FDA Gives Avelumab Breakthrough Therapy Designation for Merkel Cell Carcinoma

Avelumab has been given breakthrough therapy designation by the FDA as a possible treatment for patients with metastatic Merkel cell carcinoma (MCC) following progression on at least one prior chemotherapy regimen

Mace Rothenberg, MD

Avelumab has been given breakthrough therapy designation by the FDA as a possible treatment for patients with metastatic Merkel cell carcinoma (MCC) following progression on at least one prior chemotherapy regimen, according to a statement from the companies co-developing the PD-L1 inhibitor, Merck KGaA and Pfizer.

The designation for avelumab was based on preliminary findings from the phase II JAVELIN Merkel 200 study. Despite data being unplublished from the study until a 2016 conference, its findings have also led to fast track and orphan drug designations from the FDA for the drug.

“We are very pleased with the progress of the JAVELIN clinical development program and we are looking forward to presenting additional data on the potential of this investigational compound in Merkel cell carcinoma and other tumor types in 2016,” Mace Rothenberg, MD, senior vice president of Clinical Development and Medical Affairs and Chief Medical Officer for Pfizer Oncology, said in a statement.

There are currently no FDA-approved therapies for patients with MCC. Standard frontline therapy consists of a platinum-based chemotherapy plus etoposide, which produces an initial response rate of approximately 50%. However, most responses are not durable. More than 90% of patients will progress on chemotherapy within 10 months on average, with approximately half of these events occurring within the first 3 months.

“Metastatic Merkel cell carcinoma is a devastating disease with limited treatment options currently available for patients,” Luciano Rossetti, MD, global head of Research & Development at Merck KGaA, in Darmstadt, Germany, said in the statement. “With this breakthrough therapy designation, we are one step closer to our goal of making a significant difference to patients living with difficult-to-treat cancers, such as metastatic Merkel cell carcinoma, by researching and developing potential new treatment options.”

The FDA's breakthrough therapy designation is meant to expedite the development of promising therapies for serious or life-threatening conditions. This designation allows for better FDA guidance regarding the avelumab development program, as well as eligibility for a rolling submission of data and a priority review.

Avelumab (formally MSB0010718C) is a fully human IgG1 antibody being co-developed across a variety of settings. In addition to acting as a PD-L1 inhibitor, avelumab is also thought to elicit a response from the innate immune system to induce antibody-dependent cell-mediated cytotoxicity.

The efficacy of PD-1/PD-L1 inhibition in MCC may be related to the Merkel cell polyomavirus (MCPyV), which drives approximately 80% of cases. MCPyV-specific T-cells are present in up to 67% of patients with MCC, representing a PD-1+ and Tim-3+ exhausted T cell phenotype. Additionally, PD-L1 is expressed in about 55% of these tumors.

In the open-label phase II used as the basis for the designation, patients with metastatic MCC who received ≥1 prior chemotherapy received intravenous avelumab at 10 mg/kg every 2 weeks. The primary endpoint of the study is objective response rate by RECIST 1.1 criteria. Secondary outcome measures are focused on duration of response, progression-free survival, overall survival, and safety.

The study planned to enroll 84 patients but exceeded this goal with 88 total participants included. The clinical trial is currently closed for enrollment, with an estimated primary completion date of January 2016 (NCT02155647). In addition to MCC, avelumab is also being explored across a variety of other types of cancer that have shown susceptibility to PD-L1 inhibition. Altogether, the clinical development program for avelumab now contains more than 1400 patients.

Merck KGaA initially discovered Avelumab. The agent is now being jointly developed and commercialized along with Pfizer, following a deal worth up to $2.85 million. The collaboration included an upfront payment of $850 million along with $2 billion in regulatory milestones.

"I think we can test more cancers and more tumors quicker, and we hope to bring these drugs to patients faster," Chris Boshoff, vice president and head of Early Development, Translational, and Immuno-Oncology at Pfizer, said regarding the partnership. "Immuno-oncology will play an important role in the future of cancer treatment."