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NEW ORLEANS -- More than half of patients with advanced Merkel cell carcinoma had durable responses to treatment with the immune checkpoint inhibitor pembrolizumab (Keytruda), according to results of a small clinical trial.

Objective responses occurred in 14 of 26 patients with previously untreated disease. One additional patient had an unconfirmed response, and one patient had stable disease. Responses were durable in most cases, indicated by the fact that 12 of 14 responses were ongoing after a median follow-up of 7.6 months.

The 26 patients had a median progression-free survival (PFS) of 9 months, about three times longer than historical medians with conventional therapy, as reported here at the American Association for Cancer Research meeting and published simultaneously online in the .

"Anti-PD-1 treatment with pembrolizumab as first-line systemic therapy induced a high response rate," said , of the University of Washington and Fred Hutchinson Cancer Research Center in Seattle. "Although it's still early in follow-up, the response durability appears encouraging, and a confirmatory expansion trial of an additional 24 patients is planned."

With an annual incidence of about 2,000 cases, Merkel cell carcinoma meets the epidemiologic definition of an orphan disease. The cancer has a "fascinating" genetic background, Nghiem said. , is present in about 80% of patients with the cancer. The virus is ubiquitous in the environment -- "found in daycare [centers], on door knobs, on normal skin."

"We get exposed to it as little kids, and then 5 decades later, less than one in 3,000 people exposed to this virus will get Merkel cell carcinoma," he said.

More than 40% of patients develop advanced disease, which proves resistant to standard chemotherapy regimens in most cases. Long-term survival is less than 10%, and from diagnosis of advanced disease.

Currently, no FDA-approved therapy exists for Merkel cell carcinoma. A platinum agent plus etoposide is a typical first-line regimen, which achieves objective responses more than half the time, many of which lead to "profound" tumor shrinkage but inevitably are short lived.

The perplexing response to conventional treatment and a known association with immunosuppression led to speculati0n that an immune-targeted approach might improve outcomes in Merkel cell carcinoma, Nghiem continued. Two signaling pathways are involved in interaction between tumor-specific T cells and a target tumor cell. One can be controlled by inhibition of CTLA-4, by a drug like ipilimumab (Yervoy), for example.

The second form of signaling is a PD-1/PD-L1 mediated pathway, involving chronic stimulation that results in an "exhausted" T-cell phenotype.

"Often those T-cells are still hanging around and ready to respond, if this PD-1/PD-L1 pathway can be inhibited, and there are number of agents that can target either of those molecules," Nghiem said.

PD-L1 is expressed in more than half of Merkel cell carcinoma and is associated with improved survival, he added. PD-1 is found in Merkel cell polyomavirus-specific T cells in about two-thirds of patients.

Investigators in a multicenter trial evaluated single-agent pembrolizumab in patients with unresectable or metastatic Merkel cell carcinoma and no prior systemic therapy. The primary endpoint was objective response.

Nghiem reported that four patients attained complete response and 10 had partial response, resulting in an overall response rate of 56% (14 of 25 evaluable patients). Responses were observed in 10 of 16 patients who tested positive for the Merkel cell polyomavirus and in four of nine patients who tested negative. Pretreatment PD-L1 expression in tumors did not predict response to pembrolizumab.

In addition to the median PFS of 9 months, the study population had a 6-month PFS of 67%.

The trial is not the first to demonstrate a benefit of anti-PD-1/PD-L1 therapy in patients whose tumors did not have detectable expression of PD-L1. The lack of consistency between PD-L1 expression and clinical benefit reflects the lack of understanding about the role of the immune system and immunotherapy in treating cancer, said , of the Medical University of South Carolina in Charleston.

"Obviously, it means we don't understand some of the other factors that are playing a role," said DuBois, who moderated a press briefing where Nghiem spoke. "We know there are other checkpoint, regulatory situations in the tumor microenvironment. It's asking a lot to have it all based on just one biomarker."

"The key question in all of immunotherapy is why some tumors respond so well and why others are so resistant," DuBois added. "That's going to require more research. Undoubtedly, there are other immune modulators in play and we don't understand their role."

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