NEW ORLEANS-A rare cutaneous cancer with two very different etiologies-a virus versus ultraviolent (UV) light exposure-has been shown in both cases to respond to treatment with a PD-1 checkpoint inhibitor.
First-line treatment of Merkel cell carcinoma (MCC) with the checkpoint inhibitor pembrolizumab produced response rates at least equal to those of standard chemotherapies but of longer duration, according to data from a phase II trial presented at the American Association for Cancer Research Annual Meeting.
MCC is an aggressive skin cancer linked to UV light exposure and also to the Merkel cell polyomavirus (MCPyV). Pembrolizumab, a humanized IgG4 anti-PD-1 monoclonal antibody, produced responses in MCC tumors driven by the virus as well as those induced by exposure to UV light.
The data were simultaneously published online in the New England Journal of Medicine (DOI: 10.1056/NEJMoa1603702).
Median progression-free survival was 36 weeks, and 6-month progression-free survival was 67 percent.The objective response rate was 56 percent, said lead author Paul Nghiem, MD, PhD, Professor and Chair, Division of Dermatology, University of Washington School of Medicine and an Affiliate Investigator of the Clinical Research Division at Fred Hutchinson Cancer Research Center, Seattle.
There is no FDA-approved therapy for MCC, Nghiem noted.
And while first-line cytotoxic chemotherapy-typically platinum and etoposide-is associated with initial response rates as high as 59 percent in patients with metastatic MCC, responses are seldom durable and median progression-free survival is only 13 weeks.
MCPyV is the driving factor in about 80 percent of MCC cases. While MCC is relatively rare, with only 2,000 new cases in the U.S. annually, on average it has approximately three times the mortality rate of melanoma, Nghiem said.
An estimated 55 percent of MCC tumors express PD-L1, he explained, while MCPyV-specific T cells, which express the inhibitory co-receptor PD-1, are detectable in up to 67 percent of patients with MCC.
Study of Pembrolizumab
The trial, conducted by the Cancer Immunotherapy Trials Network, enrolled adults with unresectable or metastatic MCC and no prior systemic therapy. Pembrolizumab was given IV every 3 weeks at 2 mg/kg.
The presence of MCPyV was assessed by measuring serum antibody titers to the MCPyV oncoprotein or quantifying tumor oncoprotein expression by immunohistochemistry (IHC).
Twenty-six patients received at least one dose of pembrolizumab, with a median treatment duration of 22 weeks. Of those patients, 25 had at least one documented radiologic or clinical assessment of response.
Objective Response & Viral Status
With a median follow-up of 7.6 months, 14 of 25 evaluable patients, for a 56-percent objective response rate, including four complete responses (16%) and 11 partial responses (4%).
One additional patient had stable disease and nine had progressive disease.
The objective response rate of 56 percent is similar to responses with standard therapies, but the duration of response to pembrolizumab appears to be significantly longer than that for chemotherapy.
"And among patients who responded to pembrolizumab, 86 percent are still experiencing excellent disease control more than 6 months after starting therapy," he said.
For patients with virus-positive tumors, Nghiem reported objective responses in 62 percent (10 of 16 patients), but 44 percent of patients with virus-negative tumors (four of nine) were also responders.
PD-L1 expression in pre-treatment tumors did not predict response.
"While virus-positive tumors are known to express highly antigenic MCPyV oncoproteins, virus-negative tumors are typically UV-induced and display strikingly elevated mutational burdens generating neo-antigens," Nghiem said. "Both virus-positive and virus-negative MCC tumors appear to be immunogenic and frequently responsive to anti-PD-1 therapy, potentially through distinct mechanisms."
Responses were seen early. "By the first scan at 3 months, most patients had found where they were going to go, they differentiated themselves early," Nghiem said. "Several had failed early, but by 34 months there were already complete and partial responses."
Treatment was generally well-tolerated with mostly grade-1 or -2 adverse events. Two patients developed severe drug-related toxicities, but they improved with corticosteroid treatment and discontinuation of pembrolizumab. Both of those patients have ongoing tumor responses despite discontinuation of pembrolizumab.
Analyses of T cells specific to MCPyV and titers of oncoprotein antibodies during therapy, as well as IHC characterization of tumor biopsies including PD-L1 expression are ongoing.
Nghiem said there had not been a trial before that showed any benefit in MCC, "and there was a lot of doubt in the pharma industry that a trial could be carried out."
Robert H. Carlson is a contributing editor.