Immunotherapy with the PD-1 inhibitor pembrolizumab (Keytruda) induced durable responses in a phase 2 clinical trial of patients with Merkel-cell carcinoma (MCC) and the Merkel-cell polyomavirus (MCPyV), reported Paul T. Nghiem, MD, PhD, Head, University of Washington Dermatology, Seattle, at the 2016 American Association for Cancer Research annual meeting. Among 26 patients in the trial who received pembrolizumab, 12 of 14 patients who responded to pembrolizumab have ongoing responses after a median follow-up of 7.6 months, and the objective response rate (ORR) was 62% in patients with virus-positive tumors.
Currently, no drugs are approved by the FDA for the treatment of patients with MCC. Typically, platinum-based chemotherapy is the first-line treatment for patients with MCC, and although the ORR to chemotherapy is approximately 55%, these responses are transient, said Dr Nghiem.
MCPyV drives approximately 80% of MCC cases. More than 40% of patients with MCC have advanced disease within 3 months of initiating chemotherapy, and 90% will have disease progression by 10 months. The median survival is only 9.5 months after a diagnosis of metastatic MCC.
The rationale for investigating pembrolizumab in patients with MCC is that PD-1 on the T-cells is present in MCPyV-specific T-cells in up to 66% of patients with MCC.
The single-arm, open-label trial presented by Dr Nghiem included 26 patients with advanced or metastatic MCC who had received no previous systemic therapy. Of the 26 patients, 17 had MCPyV-positive disease. All patients received 2 mg/kg of pembrolizumab every 3 weeks, with response assessed every 9 to 12 weeks.
At the time of the data analysis, treatment duration with pembrolizumab was from 9 weeks to 49 weeks, with 56% ORR. This response rate is higher than seen with PD-1 inhibitors in the treatment of other solid tumors.
“Maybe that’s because historically, this has been a very immune-associated cancer,” Dr Nghiem said. “Viral status is a very interesting story, and an evolving one.”
Of the 16 patients with MCPyV-positive tumors, 62% had responses compared with 44% of the 9 patients with virus-negative tumors. “That was not a statistically significant difference between the virus positives and negatives, but it might suggest…there may be a better story there for virus positives,” he noted.
“We believe that the immune system is likely ‘seeing’ different targets in the virus-positive and virus-negative patients,” Dr Nghiem said. Virus-positive tumors produce viral proteins required for tumor growth, and these viral proteins may be recognized by the immune system. However, virus-negative MCC has extremely high numbers of mutations caused by ultraviolet exposure, and is more likely to be recognized by the immune system.
In this study, 4 patients had a complete response, 3 of whom had virus-positive disease; an additional 10 patients had a partial response, 7 of whom had virus-positive disease.
The responses were already evident by the first scan at 3 months, and many of these responses were “profound,” said Dr Nghiem. The responses are ongoing in 12 patients.
The median progression-free survival (PFS) was 9 months compared with a historical median PFS of approximately 3 months for patients with MCC treated with chemotherapy, Dr Nghiem said. The median 6-month PFS rate was 67% in the study.
The adverse events in this study were similar to those observed in other anti–PD-1 trials. Of note, 2 patients who discontinued pembrolizumab therapy because of toxicity are still showing response to therapy.