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Avelumab yields durable response at 1 year for advanced Merkel cell carcinoma
Avelumab conferred longer durable responses among patients with advanced chemotherapy-refractory Merkel cell carcinoma, according to updated results from a prospective study presented at the American Association for Cancer Research Annual Meeting.
“Avelumab monotherapy showed durable antitumor activity and fairly good activity overall,” Howard L. Kaufman, MD, FACS, surgical oncologist at Rutgers Cancer Institute of New Jersey, said during a press conference. “It is now approved by the FDA as a therapeutic option and includes patients 12 years and older for first-line and second-line therapy.”
Kaufman and colleagues conducted a multicenter phase 2 study of 88 patients (median age, 72.5 years) with stage IV Merkel cell carcinoma from 35 hospitals and cancer centers in North America, Europe, Asia and Australia. All patients had failed at least one round of prior chemotherapy.
Patients received 10 mg/kg avelumab (Bavencio, Pfizer) via IV every 2 weeks until disease progression, toxicity or other cause for withdrawal.
During 6 months of follow-up, the researchers observed durable responses to treatment.
Kaufman presented updated efficacy data with more than 1 year follow-up from the same cohort of patients.
As of Sept. 3, 2016, median follow-up was 16.4 months (range, 12-25.3), and 19 patients (22%) were still receiving treatment.
Causes for treatment discontinuation included disease progression (50%), mortality (8%), adverse events (8%) or withdrawal (5%).
From 6 months to 1 year, researchers observed increases in the overall response rate (31.8% to 33%) and complete response rate (9.1% to 11.4%). Partial responses occurred in 19 patients (21.6%) at 1 year follow-up. These data reflected one new complete response and one improvement from partial to complete response since 6-month follow-up.
The 6-month durable response rate was 30.6% (95% CI, 20.9-40.3). The median duration of response had not yet been reached (range, 2.8-23.3+ months; 95% CI, 18-unestimatable) because 21 responses were ongoing at the time of analysis, Kaufman said.
“While 92% of patients were in response at 6 months or more, 74% of this population remained in response at 1 year after treatment,” he said.
Patients who had one prior therapy yielded a better response rate compared with patients who received two or more prior therapies (44% vs. 22%). In addition, the higher the disease burden, the more likely a patient was to have a poor response to treatment, Kaufman said.
The estimated 1-year PFS rate was 30% (95% CI, 21-41) and 1-year OS was 52% (95% CI, 41-62), which “is quite remarkable for this disease,” Kaufman said.
The treatment was fairly well tolerated; the most common adverse events were fatigue and infusion-related reactions.
“Among these patients, the majority of responses were durable beyond 1 year and two new complete responses were reported,” Kaufman said. “It is great to watch some of these patients doing so well for so long now.” – by Melinda Stevens
Reference:
Kaufman HL, et al. Abstract CT079. Presented at: AACR Annual Meeting; April 1-5, 2017; Washington, D.C.
Disclosures: The study was funded by EMD Serono Inc. Kaufman reports advisory roles with Amgen, Celldex, Compass Therapeutics, EMB Serono Inc., Merck, Prometheus and Turnstone Biologics.
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This is an extremely important study, which is highlighted by the FDA approval. Merkel cell carcinoma is a very rare type of skin cancer that affects approximately 1,500 to 2,000 people per year in the United States. It is an extremely aggressive cancer where, historically, life expectancy is less than 1 year for metastatic Merkel cell carcinoma.
Initially, its very responsive to chemotherapy, but benefit is transient and, ultimately, people die of this cancer. There is an association with a polyoma virus, suggesting that the immune system can be important to try and control the disease if modulated appropriately. In Merkel cell carcinomas that do not have a viral association, exposure to UV radiation may cause local immunosuppression. Those Merkel cell carcinomas can have a very high mutation burden that can, therefore, lead to the concept of many new antigens that could be presented to the immune system.
Also, the risk for developing this type of cancer is increased when one is immunocompromised. Many Merkel cell carcinomas express PD-L1, which suggests that modulating the immune system by blocking PD-L1 could be beneficial. Avelumab (Bavencio, Pfizer) binds to PD-L1, inhibiting its activity.
We do not have any treatment other than the transient benefits of chemotherapy, but everything I mention is a strong rationale to look at PD-1 or PD-L1 inhibitors. PD-L1 is on the tumor, whereas PD-1 is on the immune cell. They bind each other, and we want to break this interaction and keep the immune system active. Avelumab binds to PD-L1, which leads to dramatic response in a meaningful subset of patients with Merkel cell carcinoma, and it is revolutionizing how we treat the disease.
It is important to know that, in parallel, another study by Cancer Immunotherapy Network (CITN) is being conducted the CITN09 study and is treating patients with advanced Merkel cell carcinoma with pembrolizumab (Keytruda, Merck), a PD-1 inhibitor, which is approved in several other cancers. It has a response rate over 50%. The data were published last year in The New England Journal of Medicine, and I personally treated patients on that study and have seen dramatic durable responses. Combining the two trials, the avelumab data and pembrolizumab data were similar, showing the importance of the immune checkpoints of PD-1 and PD-L1 in many Merkel cell carcinomas. This is really changing the standard of care.
This blocking of the pathway would be the most efficacious and the highest priority of treatment to use in these patients, offering them significant hope.
This study is one that shows, in a broad sense, the real dramatic evolution of how we approach cancer and the concept of immuno-oncology. It springs for us to move forward looking at other immune combinations and, ultimately, move in the direction of more personalized immunotherapy for patients. This is evidence we are moving in the right direction.
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The study presented represents longer follow-up of the 88 patients enrolled on the study. The results confirm that the PD-L1 antibody, avelumab (Bavencio, Pfizer), has really important efficacy in patients with Merkel cell cancer, a difficult-to-treat cancer.
Based upon these results, the FDA recently approved avelumab for the treatment of metastatic Merkel cell cancer. What is important to know is that, in the clinical trial, patients had to have failed prior chemotherapy to enroll. However, the FDA approval is for patients who have had prior chemotherapy or not, which is important as immunotherapy and has fewer side effects compared with the chemotherapy used to treat Merkel cell cancer.
Immunotherapy with agents such as avelumab is an important new treatment option for these patients. We also have information that the PD-1 antibodies pembrolizumab (Keytruda, Merck) is active against Merkel cell cancer.
There is a growing incidence of this cancer, which tends to affect older patients. This new approach is active against Merkel cell and much better tolerated then chemotherapy. In addition, the responses were quite durable. This represent an important step forward in managing patients with Merkel cell and is practice changing.