Avelumab for the Treatment of Metastatic Merkel Cell Carcinoma, United States of America


Avelumab

Avelumab (formerly MSB0010718C) is a human PD-L1 monoclonal antibody being investigated for the treatment of metastatic Merkel cell carcinoma (MCC). The drug is being jointly developed by Merck KGaA and Pfizer.

Avelumab received orphan drug designation (ODD) from the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA) Fast Track Designation in November 2015 and October 2015 respectively.

The marketing authorisation application (MAA) for Avelumab was accepted for review by the EMA in October 2016.

The Biologics License Application (BLA) for Avelumab was accepted by the FDA in November 2016.

Merkel cell carcinoma causes and symptoms

Merkel cell carcinoma (MCC), a skin cancer, is caused by the uncontrolled growth of Merkel cells in the skin. The disease is largely caused by Merkel cell polyomavirus (MCV) on parts of the skin in the head, neck and arms, mostly due to long-term sun exposure. A weak immune system also increases the risk of developing MCC.

"The marketing authorisation application for Avelumab was accepted for review by the EMA in October 2016."

An estimated 2,500 new cases of MCC are diagnosed in the EU every year. The disease has poor prognosis with less than 20% of patients surviving longer than five years.

Avelumab's mechanism of action

Avelumab contains a fully human anti-programmed death-ligand 1 (PD-L1) immunoglobulin G1 (IgG1) monoclonal antibody. The drug binds to programmed cell death 1 protein (PD-1) and controls PD-L1 interactions. It also enables the activation of T-cells and the adaptive immune system.

The drug can be administered intravenously.

Clinical trials on Avelumab

Pfizer and Merck submitted the MAA and BLA to the EMA and FDA respectively for the approval of Avelumab based on the results of a phase-two clinical trial known as JAVELIN Merkel 200.

The open-label, international, multi-centre clinical study enrolled 88 patients with metastatic MCC, whose disease had progressed after at least one chemotherapy treatment. It was conducted across Asia Pacific, Australia, Europe and North America.

The patients were administered with Avelumab 10mg/kg intravenously once every two weeks. The cut-off date for primary analysis was six months.

The primary endpoint of the study was best overall response according to RECIST v1.1 assessed by an independent review committee. The secondary endpoints included duration of response, progression-free survival (PFS), overall survival (OS), and safety and tolerability, pharmacokinetics, and immunogenicity.

The results of the study showed that eight patients treated with Avelumab achieved complete responses, whereas 20 patients achieved partial responses. The PFS rate at six months was 40%, which was estimated based on Kaplan-Meier method. The OS rate was 69% and the media OS was 11.3 months at six months.

Treatment-related adverse events (AEs) were reported in 62 patients. The most common AEs included fatigue, and infusion-related reactions.

The clinical trial programme on Avelumab was conducted in more than 1,400 patients suffering from various types of cancer, including breast cancer, gastric cancer, head and neck cancer, MCC, mesothelioma, melanoma, non-small cell lung cancer, ovarian cancer, renal cell carcinoma, and urothelial cancer.

Marketing commentary

Avelumab was discovered by Merck KGaA at Darmstadt, Germany. Merck and Pfizer reached an agreement to co-develop and co-commercialise Avelumab in November 2014. If approved by EMA or FDA, Avelumab will become the first treatment indicated for patients with MCC.