Merck KGaA, Darmstadt, Germany, and Pfizer Announce First Patient Treated in Phase III Combination Study with Avelumab and INLYTA® in Renal Cell Carcinoma
- If approved, avelumab, an investigational anti-PD-L1 IgG1, could be the first treatment indicated for patients with metastatic Merkel cell carcinoma
- The Marketing Authorization Application is based on Phase II data from the JAVELIN Merkel 200 study demonstrating meaningful tumor responses in patients with metastatic disease that progressed after prior chemotherapy
- JAVELIN Merkel 200 is the largest reported anti-PD-L1/PD-1 antibody study in this patient population
Merck KGaA, Darmstadt, Germany, and Pfizer Inc. (NYSE: PFE) today announced that the European Medicines Agency (EMA) has validated for review Merck KGaA, Darmstadt, Germany’s Marketing Authorization Application (MAA) for avelumab*, for the proposed indication of metastatic Merkel cell carcinoma (MCC), a rare and aggressive skin cancer, which impacts approximately 2,500 Europeans a year.1,2 Validation of the MAA confirms that submission is complete and begins the EMA’s centralized review process. If approved, avelumab, an investigational fully human anti-PD-L1 IgG1 monoclonal antibody, could be the first approved treatment indicated for metastatic MCC in the EU. Patients with metastatic MCC face a very poor prognosis, with less than 20 percent surviving beyond five years.
“While early-stage Merkel cell carcinoma can be generally managed with surgery, there are significant unmet needs in metastatic disease, where treatment options are severely limited,” said Luciano Rossetti, M.D., Executive Vice President, Global Head of Research & Development at the biopharma business of Merck KGaA, Darmstadt, Germany, which in the US and Canada operates as EMD Serono. “We are pleased that the EMA is initiating its review of avelumab, as this means we are one step closer to bringing a much-needed new treatment option to European patients.”
“This is the first of what we hope will be many regulatory milestones for avelumab,” 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 are committed to evaluating avelumab in a number of hard-to-treat cancers, and we believe it may have potential to be an important treatment option for patients with metastatic Merkel cell carcinoma.”
The avelumab metastatic MCC MAA submission is supported by data from JAVELIN Merkel 200, a multicenter, single-arm, open-label, Phase II study of 88 patients with metastatic MCC whose disease had progressed after at least one chemotherapy treatment.1 The JAVELIN Merkel 200 study represents the largest data set of any anti-PD-L1/PD-1 antibody reported in this patient population. These data were recently published in the Lancet Oncology.1
Avelumab received an Orphan Drug Designation (ODD) from the European Commission for MCC. To qualify for an ODD in the EU, a medicine must be intended for the treatment, prevention or diagnosis of a disease that is life-threatening or chronically debilitating; the prevalence of the condition in the EU must not be more than 5 in 10,000, or it must be unlikely that marketing of the medicine would generate sufficient returns to justify the investment needed for its development; and it must be for a disease where no satisfactory treatment is currently available.
The clinical development program for avelumab, known as JAVELIN, involves at least 30 clinical programs and over 2,900 patients evaluated across more than 15 different tumor types. In addition to metastatic MCC, these cancers include breast, gastric/gastro-esophageal junction, head and neck, Hodgkin’s lymphoma, melanoma, mesothelioma, non-small cell lung, ovarian, renal cell carcinoma and urothelial (primarily bladder).
*Avelumab is not approved for any indication in any market. This marks the first acceptance of an EU market authorization application to review the safety and efficacy results for the investigational product avelumab.
1. Kaufman HL et al. Avelumab in patients with chemotherapy-refractory metastatic Merkel cell carcinoma: a multicentre, single-group, open-label, phase 2 trial. Lancet Oncology 2016;17(10);1374–85.
2. IMMOMEC (European Commission). Merkel Cell Carcinoma. http://www.immomec.eu/project/objectives/background/merkel-cell-carcinoma/. Last accessed October 2016.
3. Lemos B, et al. Pathologic nodal evaluation improves prognostic accuracy in Merkel cell carcinoma: Analysis of 5,823 cases as the basis of the first consensus staging system for this cancer. Journal of the American Academy of Dermatology 2010;63:751–761.
4. European Medicines Agency. Orphan designation. http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000029.jsp. Last accessed October 2016.
5. National Cancer Institute. Merkel cell carcinoma treatment–patient version (PDQ®). http://www.cancer.gov/types/skin/patient/merkel-cell-treatment-pdq. Last accessed October 2016.
6. American Cancer Society. What is Merkel cell carcinoma? http://www.cancer.org/cancer/skincancer-merkelcell/detailedguide/skin-cancer-merkel-cell-carcinoma-what-is-merkel-cell-carcinoma. Last accessed October 2016.
7. Desch L and Kuntsfeld R. Merkel cell carcinoma: chemotherapy and emerging new therapeutic options. Journal of Skin Cancer. 2013(2013):327150. http://dx.doi.org/10.1155/2013/327150
8. Heath M, Jaimes N and Lemos B. Clinical characteristics of Merkel cell carcinoma at diagnosis in 195 patients: the AEIOU features. Journal of the American Academy of Dermatology. 2008;58:375–81. http://www.pnlab.org/clinical/documents/ClinCharacteristics.pdf
9. Poulsen M. Merkel cell carcinoma of skin: diagnosis and management strategies. Drugs Aging. 2005;22(3):219–29.
10. Swann MH and Yoon J. Merkel cell carcinoma. Seminars in Oncology. 2008;34(1):51–56.
11. NCCN Merkel Cell Carcinoma Guidelines version I. 2017. www.nccn.org/professionals/physician_gls/PDF/mcc.pdf. Last accessed October 2016.
About Renal Cell Carcinoma
Renal cell carcinoma accounts globally for 2-3% of all malignancies.3 As of 2012, more than 338,000 new cases of kidney cancer were diagnosed per year worldwide.4 In general, higher incidence rates of renal cell carcinoma occur in Eastern Asia, North America and Central/Eastern Europe.5 Early-stage renal cancers tend to have a better prognosis, compared with advanced/metastatic renal cancers.6
The five-year survival rate for localized kidney and renal pelvis cancer is approximately 90%.1 The five-year overall survival rate for patients with distant metastatic RCC is approximately 12%.1
In the past 7 years, major advances have been made in the improvement of clinical outcomes with the introduction of new therapies.7 The introduction of these therapies has extended median survival rates for metastatic renal cell carcinoma.
Avelumab (also known as MSB0010718C) is an investigational fully human anti-PD-L1 IgG1 monoclonal antibody. By inhibiting PD-L1 interactions, avelumab is thought to enable the activation of T-cells and the adaptive immune system. By retaining a native Fc-region, avelumab is thought to potentially engage the innate immune system and induce antibody-dependent cell-mediated cytotoxicity (ADCC). In November 2014, Merck KGaA, Darmstadt, Germany, and Pfizer announced a strategic alliance to co-develop and co-commercialize avelumab.
About INLYTA® (axitinib)
INLYTA is indicated for the treatment of advanced RCC after failure of one prior systemic therapy. INLYTA, a kinase inhibitor, 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 influence tumor growth, vascular angiogenesis and progression of cancer (the spread of tumors).
Selected Safety Information for INLYTA® (axitinib)
Hypertension including hypertensive crisis has been observed. Blood pressure should be well-controlled prior to initiating INLYTA. Monitor for hypertension and treat as needed. For persistent hypertension despite use of antihypertensive medications, reduce the INLYTA dose. Discontinue INLYTA if hypertension is severe and persistent despite use of antihypertensive therapy and dose reduction of INLYTA, and discontinuation should be considered if there is evidence of hypertensive crisis.
Arterial and venous thrombotic events have been observed and can be fatal. Use with caution in patients who are at increased risk for these events.
Hemorrhagic events, including fatal events, have been reported. INLYTA has not been studied in patients with evidence of untreated brain metastasis or recent active gastrointestinal bleeding and should not be used in those patients. If any bleeding requires medical intervention, temporarily interrupt the INLYTA dose.
Cardiac failure has been observed and can be fatal. Monitor for signs or symptoms of cardiac failure throughout treatment with INLYTA. Management of cardiac failure may require permanent discontinuation of INLYTA.
Gastrointestinal perforation and fistula, including death, have occurred. Use with caution in patients at risk for gastrointestinal perforation or fistula. Monitor for symptoms of gastrointestinal perforation or fistula periodically throughout treatment.
Hypothyroidism requiring thyroid hormone replacement has been reported. Monitor thyroid function before initiation of, and periodically throughout, treatment with INLYTA.
No formal studies of the effect of INLYTA on wound healing have been conducted. Stop INLYTA at least 24 hours prior to scheduled surgery.
Reversible Posterior Leukoencephalopathy Syndrome (RPLS) has been observed. If signs or symptoms occur, permanently discontinue treatment.
Monitor for proteinuria before initiation of, and periodically throughout, treatment. For moderate to severe proteinuria, reduce the dose or temporarily interrupt treatment.
Liver enzyme elevation has been observed during treatment with INLYTA. Monitor ALT, AST and bilirubin before initiation of, and periodically throughout, treatment.
For patients with moderate hepatic impairment, the starting dose should be decreased. INLYTA has not been studied in patients with severe hepatic impairment. Women of childbearing potential should be advised of the potential hazard to the fetus and to avoid becoming pregnant while receiving INLYTA.
The most common (≥20%) adverse reactions are diarrhea, hypertension, fatigue, decreased appetite, nausea, dysphonia, palmar-plantar erythrodysesthesia (hand-foot) syndrome, weight decreased, vomiting, asthenia, and constipation.
The most common (≥20%) lab abnormalities occurring in patients receiving INLYTA (all grades, vs sorafenib) included increased creatinine, decreased bicarbonate, hypocalcemia, decreased hemoglobin, decreased lymphocytes (absolute), increased ALP, hyperglycemia, increased lipase, increased amylase, increased ALT, and increased AST.
INLYTA is indicated for the treatment of advanced renal cell carcinoma (RCC) after failure of one prior systemic therapy.
For more information on INLYTA and Pfizer Oncology, including Full Prescribing Information, please visit
About SUTENT® (sunitinib malate)
SUTENT is an oral multi-kinase inhibitor that works by blocking multiple molecular targets implicated in the growth, proliferation and spread of cancer. SUTENT was approved in 2006 and is indicated for the treatment of advanced/metastatic renal cell carcinoma.
Selected Safety Information for SUTENT® (sunitinib malate)
Boxed Warning/Hepatotoxicity: Hepatotoxicity has been observed in clinical trials and postmarketing experience. This hepatotoxicity may be severe, and deaths have been reported. Monitor liver function tests before initiation of treatment, during each cycle of treatment, and as clinically indicated. SUTENT
should be interrupted for Grade 3 or 4 drug-related hepatic adverse events and discontinued if there is no
resolution. Do not restart SUTENT if patients subsequently experience severe changes in liver function tests or have other signs and symptoms of liver failure.
Women of childbearing potential should be advised of the potential hazard to the fetus and to avoid becoming pregnant.
Given the potential for serious adverse reactions (ARs) in nursing infants, a decision should be made whether to discontinue nursing or SUTENT.
Cardiovascular events, including heart failure, cardiomyopathy, myocardial ischemia, and myocardial infarction, some of which were fatal, have been reported. Use SUTENT with caution in patients who are at risk for, or who have a history of, these events. Monitor patients for signs and symptoms of congestive heart failure (CHF) and, in the presence of clinical manifestations, discontinuation is recommended. Patients who presented with cardiac events, pulmonary embolism, or cerebrovascular events within the previous 12 months were excluded from clinical studies.
SUTENT has been shown to prolong QT interval in a dose-dependent manner, which may lead to an increased risk for ventricular arrhythmias including Torsades de Pointes, which has been seen in <0.1% of patients. Monitoring with on-treatment electrocardiograms and electrolytes should be considered. Hypertension may occur. Monitor blood pressure and treat as needed with standard antihypertensive therapy. In cases of severe hypertension, temporary suspension of SUTENT is recommended until hypertension is controlled.
There have been (<1%) reports, some fatal, of subjects presenting with seizures and radiological evidence of reversible posterior leukoencephalopathy syndrome (RPLS).
Hemorrhagic events, including tumor-related hemorrhage such as pulmonary hemorrhage, have occurred. Some of these events were fatal. Perform serial complete blood counts (CBCs) and physical examinations.
Cases of Tumor Lysis Syndrome (TLS) have been reported primarily in patients with high tumor burden. Monitor these patients closely and treat as clinically indicated.
Thrombotic microangiopathy (TMA), including thrombotic thrombocytopenic purpura and hemolytic uremic syndrome, sometimes leading to renal failure or a fatal outcome, has been reported in patients who received SUTENT as monotherapy and in combination with bevacizumab. Discontinue SUTENT in patients developing TMA. Reversal of the effects of TMA has been observed after treatment was discontinued.
Proteinuria and nephrotic syndrome have been reported. Some of these cases have resulted in renal failure and fatal outcomes. Perform baseline and periodic urinalysis during treatment, with follow-up measurement of 24- hour urine protein as clinically indicated. Interrupt SUTENT and dose-reduce if 24-hour urine protein is ≥3 g; discontinue SUTENT in cases of nephrotic syndrome or repeat episodes of urine protein ≥3 g despite dose reductions.
Severe cutaneous reactions have been reported, including cases of erythema multiforme (EM), Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN), some of which were fatal. If signs or symptoms of EM,
SJS, or TEN are present, SUTENT treatment should be discontinued. If a diagnosis of SJS or TEN is suspected, treatment must not be re-started. Necrotizing fasciitis, including fatal cases, has been reported, including of the perineum and secondary to fistula formation. Discontinue SUTENT in patients who develop necrotizing fasciitis.
SUTENT has been associated with symptomatic hypoglycemia, which may result in loss of consciousness or require hospitalization. Reductions in blood glucose levels may be worse in patients with diabetes. Check blood glucose levels regularly during and after discontinuation of SUTENT. Assess whether antidiabetic drug dosage needs to be adjusted to minimize the risk of hypoglycemia.
The most common adverse reactions (≥20%) are fatigue, asthenia, fever, diarrhea, nausea, mucositis/stomatitis, vomiting, dyspepsia, abdominal pain, constipation, hypertension, peripheral edema, rash, hand-foot syndrome, skin discoloration, dry skin, hair color changes, altered taste, headache, back pain, arthralgia, extremity pain, cough, dyspnea, anorexia, and bleeding.
For more information on SUTENT and Pfizer Oncology, including Full Prescribing Information, including Boxed warning, please visit www.pfizer.com.
Alliance between Merck KGaA, Darmstadt, Germany, and Pfizer Inc., New York, US
Immuno-oncology is a top priority for Merck KGaA, Darmstadt, Germany, and Pfizer Inc. The global strategic alliance between Merck KGaA, Darmstadt, Germany, and Pfizer Inc., New York, US, enables the companies to benefit from each other’s strengths and capabilities and further explore the therapeutic potential of avelumab, an investigational anti-PD-L1 antibody initially discovered and developed by Merck KGaA, Darmstadt, Germany. The immuno-oncology alliance will jointly develop and commercialize avelumab and advance 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 in combination regimens, and is striving to find new ways to treat cancer.
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 healthcare products. Our global portfolio includes medicines and vaccines as well as many of the world's best-known consumer healthcare 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, Pfizer has worked to make a difference for all who rely on us. For more information, please visit us at www.pfizer.com. In addition, to learn more, follow us on Twitter at @Pfizer and @Pfizer_News, LinkedIn and like us on Facebook at Facebook.com/Pfizer.
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Merck KGaA, Darmstadt, Germany
Merck KGaA, Darmstadt, Germany, 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 2015, Merck KGaA, Darmstadt, Germany, generated sales of € 12.85 billion in 66 countries.
Founded in 1668, Merck KGaA, Darmstadt, Germany, is the world's oldest pharmaceutical and chemical company. The founding family remains the majority owner of the publicly listed corporate group. Merck KGaA, Darmstadt, Germany, 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, MilliporeSigma and EMD Performance Materials.
MilliporeSigma, the U.S. and Canada Life Science business of Merck KGaA, Darmstadt, Germany, has doubled its high-potent active pharmaceutical ingredients (HPAPI) production capacity with the expansion of ...