addition to ovarian cancer, these tumor types include breast, gastric/gastro-esophageal junction and head and neck cancers, melanoma, mesothelioma, Merkel cell carcinoma, non-small cell lung cancer, renal cell carcinoma and urothelial carcinoma.

About Ovarian Cancer

Every year, more than 295,000 women are diagnosed with ovarian cancer worldwide.(7) The disease is generally advanced when it is diagnosed, as it often has few to no symptoms at the early stages. This makes it difficult to detect until the disease has progressed. Symptoms can be vague or non-specific, making it easy to confuse with less serious non-cancerous conditions. The five-year survival rate ranges from approximately 30% to 50%, but for those with metastatic disease, it drops to less than 20%.(7,8)

About Avelumab

Avelumab is a human anti-programmed death ligand-1 (PD-L1) antibody. Avelumab 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, avelumab has been shown to release the suppression of the T cell-mediated antitumor immune response in preclinical models.(9-11) Avelumab has also been shown to induce NK cell-mediated direct tumor cell lysis via antibody-dependent cell-mediated cytotoxicity (ADCC) in vitro.(11-13) In November 2014, Merck and Pfizer announced a strategic alliance to co-develop and co-commercialize avelumab.

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 avelumab, an anti-PD-L1 antibody initially discovered and developed by Merck. The immuno-oncology alliance is jointly developing and commercializing avelumab and advancing Pfizer’s PD-1 antibody. The alliance is focused on developing high-priority international clinical programs to investigate avelumab 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, the vibrant science and technology company, operates across healthcare, life science and performance materials. Almost 53,000 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 2017, Merck generated sales of € 15.3 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 company operates as EMD Serono in healthcare, MilliporeSigma in life science, and EMD Performance Materials.

Pfizer Inc.: Working together for a healthier world®

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. Our global portfolio includes medicines and vaccines as well as many of the world's best-known consumer health care products. 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.

1. American Cancer Society. Facts and figures 2018. Special section: ovarian cancer. Available at: https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2018/cancer-facts-and-figures-special-section-ovarian-cancer-2018.pdf. Accessed November 2018.
2. Ledermann, JA, Raja FA, Fotopoulou C, et al. Newly diagnosed and relapsed epithelial ovarian carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2013; 24 (Supplement 6): vi24-vi32, doi:10.1093/annonc/mdt333.
3. Christie EL, Bowtell DD. Acquired chemotherapy resistance in ovarian cancer. Ann Oncol. 2017; 28 (Supplement 8):viii13-viii15.
4. Cooke SL, Brenton JD. Evolution of platinum resistance in high-grade serous ovarian cancer. Lancet Oncol. 2011; 12(12):1169-1174.
5. Tomao F, Marchetti C, Romito A, et al. Overcoming platinum resistance in ovarian cancer treatment: from clinical practice to emerging chemical therapies. Expert Opin Pharmacother. 2017;18(14):1443-1455.
6. Committee on the State of the Science in Ovarian Cancer Research; Board on Health Care Services; Institute of Medicine; National Academies of Sciences, Engineering, and Medicine. Washington (DC): National Academies Press (US); 2016 Apr 25.
7. World Cancer Research Fund / American Institute for Cancer Research. Continuous Update Project. Available at: https://www.wcrf.org/dietandcancer/cancer-trends/worldwide-cancer-data. Accessed November 2018.
8. American Cancer Society. Survival Rates for Ovarian Cancer, by Stage. Available at: https://www.cancer.org/cancer/ovarian-cancer/detection-diagnosis-staging/survival-rates.html. Accessed November 2018
9. Dolan DE, Gupta S. PD-1 pathway inhibitors: changing the landscape of cancer immunotherapy. Cancer Control. 2014;21(3):231-237.
10. 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.
11. 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.
12. Kohrt HE, Houot R, Marabelle A, et al. Combination strategies to enhance antitumor ADCC. Immunotherapy. 2012;4(5):511-527.
13. Hamilton G, Rath B. Avelumab: combining immune checkpoint inhibition and antibody-dependent cytotoxicity. Expert Opin Biol Ther. 2017;17(4):515-523.

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