Avelumab Induces Sustained Tumor Responses in Some Patients with Rare Skin Cancer

October 6, 2016 by NCI Staff

Anatomy of the skin with Merkel cells; drawing shows normal skin anatomy, including the epidermis, dermis, hair follicles, sweat glands, hair shafts, veins, arteries, fatty tissue, nerves, lymph vessels, oil glands, and subcutaneous tissue. The pullout shows a close-up of the epidermis with Merkel cells above the dermis with a vein and artery. Nerves are connected to Merkel cells. — Merkel cell carcinoma, a rare type of skin cancer, forms in Merkel cells, which are in the deepest part of the epidermis and are connected to nerves.
Credit: Terese Winslow

In a clinical trial, a new immunotherapy drug called avelumab has shown promise in patients with metastatic Merkel cell carcinoma, a rare, aggressive skin cancer with few effective treatments.

In the phase II trial, 32% of patients with metastatic Merkel cell carcinoma that had returned after earlier treatment experienced partial or complete shrinkage of their tumors when treated with the new drug. Among patients whose tumors shrank, more than 90% sustained this response for at least 6 months.

The trial is the second published this year to show that an immunotherapy drug can shrink tumors in patients with Merkel cell carcinoma.

Results from the trial were published September 1 in Lancet Oncology.

Data Support Initial Optimism

Merkel cell carcinoma is diagnosed in fewer than 2,000 people a year in the United States, mostly the elderly or people with weakened immune systems. Though chemotherapy often rapidly shrinks Merkel cell tumors, they quickly bounce back, “and no increase in survival has been shown with any chemotherapy drug for Merkel cell carcinoma,” said Elad Sharon, M.D., of NCI’s Cancer Therapy Evaluation Program, who was not involved in the trial.

“This is a uniformly fatal disease if it becomes metastatic, and the chemotherapy we have for it is pretty harsh,” said Howard Kaufman, M.D., of the Rutgers Cancer Institute of New Jersey, who led the trial.

Avelumab is an immune checkpoint inhibitor, a type of immunotherapy drug that takes the brakes off the immune system and allows immune cells to kill cancer cells more effectively. Several checkpoint inhibitors are already approved for use against other cancers, including ipilimumab (Yervoy®), pembrolizumab (Keytruda®), nivolumab (Opdivo®), and atezolizumab (Tecentriq®).

Researchers have found that the protein targeted by avelumab, called PD-L1, is overexpressed by many Merkel cell tumors. In addition, most Merkel cell tumors are associated with a virus called Merkel cell polyomavirus, which integrates its DNA into a healthy cell’s DNA, compromising the immune response. For both reasons, researchers have been optimistic that immunotherapy might be effective against the disease.

Merck KGaA developed avelumab and, in alliance with Pfizer, funded the phase II trial. The trial enrolled 88 patients from 35 cancer centers on four continents, with all of the patients having already received at least one prior round of chemotherapy. All patients in the trial received avelumab every other week until their cancer progressed or they experienced intolerable side effects.

Overall, 20 participants experienced tumor regression, and an additional 8 saw their tumors disappear entirely. Almost 80% of patients whose tumors responded to treatment did so rapidly, in the first 6 weeks, explained Dr. Kaufman.

At the time of the last patient follow-up assessment before publication, 27 of these 28 patients’ responses had lasted for at least 6 months, and 6 patients had responses that have lasted for at least a year.

“The real story here isn’t even the response rate, it’s the durability [of those responses],” said Dr. Kaufman.

Unlike with chemotherapy, few patients experienced severe side effects, and only two of the 88 patients discontinued treatment because of an adverse event, he explained.

Accumulating Evidence

Earlier this year, another phase II trial showed that pembrolizumab, which targets a protein called PD-1, is effective in Merkel cell carcinoma.

Patients in that trial had not previously received chemotherapy, and not all had metastatic disease. Response rates were slightly higher—54% overall—and, like the responses to avelumab, have been durable, said Dr. Sharon, who was an investigator for the pembrolizumab trial.

In the avelumab trial, some patients responded even if their tumors didn’t overexpress PD-L1 or were not positive for the Merkel cell polyomavirus. A similar phenomenon was seen in patients with virus-negative tumors in the pembrolizumab trial.

With the combined results from the two trials, the use of immune checkpoint inhibitors in patients with Merkel cell carcinoma is “something that looks like it might be the standard of care within the next couple of years,” said Dr. Sharon.

Avelumab is not yet approved by the FDA for the treatment of any cancer, though the agency has granted it fast-track designation and orphan drug designation based on the results of this trial. Pembrolizumab is approved for the treatment of several cancer types, and an ongoing trial for Merkel cell carcinoma is currently enrolling patients with metastatic disease that has returned after prior treatment.

More research is needed to better understand how to select patients for immunotherapy and how to improve the number of people who respond, including testing immunotherapy drugs in combination with other treatments, Dr. Kaufman said.

“But we now have two new possible immunotherapies that seem to not only get responses in some patients, but the responses seem to be quick and quite durable,” he continued. “I think that really brings new hope for patients with this disease.”