Frontline Pembrolizumab Induces Durable Responses in Merkel Cell Carcinoma

Paul T. Nghiem, MD, PhD

Anti—PD-1 therapy in the first-line induced responses in more than half of patients with advanced Merkel cell carcinoma (MCC), with encouraging durability to the responses.

In a single-arm, open-label, phase II study, responses to pembrolizumab (Keytruda) as first systemic therapy for MCC are ongoing in 12 of the 14 responders, said Paul T. Nghiem, MD, PhD, at the AACR 2016 Annual Conference.

“There has not been a trial before carried out before that showed benefit in this cancer and there was actually a lot of doubt that we fought in the pharma industry that a trial could be positive and could be carried out logistically,” said Ngiehm, professor of Medicine, Division of Dermatology, University of Washington Medical Center, Seattle.

Merkel cell polyomavirus (McPyV) is present in about 80% of cases of MCC, a disease for which no approved therapy exists. More than 40% of patients who develop MCC on their skin develop advanced disease, with poor long-term survival (approximately 10%) and median survival of about 1 year. A platinum agent plus etoposide is typically used as first-line therapy for advanced MCC. Although the response rate to chemotherapy is approximately 55%, these responses are rarely durable, he said, with 50% of patients on chemotherapy progressing in the first 3 months and 90% in the first 10 months.

The study was comprised of 26 patients with unresectable or metastatic MCC. They were treated with 2 mg/kg of intravenous pembrolizumab every 3 weeks for up to 2 years. Twenty-five of the 26 patients had at least 1 radiologic assessment. Tumors were evaluated every 9 or 12 weeks. The primary endpoint was objective response per RECIST criteria. Median follow-up was 7.6 months.

The objective response rate was 56% (n = 14). Among responders, 16% (n = 4) had a complete response and 40% (n = 10) had a partial response. One patient had an unconfirmed partial response, one had stable disease, and 36% (n = 9) had progressive disease. PD-L1 expression in pre-treatment tumors did not predict response.

“Viral status is a very interesting story and an evolving one,” he said.

Of the 16 patients with McPyV in the tumor, 62% had responses, compared with 44% of the nine patients with virus-negative tumors.

“That was not a statistically significant difference between the virus-positives and -negatives, but maybe suggests … there may be a better story there for virus-positives,” he said.

The median progression-free survival (PFS) was 9 months and the median 6-month PFS was 67%. Using historical data, median PFS for MCC patients treated with chemotherapy has been about 3 months, he noted.

Response patterns were evident by the first scan at 3 months, said Nghiem.

“At the first scan at 3 months, there were often very profound complete responses, and a lot of the partial responses, which remained very steady over time,” he said.

Responses are ongoing in 12 of 14 responders (86%). Correlative studies are ongoing for anti-McPyV antibody and T-cell responses. The trial is planned to expand to include an additional 24 patients to confirm the results.

Adverse events were similar to those seen in other trials of PD-1 inhibitors, and were managed largely with corticosteroids or by stopping pembrolizumab. In two patients who stopped treatment for drug-related toxicity, antitumor responses are ongoing.

A response rate of 56% to single-agent immune checkpoint inhibitor therapy in solid tumors is remarkably high, said Nghiem.

“Maybe that’s because historically this has been a very immune-associated cancer,” he said. “Immune status is very associated with survival. If you have CD8 T cells infiltrating into this cancer at any reasonable number — among 300 patients, not one died of cancer. It’s really linked to immune status.”

Another immunotherapy, nivolumab (Opdivo), is being studied in the second line or beyond in MCC.

“We chose first-line [for pembrolizumab] because we feel that that’s the best,” he said.

Ngiehm PT, Bhatia S, Lipson EJ, et al. Clinical activity, immune and viral correlates of PD-1 blockade with pembrolizumab as first systemic therapy in patients with advanced Merkel cell carcinoma. Presented at: AACR 2016 Annual Meeting; New Orleans, April 16-20, 2016. Abstract CT-096.

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