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Anti–PD-1/PD-L1 therapy ‘rapidly becoming’ standard of care for Merkel cell carcinoma

NEW YORK — Immunosuppressive therapies, including anti–PD-1/PD-L1 agents, have led to durable responses among patients with Merkel cell carcinoma. However, more research is needed to fulfill unmet medical needs, according to a presenter at HemOnc Today Melanoma and Cutaneous Malignancies.

“This is a very aggressive cancer. The mortality rate of all Merkel cell is 45% — three times more fatal compared with melanoma which is considered an aggressive skin cancer — so we need more options,” Shailender Bhatia, MD, oncologist and assistant professor in the department of medicine at Seattle Cancer Care Alliance, said during his presentation.

The field has changed after the Merkel cell polyomavirus was first discovered in 2008.

Shailender Bhatia
Shailender Bhatia

The virus is known to be associated with disease, and 80% of the cases are based in the United States.

Overall, there is a lack of prospective data for this disease, Bhatia said.

Clinical trials investigating cytotoxic chemotherapy for the treatment of Merkel cell carcinoma have shown the therapy produces initial high response rates, but they are not durable.

A study by Iyer and colleagues at University of Washington, published in Cancer Medicine, included 62 patients treated with first-line and second-line chemotherapy. For first-line treatment, the overall response rate was 53% (complete response, 13%). However, the median PFS was only 3 months.

Second-line therapy resulted in poorer outcomes. The ORR was 23% (complete response, 3%) with a median PFS of only 2 months.

“Why are these responses less durable? Chemotherapy may be suppressing the immune system, and maybe that’s what’s compromising the good regression we see early on,” Bhatia said.

However, there has been a strong rational for immunotherapy in Merkel cell carcinoma with promising trial results so far.

In a study by Nghiem and colleagues, published in The New England Journal of Medicine, 24 patients were treated with anti–PD-1 antibody pembrolizumab (Keytruda, Merck). An ORR of 56% was observed, irrespective of whether the patient had virus-positive or virus-negative disease. Regression was seen in cutaneous tumors within days of the first dose.

The National Comprehensive Cancer Network now lists pembrolizumab as an option for disseminated disease, Bhatia said.

In a phase 2 study by Kaufman and colleagues, published in 2016 in The Lancet Oncology, 88 patients with chemotherapy-refractory metastatic Merkel cell carcinoma received 10 mg/kg avelumab (Bavencio; EMD Serono, Pfizer) — an anti–PD-L1 monoclonal antibody — via IV every 2 weeks until disease progression, toxicity or other cause for withdrawal.

“A substantial proportion of patients had significant tumor regressions —  the objective response rate was 32% — and because of the higher number of patients, the confidence interval for response rates were quite narrow,” Bhatia said.

The median time to response was 6 weeks, with the trial ongoing and more results expected. Based on these data, the FDA approved avelumab for the treatment of patients aged 12 years and older with metastatic Merkel cell carcinoma this month.

“This is quite different from other immunotherapies. Responses are happening fairly quickly and we don’t have [all the] data, but I have anecdotal experiences that suggest responses are happening in patients even with rapidly progressive disease in unfavorable locations,” Bhatia said.

“It is fair to say that PD-1/PD-L1 blockade is rapidly becoming the new standard in Merkel cell carcinoma,” Bhatia added. “We get frequent and durable responses, minimal toxicity, responses regardless of virus status and responses in both patients who are treatment naive and treatment experienced with chemotherapy.”

Despite the early success of immunotherapies, major unmet medical needs exist for PD-1 refractory patients. Other challenges include that PD-1 blockade is effective only in a subset of patients, immune-suppressed patients have limited options for treatment and patients at high risk for recurrence need effective systemic adjuvant therapy options.

“There is a lot of effort going toward all these unmet needs,” Bhatia said. “We need options beyond chemotherapy. The obvious question is should we be using PD-1/PD-L1 in the adjuvant arena, and the answer is yes. There are trials already planned, and I think this is the way to go in the future.” – by Melinda Stevens

Reference:

Bhatia S. Merkel cell carcinoma (MCC) in the checkpoint era. Presented at: HemOnc Today Melanoma and Cutaneous Malignancies; March 24-25, 2017; New York.

Disclosures: Bhatia reports institution research support from Bristol-Myers Squibb, EMD-Serono, Immune Design, Merck, NantKwest and Oncosec; an unpaid advisory board position for EMD-Serono; and honorarium from Genentech.

NEW YORK — Immunosuppressive therapies, including anti–PD-1/PD-L1 agents, have led to durable responses among patients with Merkel cell carcinoma. However, more research is needed to fulfill unmet medical needs, according to a presenter at HemOnc Today Melanoma and Cutaneous Malignancies.

“This is a very aggressive cancer. The mortality rate of all Merkel cell is 45% — three times more fatal compared with melanoma which is considered an aggressive skin cancer — so we need more options,” Shailender Bhatia, MD, oncologist and assistant professor in the department of medicine at Seattle Cancer Care Alliance, said during his presentation.

The field has changed after the Merkel cell polyomavirus was first discovered in 2008.

Shailender Bhatia
Shailender Bhatia

The virus is known to be associated with disease, and 80% of the cases are based in the United States.

Overall, there is a lack of prospective data for this disease, Bhatia said.

Clinical trials investigating cytotoxic chemotherapy for the treatment of Merkel cell carcinoma have shown the therapy produces initial high response rates, but they are not durable.

A study by Iyer and colleagues at University of Washington, published in Cancer Medicine, included 62 patients treated with first-line and second-line chemotherapy. For first-line treatment, the overall response rate was 53% (complete response, 13%). However, the median PFS was only 3 months.

Second-line therapy resulted in poorer outcomes. The ORR was 23% (complete response, 3%) with a median PFS of only 2 months.

“Why are these responses less durable? Chemotherapy may be suppressing the immune system, and maybe that’s what’s compromising the good regression we see early on,” Bhatia said.

However, there has been a strong rational for immunotherapy in Merkel cell carcinoma with promising trial results so far.

In a study by Nghiem and colleagues, published in The New England Journal of Medicine, 24 patients were treated with anti–PD-1 antibody pembrolizumab (Keytruda, Merck). An ORR of 56% was observed, irrespective of whether the patient had virus-positive or virus-negative disease. Regression was seen in cutaneous tumors within days of the first dose.

The National Comprehensive Cancer Network now lists pembrolizumab as an option for disseminated disease, Bhatia said.

In a phase 2 study by Kaufman and colleagues, published in 2016 in The Lancet Oncology, 88 patients with chemotherapy-refractory metastatic Merkel cell carcinoma received 10 mg/kg avelumab (Bavencio; EMD Serono, Pfizer) — an anti–PD-L1 monoclonal antibody — via IV every 2 weeks until disease progression, toxicity or other cause for withdrawal.

“A substantial proportion of patients had significant tumor regressions —  the objective response rate was 32% — and because of the higher number of patients, the confidence interval for response rates were quite narrow,” Bhatia said.

The median time to response was 6 weeks, with the trial ongoing and more results expected. Based on these data, the FDA approved avelumab for the treatment of patients aged 12 years and older with metastatic Merkel cell carcinoma this month.

“This is quite different from other immunotherapies. Responses are happening fairly quickly and we don’t have [all the] data, but I have anecdotal experiences that suggest responses are happening in patients even with rapidly progressive disease in unfavorable locations,” Bhatia said.

“It is fair to say that PD-1/PD-L1 blockade is rapidly becoming the new standard in Merkel cell carcinoma,” Bhatia added. “We get frequent and durable responses, minimal toxicity, responses regardless of virus status and responses in both patients who are treatment naive and treatment experienced with chemotherapy.”

Despite the early success of immunotherapies, major unmet medical needs exist for PD-1 refractory patients. Other challenges include that PD-1 blockade is effective only in a subset of patients, immune-suppressed patients have limited options for treatment and patients at high risk for recurrence need effective systemic adjuvant therapy options.

“There is a lot of effort going toward all these unmet needs,” Bhatia said. “We need options beyond chemotherapy. The obvious question is should we be using PD-1/PD-L1 in the adjuvant arena, and the answer is yes. There are trials already planned, and I think this is the way to go in the future.” – by Melinda Stevens

Reference:

Bhatia S. Merkel cell carcinoma (MCC) in the checkpoint era. Presented at: HemOnc Today Melanoma and Cutaneous Malignancies; March 24-25, 2017; New York.

Disclosures: Bhatia reports institution research support from Bristol-Myers Squibb, EMD-Serono, Immune Design, Merck, NantKwest and Oncosec; an unpaid advisory board position for EMD-Serono; and honorarium from Genentech.

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