PD-1/PD-L1 Inhibitors Arrive in Merkel Cell Carcinoma

Celeste Lebbé, MD, PhD

Immune checkpoint inhibitors against PD-1 and PD-L1 are showing promise across clinical trials for patients with Merkel cell carcinoma (MCC), with an approval already granted for avelumab (Bavencio) and another pending for pembrolizumab (Keytruda).

Despite the rarity of MCC, more than 4 studies have already reported results for PD-1/PD-L1 inhibitors, including a phase II trial of pembrolizumab, a phase I/II of nivolumab (Opdivo), and two phase II studies of avelumab. The importance of PD-1/PD-L1 inhibitors in MCC was emphasized during a talk by Celeste Lebbé, MD, PhD, at the 2017 European Post-Chicago Melanoma/Skin Cancer Meeting in Munich, Germany.

“The take home message is that anti—PD-1/PD-L1 inhibitors are a breakthrough for patients with a rare cancer with an unmet medical need and hopefully they should soon become available as first-line therapy worldwide,” said Lebbé, from the Hôpital Saint Louis, in Paris, France. “I think it’s unusual to have such a large amount of clinical data for a rare cancer even though they are small clinical trials and I hope this will be a good example to follow for other rare cancers.”

The historic standard of care for MCC has been chemotherapy. In the frontline setting, the objective response rate (ORR) with chemotherapy is around 57%, which drops to 23% with limited durability (around 4 months) in the second-line setting. Median progression-free survival (PFS) in the first- and second-line setting are 3 months and 61 days, respectively.

There is a strong rationale for targeting PD-1/PD-L1 in MCC, Lebbé explained. MCC is characterized by PD-L1 expression on tumor cells (TC) and adjacent immune cell infiltrates (IC). Additionally, the Merkel cell polyomavirus (MCPyV), which occurs in 80% of tumors, causes T cell dysfunction (CD8⁺ T cells increase with larger tumor burden, exhausted phenotype [PD-1⁺, Tim-3⁺]) and tumors that are MCPyV-negative tend to have higher mutation and neoantigen burdens, which also signal better efficacy with anti—PD-1/PD-L1 agents.

In the studies for patients with MCC, response rates were similar to chemotherapy with durations of response that were not yet reached with more than a year of follow-up in some scenarios. Patient populations in these studies were relatively small, reflective of the rare status of MCC.

The pembrolizumab study enrolled 26 patients with primarily stage IV MCC (92%). Fifty-six percent of tumors were PD-L1—positive on at least 1% of cells. The ORR was 56%, and, after a median follow-up of 33 weeks, the median duration of response was not yet reached (range, 2.2-9.7+ months). The PFS rate at 6 months was 67%.

The nivolumab study enrolled 25 patients with MCC who received ≤2 prior lines of therapy. Twenty percent of tumors were positive for PD-L1. The ORR was 64% and 75% of responses occurred at approximately 8 weeks. At the time of data cutoff, 75% of responses were ongoing. The median PFS was 9 months and the overall survival (OS) rate was 80% at 9 months.

In the JAVELIN Merkel 200 study, which led to the approval of avelumab, 88 patients received treatment with the PD-L1 inhibitor. Patients in the trial received ≥3 prior therapies and all had metastatic MCC (66% were PD-L1­­—positive). After at least 1 year of follow-up in the first avelumab study, the ORR was 33% and 10 patients had experienced a complete response (11%), with 72% of responses still ongoing. The median time to response was 6.1 weeks. The PFS rate at 1 year was 30% and the median PFS was 2.7 months. Median OS was 12.9 months.

A second study of avelumab in untreated patients with stage IV MCC was presented at the 2017 ASCO Annual Meeting from an interim analysis of 29 patients. The trial plans to enrolled 112 total participants. The ORR at this analysis was 63% after ≥13 weeks of follow-up.

“So what are the next steps for anti-PD1/PD-L1 inhibitors in MCC?” asked Lebbé. “Luckily for patients we have decided to not go for a randomized trial comparing PD-1 inhibitors with chemotherapy. The next steps will certainly consist of evaluating combinations and sequences with chemotherapy and radiotherapy. MCC, in contrast with melanoma, is radiosensitive.”

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