Zosia Chustecka

April 19, 2016

NEW ORLEANS, LA — The first-ever positive clinical trial in a rare skin cancer, Merkel-cell carcinoma (MCC), has shown one of the highest response rates yet seen with immunotherapy. The trial was conducted in 26 patients who received pembrolizumab (Keytruda, Merck), 14 of whom responded (56%), and 12 with ongoing response.

Immunotherapies acting on the programmed cell death (PD) pathways have typically shown responses in about a third of patients.

"The responses were rapid, and were either present or not," said principal investigator Paul Nghiem MD, PhD, affiliate investigator, clinical research division, Fred Hutchinson Cancer Research Center, and professor of medicine, division of dermatology, University of Washington School of Medicine, Seattle. The first scan, at 3 months, showed who was or was not responding, he said.

Dr Paul Nghiem

Some of the responses were dramatic. One patient with metastases that compromised bladder control, leading to toilet visits every hour, reported improvement within a week and went on to have a complete response, even after stopping pembrolizumab because of adverse events.

"Even one or two doses of this drug have a profound and lasting effect," he added. "The balance of the immune system can be tweaked with a single dose."

The new results in MCC were reported here at the American Association for Cancer Research annual meeting and simultaneously published online in the New England Journal of Medicine.

The trial has now been expanded to include an additional 24 patients, and Dr Nghiem hopes that the data being collected "will contribute to meaningful new therapeutic options becoming available for these patients."

There is currently no FDA-approved therapy for MCC. Patients are usually treated with chemotherapy, which shows a response in about 55% of patients, but these responses do not last; half of the patients relapse by 3 months, and 90% by 10 months, Dr Nghiem said.

He said that it had initially been challenging to get industry interested in doing a trial in MCC because it is so rare, and he was delighted that it became possible as a collaboration with the National Cancer Institute's Cancer Therapy Evaluation Program, the Cancer Immunotherapy Trials Network, and Merck & Co.

Rare Tumor

Merkel-cell carcinoma is an aggressive skin cancer affecting about one in 3000 people in the United States. It is about 35 times less common that melanoma, but on average about 3 times more likely to kill a patient than melanoma, Dr Nghiem said.

It is associated with exposure to ultraviolet (UV) light and with immunosuppression (so is seen in patients who have received organ transplants or have HIV infection or are elderly), and is also associated with the Merkel polyomavirus, Dr Nghiem explained.

Most of us are exposed to this virus in childhood and we carry it on our skin where it causes no detectable problems, he said, but in rare instances it appears again about 50 years later in association with this tumor.

But not all MCCs are positive for the virus. Of the 26 patients enrolled in the trial, 17 were positive for the virus.

However, responses were seen whether or not there was virus present. The response rate was 62% among patients with virus-positive tumors (10 of 16 patients) and 44% among those with virus-negative tumors (4 of 9 patients).

"We believe that the immune system is likely 'seeing' different targets in the virus-positive and virus-negative patients," Dr Nghiem commented. But the drug works in both cases, he added.

The virus-positive tumors produce the viral proteins needed for the tumors to grow, and these viral proteins may be readily seen by the immune system. In contrast, virus-negative MCC has extremely high numbers of mutations caused by UV exposure. These mutations can change the normal cellular proteins so they no longer appear as "self" and the immune system can then see and attack these tumors.

"Thus, potentially through distinct mechanisms (viral antigen expression or high tumor mutational load), both virus-positive and virus-negative Merkel-cell carcinomas appear to be immunogenic and susceptible to immune therapy by inhibition of the PD-1 pathway," the researchers write in the paper.

The trial was open label, single arm, and all patients received pembrolizumab at 2 mg/kg every 3 weeks. At the time of analysis, patients had received between 4 and 49 weeks of therapy.

The objective response rate among the 25 patients with at least one evaluation during treatment was 56% (95% confidence interval, 35 to 76); 4 patients had a complete response, and 10 had a partial response.

With a median follow-up of 33 weeks (range, 7 to 53), relapses occurred in 2 of the 14 patients who had had a response (14%). The response duration ranged from at least 2.2 months to at least 9.7 months.

Drug-related grade 3 or 4 adverse events occurred in 15% of the patients. Two patients stopped taking the drug because of adverse events and were treated with prednisone, Dr Nghiem said.

However, in his discussion of the data at the meeting, Winald R. Gerritsen, MD, professor of dermatology at the Radboud University Medical Center, Millingen aan de Rijn, Netherlands, emphasized the other side of this finding, and said that the drug was very well tolerated in 85% of patients, which is "a major step forward for treating elderly patients."

Dr Gerritsen also said that after 3 months on pembrolizumab the immune system appears to reach an equilibrium, and he described the responses seen as "remarkable."

"It really is spectacular. It looks like we are fighting the flu or infectious disease, the way the immune system is responding to this drug," he added.

The study was supported by grants from the National Cancer Institute and by Merck. Dr Nghiem is a consultant for EMD Serono, and receives funding from Bristol-Myers Squibb to perform biomarker studies in Merkel-cell carcinoma trials.

American Association for Cancer Research (AACR) 2016 Annual Meeting. Abstract CT-096 presented April 19, 2016.

NEJM. Published online April 19, 2016. Abstract

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