FDA Accepts sBLA and Grants Priority Review for BAVENCIO® (avelumab) Plus INLYTA® (axitinib) for the Treatment of Advanced Renal Cell Carcinoma

Author: Merck / 2023-07-22 18:36 / Source: Merck

FDA Accepts sBLA and Grants Priority Review for BAVENCIO® (avelumab) Plus INLYTA® (axitinib) for the Treatment of Advanced Renal Cell Carcinoma

DARMSTADT,Germany and NEW YORK,Feb. 12,2019 --

Not intended for US,Canada and UK-based media

Merck and Pfizer Inc. (NYSE: PFE) today announced that the US Food and Drug Administration (FDA) has acceptedfor Priority Reviewthe supplemental Biologics License Application (sBLA) for BAVENCIO®(avelumab) in combination with INLYTA®(axitinib)* for patients with advanced renal cell carcinoma (RCC). The application has been given a target action date inJune 2019.

"The combination of BAVENCIO with INLYTA builds on Pfizer's significant heritage in advancing standards of care for patients with advanced RCC and has the potential to make a meaningful impact for the lives of patients," said ChrisBoshoff,M.D.,Ph.D.,Chief Development Officer,Oncology,Pfizer Global Product Development. "We look forward to working with the FDA to bring this potential new treatment option to patients as quickly as possible."

"Our alliance is focused on the development of potential new treatment options for patients with cancers that have high unmet medical needs,including the broad spectrum of people living with advanced RCC," said Luciano Rossetti,Executive Vice President,Head of Global Research & Development at the Biopharma business of Merck. "This regulatory milestone,which closely follows the acceptance of our application in Japan,represents an important step forward for science and for patients."

The submission is based on data from the pivotal Phase III JAVELIN Renal 101 trial,which were presented in a Presidential Symposium at the European Society of Medical Oncology (ESMO) 2018 Congress in Munich. In December 2017,the FDA granted Breakthrough Therapy Designation for BAVENCIO in combination with INLYTA for treatment-naïve patients with advanced RCC.

Despite available therapies,the outlook for patients with advanced RCC remains poor.[1]Approximately 20% to 30% of patients are first diagnosed at the metastatic stage.[2]The five-year survival rate for patients with metastatic RCC is approximately 12%.[1]

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 differenttumortypes. In addition to RCC,thesetumortypes include breast,gastric/gastro-esophagealjunction,and head and neck cancers,Merkel cell carcinoma,non-small cell lung cancer,and urothelial carcinoma.

*The combination of BAVENCIO and INLYTA is under clinical investigation for advanced RCC,and there is no guarantee this combination will be approved for advanced RCC by any health authority worldwide. In the US,INLYTA is approved as monotherapy for the treatment of advanced RCC after failure of one prior systemic therapy. INLYTA is also approved by the European Medicines Agency (EMA) for use in the EU in adult patients with advanced RCC after failure of prior treatment with SUTENT®(sunitinib) or a cytokine.

About Renal Cell Carcinoma

RCC is the most common form of kidney cancer,accounting for about 2% to 3% of all cancers in adults.[3],[4]The most common type of RCC is clear cell carcinoma,accounting for approximately 70% of all cases.[3]In 2019,an estimated 73,820 new cases of kidney cancer will be diagnosed in the US.[5]

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.[6]-[8]BAVENCIO has also been shown to induce NK cell-mediated directtumorcell lysis via antibody-dependent cell-mediated cytotoxicity (ADCC) in vitro.[8]-[10]In November 2014,Merck and Pfizer announced a strategic alliance to co-develop and co-commercialize BAVENCIO.

Approved Indications in the US

In the US,the FDA granted accelerated approval for BAVENCIO for the treatment of (i) adults andpediatricpatients 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 12months ofneoadjuvantor adjuvant treatment with platinum-containing chemotherapy. These indications are approved under accelerated approval based ontumorresponse 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 more than 45 countries globally,with the majority of these approvals in a broad indication that is not limited to a specific line of treatment.

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-fetaltoxicity.

Common adverse reactions (reported in at least 20% of patients) in patients treated with avelumab for mMCC and patients with locally advanced ormUCinclude fatigue,musculoskeletal pain,diarrhea,nausea,infusion-related reaction,peripheraledema,decreased appetite/hypophagia,urinary tract infection and rash.

About INLYTA®(axitinib)

INLYTA is an oral therapy that is designed to inhibit tyrosine kinases,including vascular endothelial growth factor (VEGF) receptors 1,2 and 3; these receptors can influencetumorgrowth,vascular angiogenesis and progression of cancer (the spread oftumors). In the US,INLYTA is approved for the treatment of advanced renal cell carcinoma (RCC) after failure of one prior systemic therapy. INLYTA is also approved by the European Medicines Agency (EMA) for use in the EU in adult patients with advanced RCC after failure of prior treatment withsunitinibor a cytokine.

INLYTA Important Safety Information from the US FDA Approved Label

In the study of advanced RCC after failure of one prior systemic therapy,the warnings and precautions for INLYTA include hypertension,including hypertensive crisis,arterial and venous thrombotic events,hemorrhagicevents,cardiac failure,gastrointestinal perforation and fistula,hypothyroidism,wound healing complications,reversible posterior leukoencephalopathy syndrome (RPLS),proteinuria,liver enzyme elevation,hepatic impairment,andfetalharm during pregnancy.

Common adverse events (reported in at least 20% of patients) in patients receiving INLYTA werediarrhea,hypertension,fatigue,decreased appetite,dysphonia,hand-foot syndrome,weight decreased,vomiting,asthenia,and constipation.

For more information and full Prescribing Information,visitwww.INLYTA.com.

About SUTENT®(sunitinibmalate)

Sunitinibis a small molecule that inhibits multiple receptor tyrosine kinases,some of which are implicated intumorgrowth,pathologic angiogenesis,and metastatic progression of cancer.Sunitinibwas evaluated for its inhibitory activity against a variety of kinases (>80 kinases) and was identified as an inhibitor of platelet-derived growth factor receptors (PDGFRα and PDGFRβ),vascular endothelial growth factor receptors (VEGFR1,VEGFR2 and VEGFR3),stem cell factor receptor (KIT),Fms-like tyrosine kinase-3 (FLT3),colony stimulating factor receptor Type 1 (CSF-1R),and the glial cell-line derived neurotrophic factor receptor (RET).

SUTENT is indicated in the US for the treatment of gastrointestinal stromaltumor(GIST) after disease progression on or intolerance toimatinibmesylate; the treatment of advanced RCC; the adjuvant treatment of adult patients at high risk of recurrent RCC following nephrectomy; and the treatment of progressive,well-differentiated pancreatic neuroendocrinetumors(pNET) in patients withunresectablelocally advanced or metastatic disease.

SUTENT Important Safety Information from the US FDA Approved Label

Boxed Warning/Hepatotoxicity has been observed in clinical trials andpostmarketingexperience. Hepatotoxicity may be severe,and in some cases fatal. Monitor hepatic function and interrupt,reduce,or discontinue dosing as recommended. Fatal liver failure has been observed. Monitor liver function tests before initiation of treatment,during each cycle of treatment,and as clinically indicated. Interrupt SUTENT for Grade 3 or 4 drug-related hepatic adverse reactions and discontinue if there is no resolution. Do not restart SUTENT if patients subsequently experience severe changes in liver function tests or have signs and symptoms of liver failure.

Additional warnings and precautions for SUTENT include cardiovascular events,QT prolongation andTorsadesde Pointes,tumorlysis syndrome (TLS),thromboticmicroangiopathy(TMA),dermatologic toxicities including erythemamultiforme,Sevens-Johnson syndrome,and toxic epidermal necrolysis,necrotizing fasciitis,thyroid dysfunction,hypoglycemia,osteonecrosis of the jaw (ONJ),impaired wound healing,embryofetaltoxicity and impaired reproductive potential,potential harm during lactation,venous thromboembolic events,and pancreatic function.

Common adverse reactions (reported in at least 20% of patients) in patients receiving SUTENT for treatment-naïve metastatic RCC werediarrhea,anorexia,altered taste,mucositis/stomatitis,pain in extremity/limb discomfort,bleeding,all sites,dyspepsia,arthralgia,abdominal pain,rash,back pain,cough,dyspnea,skin discoloration/yellow skin,headache,constipation,dry skin,fever,and haircolorchanges.

Common adverse reactions (reported in at least 20% of patients) in patients receiving SUTENT for adjuvant treatment of RCC,GIST orpNET- and more commonly than in patients given placebo - weremucositis/stomatitis/oral syndromes,hypothyroidism/TSH increased,haircolorchanges,skin discoloration,bleeding events,epistaxis,anddysgeusia.

For more information and full Prescribing Information,visitwww.SUTENT.com.

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,a leading science and technology company,operates across healthcare,life science and performance materials. Around 51,000 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 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 business sectors of Merck operate as EMDSeronoin healthcare,MilliporeSigmain life science,and EMD Performance Materials.

Pfizer Inc.: Working together for a healthierworld®

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. We routinely post information that may be important to investors on our website atwww.pfizer.com. In addition,to learn more,please visit us onwww.pfizer.comand 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 February 11,2019. 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 potential new indication for BAVENCIO in combination with INLYTA (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; 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 ofunfavorablefurther analyses of existing clinical data and uncertainties regarding whether the other primary endpoint of JAVELIN Renal 101 will be met; 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 INLYTA for the potential new indication in any other jurisdictions or in any jurisdictions for any other potential indications for BAVENCIO or combination therapies; whether and when the pending applications in the U.S. and Japan for BAVENCIO in combination with INLYTA for the potential new indication 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 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 impactinglabeling,manufacturing processes and/or other matters that could affect the availability or commercial potential of BAVENCIO or combination therapies,including BAVENCIO in combination with INLYTA for the potential new indication; 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 31,2017,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 atwww.sec.govandwww.pfizer.com.

References

National Cancer Institute: SEER Stat Fact Sheets: Kidney and renal pelvis. Available from: http://seer.cancer.gov/statfacts/html/kidrp.html. Accessed February 2019.

LjungbergB,Campbell S and Cho H. The Epidemiology of Renal Cell Carcinoma.EurUrol. 2011;60:615-621.

American Cancer Society. What is kidney cancer? Available from: https://www.cancer.org/cancer/kidney-cancer/about.html. Accessed February 2019.

EscudierB,Porta C,SchmidingerM et al Renal cell carcinoma: ESMO clinical practice guidelines for diagnosis,treatment and follow-up.AnnalOncol. 2014; 25(Suppl3):iii49-iii56.

American Cancer Society. Cancer facts and figures 2019. Available at:https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2019/cancer-facts-and-figures-2019.pdf. Accessed February 2019

Dolan DE,Gupta S. PD-1 pathway inhibitors: changing the landscape of cancer immunotherapy. Cancer Control. 2014;21(3):231-237.

DahanR,Sega E,EngelhardtJ,Selby M,KormanAJ,RavetchJV.FcγRsmodulate the anti-tumoractivity of antibodies targeting the PD-1/PD-L1 axis. Cancer Cell. 2015;28(3):285-295.

BoyerinasB,JochemsC,FantiniM,et al. Antibody-dependent cellular cytotoxicity activity of a novel anti-PD-L1 antibody avelumab (MSB0010718C) on humantumorcells. CancerImmunolRes. 2015;3(10):1148-1157.

KohrtHE,HouotR,MarabelleA,et al. Combination strategies to enhance antitumor ADCC. Immunotherapy. 2012;4(5):511-527.

Hamilton G,RathB. Avelumab: combining immune checkpoint inhibition and antibody-dependent cytotoxicity. ExpertOpinBiolTher. 2017;17(4):515-523.

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