EMA Initiates Review of Avelumab Application for Merkel Cell Carcinoma

The European Medicines Agency (EMA) has accepted and validated a marketing authorization application for avelumab as a treatment for patients with metastatic Merkel cell carcinoma.

Luciano Rossetti, MD

Luciano Rossetti, MD

The European Medicines Agency (EMA) has accepted and validated a marketing authorization application for avelumab as a treatment for patients with metastatic Merkel cell carcinoma, according to a statement from the codevelopers of the PD-L1 inhibitor, Merck KGaA and Pfizer.

The application was based on findings from the phase II JAVELIN Merkel 200 study, which were presented at the 2016 ASCO Annual Meeting and published in theLancet Oncology.1,2In the open-label trial, the objective response rate (ORR) with avelumab was 31.8%, which included a 9.1% complete response rate. After a median follow-up of 10.4 months, 82% of patients continued to respond to therapy.

"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," Luciano Rossetti, MD, executive vice president, Global Head of Research & Development at the biopharma business of Merck KGaA, Darmstadt, Germany, said in a statement. "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."

In the trial, 88 previously treated patients at a median age of 72.5 years received avelumab at 10 mg/kg every 2 weeks. Patients had received at least one prior therapy (59.1%), with 11.4% having ≥3 prior system treatments. Most patients in the study were male (73.9%) and the ECOG performance status was 0 (55.7%) and 1 (44.3%).

The most common site of primary tumor was the skin (76.1%) and all patients had metastatic involvement at the time of study entry. Visceral disease was present for 53.4% of patients. Overall, 65.9% of patients were PD-L1-positive and 52.3% were positive for the Merkel cell polyomavirus (MCPyV). Eight percent of patients were negative for both PD-L1 and MCPyV and 40.9% were positive for both markers.

Median progression-free survival (PFS) with avelumab was 2.7 months (95% CI, 1.4-6.9). The 6-month PFS rate was 40%. The median overall survival (OS) was 11.3 months (95% CI, 7.5-14.0) and the 6-month OS rate was 69%.

In addition to responses, 10.2% of patients had stable disease and 20.5% were not evaluable for response. Ninety-two percent of patients responded for ≥6 months (95% CI, 70-98) and the durable response rate was 29.1%.

The ORR was 34.5% in the PD-L1-positive arm and 18.8% in the PD-L1-negative group. The response rate in those who were not evaluable for PD-L1 status was 35.7%. The ORRs were 26.1% and 35.5% in the MCPyV-positive and -negative arms, respectively. In those not evaluable for the virus the ORR was 45.5%. Patients who were positive for both markers had an ORR of 30.6% and those negative for both markers had an ORR of 28.6%.

Treatment-related adverse events (AEs) of any grade were experienced by 70.5% of patients in the study. The most common AEs, which were mostly grade 1/2, were fatigue (23.9%), infusion-related reaction (17%), diarrhea (9.1%), nausea (9.1%), asthenia (8%), rash (6.8%), decreased appetite (5.7%), and maculopapular rash (5.7%).

Grade 3 AEs were experienced by 4.5% of patients and were mostly laboratory abnormalities, such as lymphopenia, blood CPK increase, transaminase increase, and blood cholesterol increase. There were no grade 4 AEs or deaths related to avelumab. Two patients discontinued treatment due to AEs.

"This is the first of what we hope will be many regulatory milestones for avelumab," Chris Boshoff, MD, PhD, senior vice president and head of Immuno-oncology, Early Development and Translational Oncology, Pfizer Global Product Development, said in a statement. "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."

In the United States, avelumab has received a breakthrough therapy designation as a potential treatment for patients with Merkel cell carcinoma. An application for avelumab in Merkel cell carcinoma has also been submitted to the FDA. In addition to Merkel cell carcinoma, avelumab is also being explored across a variety of other types of cancer that have shown susceptibility to PD-L1 inhibition.


  1. Kaufman H, Russell JS, Hamid O, et al. Avelumab (MSB0010718C; anti-PD-L1) in patients with metastatic Merkel cell carcinoma previously treated with chemotherapy: Results of the phase 2 JAVELIN Merkel 200 trial.J Clin Oncol. 2016;34 (suppl; abstr 9508).
  2. Kaufman H, Russell JS, Hamid O, et al. Avelumab in patients with chemotherapy-refractory metastatic Merkel cell carcinoma: a multicentre, single-group, open-label, phase 2 trial.Lancet Oncol. 2016;17(10):1374-1385.
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