Avelumab Produces Durable Responses in Merkel Cell Carcinoma, Becomes First Drug Approved for the Rare Disease

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Avelumab (Bavencio) achieved durable responses in patients with metastatic Merkel cell carcinoma, according to longer-term follow-up of the phase II JAVELIN study, the largest study conducted to date in this relatively rare orphan cancer.1 Results were presented at the 2017 American Association for Cancer Research (AACR) Annual Meeting, 10 days after avelumab was approved by the U.S. Food and Drug Administration to treat advanced Merkel cell carcinoma in patients over the age of 12 years. Approval was based on data from the JAVELIN trial.

The updated response rate was 33% at a median of 16.4 months of follow-up, and 74% of responders remained in response for more than 1 year.

Rare but Aggressive Disease

Avelumab is now available for oncologists to order. It is important that patients with this rare aggressive tumor get access to these drugs as soon as possible.
— Howard L. Kaufman, MD, FACS

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“This is the first drug to be approved for the treatment of Merkel cell carcinoma, a devastating disease,” stated lead author Howard L. Kaufman, MD, FACS, a surgical oncologist at Rutgers Cancer Institute of New Jersey, New Brunswick. “Given the lack of effective treatment options for patients with metastatic Merkel cell carcinoma whose cancer has returned after chemotherapy, we are excited to see such a high objective response rate. It is also noteworthy to see that nearly all of the initial responses to avelumab were durable, with the majority of responses ongoing for more than a year.”

Merkel cell carcinoma is a rare but aggressive cancer, typically appearing on the skin, with fewer than 2,000 cases in the United States each year. Before avelumab, there was no approved standard of care drugs. The disease is considered chemosensitive, but responses to chemotherapy are not durable, and metastatic disease is uniformly fatal. About 50% to 80% of cases are associated with Merkel cell polyomavirus infection. Risk factors include exposure to ultraviolet light, advanced age, and immunosuppression.

The rationale for treatment of Merkel cell carcinoma with avelumab, a programmed cell death ligand 1 (PD-L1) antibody, is that blocking PD-L1 allows antitumor T cells to remain active; the drug does not bind to PD-L2, the other ligand that interacts with programmed cell death protein 1. The drug is given every 2 weeks. Evidence suggests that avelumab produces antibody-dependent cell-mediated cytotoxicity, contributing to its antitumor effect.


The phase II, prospective, open-label, international JAVELIN trial enrolled 88 patients with histologically confirmed metastatic Merkel cell carcinoma who had received at least 1 prior therapy in the metastatic setting. About 25% were younger than age 65, about 75% were men, and 75% had a cutaneous presentation. The study did not select patients according to the level of PD-L1 expression or polyomavirus status.

Avelumab at 10 mg/kg was given intravenously every 2 weeks until disease progression or toxicity. The primary endpoint was best objective response rate.

Six-month results were previously published in The Lancet Oncology.2 At this year’s AACR meeting, Dr. Kaufman presented longer-term follow-up at 1 year.

This was a heavily pretreated population. About 59% had received 1 prior therapy, 35% had experienced treatment failure on 2 or more lines, 53% had evidence of visceral metastasis, and 21% had lymph node–only disease.

Sixty-five percent of tumors were PD-L1–positive (ie, 1% or greater expression on immunohistochemistry with a proprietary assay). Fifty-two percent tested positive for the Merkel cell polyomavirus.

Treatment Outcomes

At a median follow-up of 16 months, treatment was ongoing in 21.6% of patients, and 78.4% discontinued treatment. Fifty percent discontinued treatment due to disease progression, and 8% did so due to adverse events. Follow-up is ongoing in 16 patients off treatment (18.2%).

At 1 year of follow-up, a slight increase in objective response rate was observed: 33% vs 31.8% at 6 months. Two additional patients achieved a complete response at 1 year, bringing the number up to 10 (11.4%). About 10% had stable disease at both 6 months and 1 year.

Median duration of response has not yet been reached. At 6 months, 92% of patients were in response; by 1 year, 74% remained in response. Response is reached fairly quickly, Dr. Kaufman said; median time to response was 6 weeks.

Avelumab in Merkel Cell Carcinoma

  • For the first time, a drug has been approved by the U.S. Food and Drug Administration for Merkel cell carcinoma, a rare aggressive disease.
  • Promising results of the phase II JAVELIN trial led to approval for treatment of metastatic Merkel cell carcinoma.

JAVELIN demonstrated a 1-year survival rate of 52% with avelumab therapy. Dr. Kaufman said that this compares favorably with three other studies of chemotherapy, which showed no survivors at 12 months.

Subgroup analysis failed to identify a group that stood out in terms of response. The level of PD-L1 expression had a slight impact on response, with higher expression associated with better response. The presence of polyomavirus had no impact on response.

Safety was manageable. Adverse events primarily consisted of fatigue (50%, all grades) and infusion-related reactions (21.6%, all grades), with very few grade 3 or 4 events.

“Maturing data suggest a long-term survival benefit in a proportion of patients,” Dr. Kaufman said.

Study Implications

The drug is currently under study in several other cancers, including bladder, lung, gastric, ovarian, and renal cell carcinomas, and also as a first-line option for metastatic Merkel cell carcinoma.

“Older patients are just as likely to respond as younger patients. We are not seeing as much toxicity in the elderly as we might expect. Age in and of itself should no longer be considered a contraindication for these patients,” Dr. Kaufman said. “This is a terrible disease. We now have a drug that can treat it. Pembrolizumab [Keytruda] has shown encouraging responses in this disease as well,” he added.

“I think newly diagnosed patients should be moved to a PD-L1 inhibitor. Avelumab is now available for oncologists to order. It is important that patients with this rare aggressive tumor get access to these drugs as soon as possible,” he concluded. ■

Disclosure: The study was funded by EMD Serono Inc. Dr. Kaufman has served on advisory boards for Amgen, Celldex, Compass Therapeutics, EMD Serono Inc, Merck, Prometheus, and Turnstone Biologics.


1. Kaufman HL, Russell JS, Hamid O, et al: Durable responses to avelumab (anti-PD-L1) in patients with Merkel cell carcinoma progressed after chemotherapy: 1-year efficacy update. 2017 AACR Annual Meeting. Abstract CT079. Presented April 3, 2017.

2. Kaufman HL, Russell JS, 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 17:1374-1385, 2016.

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