Merck KGaA

Merck and Pfizer Provide Update on Phase III JAVELIN Gastric 300 Study in Patients With Pre-Treated Advanced Gastric Cancer

Darmstadt, Germany and New York (ots/PRNewswire) - Not intended for UK-based media

- Pivotal Phase III Javelin trial investigating avelumab as 
  third-line treatment for patients with unresectable, recurrent or 
  metastatic gastric cancer did not meet its pre-specified primary 
  endpoint of superior overall survival compared to chemotherapy  
- First global trial of a checkpoint inhibitor versus an active 
  chemotherapy comparator rather than placebo in this hard-to-treat 
  patient population  
- Safety profile was consistent with that observed in previously 
  reported studies of avelumab; no new safety signals were identified
   

Merck and Pfizer Inc. (NYSE: PFE) today announced that the Phase III JAVELIN Gastric 300 trial did not meet its primary endpoint of superior overall survival (OS) with single-agent avelumab* compared with physician's choice of chemotherapy. The trial investigated avelumab as a third-line treatment for unresectable, recurrent or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma patients whose disease progressed following two prior therapeutic regimens, regardless of programmed death ligand-1 (PD-L1) expression. The safety profile of avelumab was consistent with that observed in the overall JAVELIN clinical development program.

"Gastric cancer in the third-line setting is a particularly hard-to-treat and heterogeneous disease, and importantly, this was the first trial conducted with a checkpoint inhibitor compared to an active chemotherapy comparator rather than placebo in a global patient population," said Luciano Rossetti, M.D., Executive Vice President, Global Head of Research & Development at the Biopharma business of Merck. "Data from this study will provide valuable information for physicians treating this late stage disease. We remain committed to our ongoing gastric cancer program with avelumab including the JAVELIN Gastric 100 study in the first-line switch maintenance setting."

"Gastric cancer is a leading cause of cancer death globally with clear unmet needs, and the results provide important insights as we continue to investigate the role of avelumab for the treatment of gastric cancer," said Chris Boshoff, M.D., Ph.D., Senior Vice President and Head of Immuno-Oncology, Early Development and Translational Oncology, Pfizer Global Product Development. "With approvals for two cancers in 2017, our companies have made tremendous progress with avelumab on behalf of patients this year, and we are confident that our broad clinical development program in both monotherapy and combinations across a range of cancers will continue to bring new potential treatment options to patients."

The JAVELIN Gastric 300 data will be further examined in an effort to better understand the results and will also be submitted for presentation at an upcoming medical congress. The outcome of JAVELIN Gastric 300 does not have any impact on current avelumab approvals.

JAVELIN Gastric 300 is a Phase III, multicenter, international, randomized, open-label clinical trial investigating avelumab plus best supportive care versus physician's choice of protocol-specified chemotherapy (paclitaxel or irinotecan monotherapy) plus best supportive care in patients with unresectable, recurrent or metastatic gastric or GEJ adenocarcinoma whose disease has progressed following two prior therapeutic regimens. The trial enrolled 371 patients from 147 sites in Asia, Australia, Europe, North America and South America. The primary endpoint was OS.

The avelumab gastric clinical development program also includes JAVELIN Gastric 100, a multicenter, randomized, open-label Phase III study evaluating avelumab as first-line maintenance therapy following induction chemotherapy in unresectable, locally advanced or metastatic gastric or GEJ cancer. The trial will continue as planned.

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

About Gastric/Gastroesophageal Junction Cancer

Globally, gastric cancer is the fifth most common cancer but the third most common cause of cancer death.[1],[2] In 2012, there were approximately 950,000 new cases and 723,000 deaths worldwide.[3] Of these cancers, 90 to 95 percent were adenocarcinomas.[4] Incidence varies by country, with higher rates seen in Central/Eastern Europe, Eastern Asia and South America.[5] Survival in advanced disease is poor and generally less than one year.[6] Globally, there is no recommended therapeutic approach for patients who progress after two lines of therapy for recurrent or metastatic gastric cancer.

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.[7]-[9] Avelumab has also been shown to induce NK cell-mediated direct tumor cell lysis via antibody-dependent cell-mediated cytotoxicity (ADCC) in vitro.[9]-[11] In November 2014, Merck and Pfizer announced a strategic alliance to co-develop and co-commercialize avelumab.

Approved Indications in the US

The 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 (MCC) and (ii) patients with locally advanced or metastatic urothelial carcinoma (UC) 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.

Important Safety Information from the US FDA Approved Label

The warnings and precautions for BAVENCIO include immune-mediated adverse reactions (such as pneumonitis, hepatitis, colitis, endocrinopathies, nephritis and renal dysfunction, and other adverse reactions), infusion-related reactions and embryo-fetal toxicity.

Common adverse reactions (reported in at least 20% of patients) in patients treated with BAVENCIO for mMCC and patients with locally advanced or metastatic UC include fatigue, musculoskeletal pain, diarrhea, nausea, infusion-related reaction, peripheral edema, decreased appetite/hypophagia, urinary tract infection and rash.

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 is a leading science and technology company in healthcare, life science and performance materials. Around 50,000 employees work to further develop technologies that improve and enhance life - from biopharmaceutical therapies to treat cancer or multiple sclerosis, cutting-edge systems for scientific research and production, to liquid crystals for smartphones and LCD televisions. In 2016, Merck generated sales of EUR 15.0 billion in 66 countries.

Founded in 1668, Merck is the world's oldest pharmaceutical and 
chemical company. The founding family remains the majority owner of 
the publicly listed corporate group. Merck, Darmstadt, Germany holds 
the global rights to the "Merck" name and brand except in the United 
States and Canada, where the company operates as EMD Serono, 
MilliporeSigma 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. 
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Pfizer Disclosure Notice

The information contained in this release is as of November 28, 2017. 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), the Merck-Pfizer Alliance involving anti-PD-L1 and anti-PD-1 therapies, 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 study commencement and completion dates and regulatory submission dates, as well as the possibility of unfavorable study results, including unfavorable new clinical data and additional analyses of existing clinical data; risks associated with interim data; the risk that clinical trial data are subject to differing interpretations, and, even when we view data as sufficient to support the safety and/or effectiveness of a product candidate, regulatory authorities may not share our views and may require additional data or may deny approval altogether; whether and when any other drug applications may be filed in any jurisdictions for potential indications for BAVENCIO, combination therapies or other product candidates; whether and when regulatory authorities in any other jurisdictions where applications are pending or may be submitted for BAVENCIO, combination therapies or other product candidates may approve any such applications, which will depend on the assessment by such regulatory authorities of the benefit-risk profile suggested by the totality of the efficacy and safety information submitted; decisions by regulatory authorities regarding labeling and other matters that could affect the availability or commercial potential of BAVENCIO, combination therapies or other product candidates; 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, 2016, 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 http://www.sec.gov and http://www.pfizer.com.

References

 1. Ferlay J, Soerjomataram I, Ervik M, Dikshit R, Eser S, Mathers C,
    Rebelo M, Parkin DM, Forman D, Bray, F. GLOBOCAN 2012 v1.1, 
    Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11 
    [Internet]. Lyon, France: International Agency for Research on 
    Cancer; 2014. Available at: http://globocan.iarc.fr. Accessed: 
    November 2017.
 2. International Agency for Research on Cancer. GLOBOCAN 2012 
    Available at: 
 http://globocan.iarc.fr/old/FactSheets/cancers/stomach-new.asp. 
    Accessed: November 2017.  
 3. Chapter 1, Cancer Worldwide. In: Stewart BW, Wild CP (eds). World
    Cancer Report 2014: International Agency for Research on Cancer, 
    World Health Organization; 2014.
 4. Waddell T et al. Ann Oncol 2013;24(Suppl 6):vi57-63.
 5. International Agency for Research on Cancer. WHO. GLOBOCAN 2012: 
    Estimated Cancer Incidence, Mortality, and Prevalence Worldwide 
    in 2012 2012 [06 April 2015]. Available from: 
 http://globocan.iarc.fr/Default.aspx. Accessed: November 2017.
 6. Shah MA. J Clin Oncol 2015;33:1760-9.
 7. Dolan DE, Gupta S. PD-1 pathway inhibitors: changing the 
    landscape of cancer immunotherapy. Cancer Control. 
    2014;21(3):231-237.
 8. 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.
 9. 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.
10. Kohrt HE, Houot R, Marabelle A, et al. Combination strategies to 
    enhance antitumor ADCC. Immunotherapy. 2012;4(5):511-527.
11. 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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