Pembrolizumab, Avelumab Show Promise in Merkel Cell Carcinoma

Luciano Rossetti, MD

Encouraging findings and regulatory milestones have recently been announced for the PD-1/PD-L1 inhibitors pembrolizumab and avelumab for patients with metastatic Merkel cell carcinoma (MCC), raising hopes that new therapies could be on the horizon for this rare aggressive type of skin cancer.

At the 2015 European Cancer Congress, impressive early findings from a phase II study were presented for pembrolizumab in patients with metastatic MCC. In the study, the objective response rate (ORR) with pembrolizumab was 71%, which included a complete response in 2 of 14 patients. Moreover, these responses appeared to be durable, reported lead investigator Paul Nghiem, MD, PhD.

Although results have not yet been announced for avelumab in MCC, the agent was granted an orphan drug designation by the FDA in September, which was quickly followed by a fast track designation in October. Together, these designations will help facilitate the submission of data for avelumab to the FDA, if positive results are demonstrated.

“We are pleased that the FDA continues to acknowledge the current high unmet needs for patients with metastatic Merkel cell carcinoma through these recent regulatory designations for avelumab,” Luciano Rossetti, MD, Global Head of Research & Development of the biopharmaceutical business of Merck KGaA, Darmstadt, Germany, said in a statement. “We look forward to working closely with the FDA on an expedited review process for avelumab, and we hope to be able to provide a potential new treatment option for patients with this difficult-to-treat cancer in the future.”

MCC, which occurs in approximately 2,000 patients in the United States each year, is associated with UV exposure, an age >50, and immune suppression. More than 40% of patients with MCC develop distant metastatic disease, which is associated with a poor prognosis.

At this time, there are no FDA-approved therapies for patients with this rare disease. Standard therapy for patients with MCC consists of a platinum-based chemotherapy plus etoposide. The initial response to this doublet is around 50%, although these responses are not durable. On average, >90% of patients will progress on chemotherapy within 10 months, with approximately half of these events occurring within the first 3 months.

The Merkel cell polyomavirus (MCPyV), which was discovered in 2008, is present and driving approximately 80% of MCC 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 MCC tumors.

Paul Nghiem, MD, PhD

"Obviously PD-1 has been variably effective across a variety of tumors, sometimes very effective, but no data was available for Merkel cell carcinoma," Nghiem, professor of Dermatology/Medicine at Fred Hutchinson Cancer Research Center, University of Washington Medicine, said when he presented the data. "Biomarker analyses are ongoing and will address the response rate in virus-positive versus virus-negative MCC and whether PD-1 increases the number and/or function of preexisting virus-specific T cells in the blood or tumor."

In the open-label phase II study led by Nghiem, the humanized IgG4 anti—PD-1 monoclonal antibody pembrolizumab was administered at 2 mg/kg every 3 weeks. All enrolled participants had advanced unresectable MCC with a good performance status and no history of autoimmune disease.

At the analysis, 24 previously untreated patients were enrolled. Responses were defined by RECIST criteria every 9 to 12 weeks. Progressive disease was defined as the appearance of a new lesion. At the time of the analysis, scans were available for 14 patients.

Of the evaluable patients, 10 responded to pembrolizumab, representing a 71% response rate. These responses consisted of 2 complete responses and 8 partial responses. Three patients had progressive disease and 1 patient had stable disease at the time of the analysis on September 18, 2015.

"By the time of the first assessment, which was typically around the 12- to 13-week time point, there was a profound shrinkage that has not rebounded," Nghiem explained. "If you recall for chemotherapy, half of patients already have new lesions and regression at 90 days. These responses appear to be durable."

Adverse events (AEs) were similar to prior studies exploring PD-1 inhibition in other types of cancer. After 1 dose of pembrolizumab, 1 patient experienced a grade 4 myocarditis and one patient developed grade 4 transaminase elevation after 2 doses. These AEs improved after discontinuing treatment and once corticosteroids were initiated. Despite only receiving limited treatment, both patients experienced responses.

"This is a very early analysis, and in some ways that is exciting, because we've seen very positive data at this point," Nghiem said. "This is an orphan disease for which there is no FDA-approved medication at this time, so there's a capacity that this could really matter for patients."

Avelumab (formally MSB0010718C) is a fully human IgG1 antibody being co-developed by Merck KGaA and Pfizer across a variety of settings. The recent FDA designations for the drug in MCC were based on the phase II JAVELIN Merkel 200 study, which has not yet reported findings.

In this phase II open-label study, intravenous avelumab at 10 mg/kg every 2 weeks is being explored in patients with metastatic MCC who received ≥1 prior chemotherapy. The primary endpoint of the study is ORR by RECIST 1.1 criteria. Secondary outcome measures are focusing 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 study is currently closed for enrollment, with an estimated primary completion date of January 2016 (NCT02155647).

Mace Rothenberg, MD

“We look forward to working with our partners at Merck KGaA, Darmstadt, Germany, on the development of avelumab in patients with relapsed and refractory Merkel cell carcinoma,” Mace Rothenberg, MD, senior vice president of Clinical Development and Medical Affairs and chief medical officer for Pfizer Oncology, said in a statement. “Fast track designation will enable us to coordinate these efforts more closely with the FDA.”

The phase II study exploring pembrolizumab in Merkel cell carcinoma is currently full; however, the researchers are considering an expansion cohort for the study. This expansion could explore those with chemotherapy pretreated MCC, according to Nghiem. The study is being conducted in collaboration with the NCI (NCT02267603).

Nghiem P, Bhatia S, Daud A, et al. Activity of PD-1 blockade with pembrolizumab as first systemic therapy in patients with advanced Merkel cell carcinoma. Presented at: 2015 European Cancer Congress; September 25-29; Vienna, Austria. 22LBA.