Immune checkpoint inhibitors are providing rapid and durable responses for patients with metastatic Merkel cell carcinoma.
Based on results from phase 2 clinical trials investigating immune checkpoint inhibitor, treatment for Merkel cell carcinoma (MCC) may be on the brink of a paradigm change, said Isaac Brownell, M.D., Ph.D., at the 16th World Congress on Cancers of the Skin in Vienna, Austria.
Avelumab (EMD Serono), an investigational anti-programmed death ligand-1 (anti-PD-L1) monoclonal antibody, was found to well-tolerated and effective in patients with chemotherapy-resistant metastatic MCC, providing rapid and durable responses.1 Similarly, the PD-1 inhibitor pembrolizumab (Keytruda, Merck) demonstrated therapeutic benefit as a first-line treatment for metastatic MCC.2
The FDA granted avelumab breakthrough therapy, fast-track, and orphan drug designations in MCC and is reviewing the biologics license application for treatment of chemotherapy-resistant metastatic MCC. Meanwhile, follow-up is continuing in the phase 2 studies of avelumab and pembrolizumab and another phase 2 trial is underway investigating avelumab as first-line therapy for patients with metastatic MCC.
“MCC is a rare and aggressive skin cancer for which the prognosis has been very poor in patients with advanced disease. Once metastasis occurs, median survival is only about 9 months as progression tends to occur within a few months after starting conventional treatment with cytotoxic chemotherapy,” according to Dr. Brownell, Investigator, Dermatology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD.
“Now, it appears we can offer more hope to these patients,” he says
Interest in treating MCC with immune checkpoint inhibitors stems for growing evidence that the tumor is highly regulated by the immune system.
“The immunocompromised population has a much higher incidence of MCC and a worse prognosis. Tumors in a small percentage of patients would spontaneously regress, and the presence of CD8+ tumor infiltrating lymphocytes conferred an improved prognosis,” Dr. Brownell explains.
“All of these findings suggested that immunotherapy might be a good strategy for treating MCC, and the advent of immune checkpoint inhibitors made it a more accessible approach,” he says.
In particular, there was interest in agents blocking the PD-1 immune inhibitory pathway based on the finding of high expression of PD-L1 on MCC tumors and of PD-1 by Merkel-cell polyomavirus-specific T cells.
“Merkel cell polyomavirus is the seventh identified human oncovirus and the first polyomavirus that has been linked to a human malignancy,” Dr. Brownell says.
The international, multicenter phase 2 study of avelumab for treatment of chemotherapy-resistant metastatic MCC enrolled 88 patients with stage IV disease. Forty percent of patients had received at least two prior systemic anticancer treatments and about half of the patients had visceral disease.
Avelumab 10 mg/kg was administered as an intravenous infusion every two weeks. Confirmed objective response was assessed as the primary endpoint, and after a median follow-up of 10.4 months, it was achieved by 28 (31.8%) patients, of which eight benefited with a complete response and 20 had a partial response. Two of the eight patients with a complete response had visceral disease.
At the time of the data analysis, 23 patients had an ongoing objective response, and 92% of responses were durable for at least six months.
“Seeing objective responses in treatment-resistant MCC is truly remarkable, and whereas median progression-free survival with chemotherapy is only about three months, some patients with complete responses are remaining disease-free for over one year,” Dr. Brownell says.
Inclusion criteria required patients to be immune-competent. There were no criteria regarding PD-L1 expression or Merkel cell polyomavirus status, and in subgroup analyses, neither of those characteristics predicted response to avelumab.
The study investigating pembrolizumab as first-line therapy enrolled 26 patients who were treated with a dose of 2 mg/kg every three weeks. After a median follow-up of 7.6 months (range 7 to 53 weeks), 14 (56%) of 25 evaluable patients demonstrated an objective response, of which four were complete responses. Response duration ranged from at least 2.2 months to at least 9.7 months. Again, PD-L1 expression and Merkel cell polyomavirus status did not predict treatment response.
“The higher response rate in this study may be explained by the fact that patients treated in the first-line setting may have less advanced disease and less resistant tumors. It will be interesting to see what the objective response rate is with avelumab as first-line treatment for advanced MCC, but definitive understanding of the relative efficacy of anti-PD-L1 versus anti-PD-1 treatment would require a head-to-head trial of the two strategies,” Dr. Brownell says.
Both avelumab and pembrolizumab have been well-tolerated in patients with MCC, and their side effect profiles are consistent with the adverse events associated with pembrolizumab treatment in patients with melanoma.
“Unlike conventional chemotherapy that causes cytotoxic side effects, immune checkpoint inhibitors primarily cause immune-related adverse events. With appropriate safety monitoring, however, autoimmune events such as colitis, pneumonitis, and hypophysitis, are being recognized early and treated promptly so that they are less likely to become severe,” Dr. Brownell says.
Disclosures: Dr. Brownell reports no relevant financial interests to disclose. Dr. Brownell’s opinions are his own and do not necessarily represent the official views of the NIH.
1. Kaufman HL, Russell J, Hamid O, et al. Avelumab in patients with chemotherapy-refractory metastatic Merkel cell carcinoma: a multicentre, single-group, open-label, phase 2 trial. Lancet Oncol. 2016;17(10):1374-1385.
2. Nghiem PT, Bhatia S, Lipson EJ, et al. PD-1 blockade with pembrolizumab in advanced Merkel-cell carcinoma. N Engl J Med. 2016 30;374(26):2542-2552.