PD-1 blocker pembrolizumab may be a promising therapy for advanced Merkel-cell carcinoma

1. Using immune checkpoint blockade, this phase 2 study showed favourable complete and partial response rates, and increased progression free survival at 6 months, when using programmed cell death-1 (PD-1) blocker pembrolizumab as a first-line therapy for advanced Merkel-cell carcinoma.

2. Responses to pembrolizumab were seen in both positive and negative Merkel-cell polyomavirus (MCPyV) tumours, and while significant pembrolizumab associated toxicity was observed in a small proportion of patients, these subsided when the drug was discontinued and glucocorticoid was given.

Evidence Rating Level: 2 (Good)       

Study Rundown: Merkel-cell carcinoma is a rare and highly aggressive skin cancer, and in advanced cases, standard chemotherapy only offers a 3-month progression-free survival. Merkel-cell carcinoma is often associated with MCPyV, which produces MCPyV T-antigen specific T-cells that increase as the cancer progress and simultaneously decreases effectiveness of therapy. Merkel-cell carcinomas also express PD-1 on tumour infiltrating lymphocytes, and its ligand (PD-L1) is expressed on tumour cells and macrophages which have an immunosuppressive effect when binding to its receptor. The use of immune checkpoint blockade using PD-1 blockers has shown promising therapeutic results in non-small cell, melanoma and renal cell cancers. This phase 2, multicenter trial assessed the efficacy of PD-1 blocker pembrolizumab in patients with advance Merkel-cell carcinoma who had not had prior systemic therapy, as well as to assess treatment outcomes according to MCPyV status. There was an overall favourable partial and complete response rate, and improved progression-free survival at 6 months. There was a response to pembrolizumab regardless of MCPyV status, and the toxicity profile did not appear to be overly burdensome. The major strengths of this study include presentation of an initial positive therapeutic finding using PD-1 blocker pembrolizumab to treat advanced Merkel-cell carcinoma, which provides patient with a potential treatment option. The associated toxicity profile seems to be relatively minimal and manageable. However, small sample size, lack of long-term data and lack of direct comparison to standard therapy via a randomized controlled trial, limits the generalizability of this study.

Click to read the study, published today in NEJM

Relevant Reading: The blockade of immune checkpoints in cancer immunotherapy.

In-Depth [prospective cohort]: This multicenter phase 2 study was aimed at patients with advanced Merkel-cell carcinoma, who did not receive any prior systemic therapy, to be treated with pembrolizumab (PD-1 blocker) using a dose of 2 mg per kilogram body weight. The primary endpoint was objective response rate, as measured by the Response Evaluation Criteria in Solid Tumours (v 1.1).

There were a total of 26 patients with stage IIIB or IV Merkel-cell carcinoma enrolled in the study from January 2015 to December 2015, who received at least a single dose of pembrolizumab. In total, 25 patients had at least one tumour assessment during treatment. Of those 25 patients, 14 had a confirmed response; 4 with a complete response and 10 with a partial response, representing an objective response rate of 56% (95%CI 35-76). One patient continued to receive treatment whose response was not known. One patient out of 25 (4%) had stable disease, while 9/25 (36%) patients had progressive disease. The median follow-up time was 33 weeks (range 7-35), and median duration of treatment for all 26 patients was 27 weeks (range 3 – 57). In terms of MCPyV status, of those who were positive, 62% (10/16) had an objective response, and of those who were negative, 44% (4/9) had an objective response. The rate of progression-free survival at 6 months was 67% (95%CI 49-86). There were 9 patients who had progressive disease, among whom 4 where progression occurred in pre-existing target lesions, 2 who had new metastatic sites, and 3 who had both. Pembrolizumab-associated adverse events of any nature occurred in 77% of the patients, where the most common were fatigue and laboratory abnormalities. There was grade 3 or 4 toxicity seen in 4/26 (15%) of the patients, which were adequately managed with cessation of pembrolizumab, and initiation of glucocorticoids.

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