Avelumab Promising in Metastatic Merkel Cell Carcinoma, a Disease With No Standard Treatment

The experimental immunotherapy avelumab demonstrated durable responses and promising early survival data for patients with pretreated metastatic Merkel cell carcinoma.

The experimental immunotherapy avelumab demonstrated durable responses and promising early survival data for patients with pretreated metastatic Merkel cell carcinoma, according to phase 2 findings from the JAVELIN Merkel 200 trial presented during the 2016 annual meeting of the American Society of Clinical Oncology (ASCO), a gathering of 30,000 oncology professionals in Chicago.

Merkel cell carcinoma is a rare and aggressive skin cancer that is most prevalent in older people. Avelumab is a PD-1 inhibitor, which works by removing checks and balances that prevent the body’s immune system from going into overdrive; this frees up the immune system to recognize and fight cancer.

In the open-label trial, the objective response rate (ORR) with avelumab was 31.8 percent, which included a 9.1 percent complete response rate. Median progression-free survival (PFS) with avelumab was 2.7 months. Median overall survival (OS) was 11.3 months and the six-month OS rate was 69 percent.

Based on these data, Merck KGaA and Pfizer, the companies co-developing the PD-L1 inhibitor, plan to submit an application to the U.S. Food and Drug Administration for regulatory approval. Prior to the release of the data, avelumab had received a breakthrough therapy designation from the FDA as a potential treatment for patients with Merkel cell carcinoma.

"Clinical results support the use of avelumab as a new therapeutic option for advanced or metastatic Merkel cell carcinoma patients," said lead investigator Howard L. Kaufman, of Rutgers Cancer Institute. "This has the potential to change clinical practice in an aggressive malignancy without a current standard of care."

In the trial, 88 previously treated patients at a median age of 72.5 years received avelumab at 10 mg/kg every two weeks. Patients had received at least one prior therapy (59.1 percent), with 11.4 percent having had three or more prior systemic treatments. Most patients in the study were male (73.9 percent), and their ECOG performance status was 0 (55.7 percent) and 1 (44.3 percent), meaning that their ability to complete daily activities had not been compromised by their disease.

The most common site of primary tumor was the skin (76.1 percent), and all patients had metastatic involvement at the time of study entry. Visceral disease was present for 53.4 percent of patients. Overall, 65.9 percent of patients had tumor tissue that tested positive for the protein PD-L1, which can be associated with a better response to PD-1 immunotherapy, and 52.3 percent were positive for the Merkel cell polyomavirus (MCPyV), which is thought to play a role in causing the cancer. Eight percent of patients were negative for both PD-L1 and MCPyV, and 40.9 percent were positive for both markers.

In addition to the ORR that was logged in the study, 10.2 percent of patients were found to have stable disease and 20.5 percent were not evaluable for response. At the March 2016 data cutoff, the median duration of response had not yet been reached. Ninety-two percent of patients responded for six months or more, and the six-month durable response rate was 29.1 percent.

“To see a tumor response in almost a third of patients in this trial, and for the majority to keep responding after six months, represents a potential breakthrough for this challenging disease,” Kaufman said in a press release. “Currently, the only treatment option available for advanced stages of this aggressive type of skin cancer is chemotherapy, where the response rates are not adequate or durable.”

The ORR in patients with visceral metastases was 34 percent. Those with low disease burden at baseline experienced a greater response with avelumab. In patients in the lowest quartile for disease burden, the ORR was 42.9 percent. Those treated with just one prior therapy had an ORR of 40.4 percent versus 19.4 percent in those treated with two or more prior therapies.

The ORR was 34.5 percent in the PD-L1-positive arm and 18.8 percent in the PD-L1-negative group. The response rate in those who were not evaluable for PD-L1 status was 35.7 percent. In patients who were MCPyV-positive, the ORR was 26.1 percent. In the MCPyV-negative arm, ORR was 35.5 percent, and in those not evaluable for the virus, the ORR was 45.5 percent. Patients who were positive for both markers had an ORR of 30.6 percent, and those negative for both markers had an ORR of 28.6 percent.

"Avelumab showed durable antitumor activity in patients with chemotherapy-refractory metastatic Merkel cell carcinoma. The response was rapid and sustained," said Kaufman. "Efficacy was seen in patients with PD-L1-positive and -negative tumors and those with MCPyV-positive and -negative tumors."

Treatment-related side effects of any severity were experienced by 70.5 percent of patients in the study. The most common side effects, which were mostly mild or moderate, were fatigue (23.9 percent), infusion-related reaction (17 percent), diarrhea (9.1 percent), nausea (9.1 percent), weakness (8 percent), rash (6.8 percent), decreased appetite (5.7 percent), and maculopapular rash (5.7 percent).

Serious side effects were experienced by 4.5 percent of patients and were mostly laboratory abnormalities, such as a low level of lymphocytes (a type of white blood cells); blood CPK increase, potentially indicating injury or stress to the muscles, heart or brain; transaminase increase, which can indicate liver problems; and blood cholesterol increase. There were no severe side effects or deaths related to avelumab. Two patients discontinued treatment due to side effects.

"Avelumab was well-tolerated in this second-line-or-greater Merkel cell carcinoma population," said Kaufman. "Most treatment-related (side effects) were low-grade and there were no grade 4 (severe) treatment-related (side effects) or fatal outcomes."

In addition to Merkel cell carcinoma, avelumab is being explored across a variety of other types of cancer that have shown susceptibility to PD-L1 inhibition. Altogether, the clinical development program for avelumab now contains more than 2,200 patients.