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Avelumab for MCC
Avelumab: A New Treatment Paradigm for Metastatic Merkel Cell Carcinoma

Released: May 19, 2017

Expiration: May 18, 2018

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Merkel cell carcinoma (MCC) is a rare but aggressive skin cancer diagnosed in approximately 1500 patients annually in the United States. The disease is increasing in incidence, and more than one third of patients with MCC die from the disease—making it twice as lethal as melanoma. Although MCC is chemosensitive, there is still an unmet need for effective treatments that can extend survival. Recent clinical trials have demonstrated that anti–PD-L1/PD-1 antibodies are effective and safe in MCC and have led to the FDA approval of the PD-L1 inhibitor avelumab for metastatic MCC. For the first time, we have a new class of agents that can improve the prognosis of our patients with advanced MCC.

MCC: An Unmet Need for Effective Treatments
Approximately 80% of MCC cases are associated with a unique virus, the Merkel cell polyomavirus (MCPyV), although the clinical and prognostic implications of this are unclear. Other risk factors for MCC include advancing age, exposure to ultraviolet radiation, and immune suppression.

Treatment of early-stage, localized disease usually entails complete surgical excision and/or local radiation. Once the tumor metastasizes, OS is approximately 9 months and only 18% of those with stage IV disease survive 5 years. Chemotherapy (eg, with a platinum-based agent or cyclophosphamide, doxorubicin, and vincristine) is effective for tumor regression but has not been associated with long-term survival. Before 2017, no agents had received regulatory approval for treatment of MCC.

Avelumab: The First Systemic Therapy Approved for MCC
Recent evidence reveals that most MCC tumors express PD-L1, a receptor that inhibits infiltrating antitumor T-cells. The presence of PD-L1 in MCC suggests that the disease might be amenable to treatment with T-cell checkpoint inhibitors targeting the PD-1/PD-L1 pathway. Avelumab is a fully human IgG1 monoclonal antibody that binds to PD-L1, counteracting T-cell suppression and thereby mediating antitumor activity. In vitro data suggest that the drug can also induce antibody-dependent cytotoxicity.

In the single-arm, open-label phase II JAVELIN Merkel 200 clinical trial, 88 patients with stage IV metastatic MCC who had progressed after at least 1 round of chemotherapy were treated with IV avelumab 10 mg/kg every 2 weeks until disease progression or unacceptable toxicity. In an extended analysis after a median follow-up of 16.4 months, the ORR was 33%. Among treated patients, 11.4% had CRs and 21.6% had PRs. At 1 year, 23.9% of patients treated with avelumab were still in response—suggesting that therapeutic responses to avelumab are durable.

Avelumab was well tolerated; common adverse events included fatigue and infusion-related drug reactions. Fortunately, the infusion reactions could be successfully prevented through premedication with an antihistamine and acetaminophen. In the extended analysis, 3 patients had experienced grade 3/4 immune-mediated adverse events. These immune-related events are unique to checkpoint inhibitors and are generally managed with steroids.

Based on data from the JAVELIN Merkel 200 trial, the FDA granted accelerated approved of avelumab for patients with metastatic MCC. Nonetheless, the approval will require further clinical studies to confirm preliminary results. I find it encouraging that an interim analysis of an ongoing extension of the JAVELIN Merkel 200 trial reported very high response rates in the first 16 patients enrolled.

Another checkpoint inhibitor, pembrolizumab, which is a monoclonal antibody against the PD-1 checkpoint, has also been investigated in a phase II trial in treatment-naive patients with recurrent advanced or metastatic MCC. The study reported an ORR of 56% with responses observed in both MCPyV-positive and MCPyV-negative tumors and a PFS rate of 67% at 6 months. Based on these promising data, the trial has been expanded to a total of 50 patients. Pembrolizumab is currently approved to treat melanoma, non–small-cell lung cancer, head and neck cancer, and Hodgkin’s lymphoma.

Your Thoughts?
Have you used avelumab or pembrolizumab for your patients with metastatic MCC? If so, did your patient experience a durable response? Please leave your feedback below.

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