Anti-PD-1 Drug Shows Durable Antitumor Response in Metastatic Melanoma

Slide from a 53-year-old woman with metastatic melanoma to multiple subcutaneous sites and retroperitoneum.

The anti-programmed death 1 (PD-1) drug nivolumab may increase overall survival in patients with advanced melanoma with a safe and acceptable long-term safety profile, according to the results of a study published recently in the Journal of Clinical Oncology.

“Nivolumab appears to be generally well-tolerated even with long-term administration, and is effective in a significant proportion of patients with advanced melanoma,” study author Suzanne Topalian, MD, professor of surgery and oncology, and director of the melanoma program at Johns Hopkins, told Cancer Network. “This suggests that nivolumab (and potentially similar drugs) provide a basis for combination treatment regimens with other drugs or treatment modalities, which are predicted to be more effective than monotherapies based on laboratory models.”

Previous research has detailed rates of tumor regression in patients with advanced cancers who were treated with drugs that blocked the PD-1 immunosuppressive pathway including anti-PD-1 and anti-PD-L1 drugs.

“The new report goes beyond response rates to examine what happens to treated patients in the long-term-their survival, the durability of tumor regressions, and the safety profile of prolonged administration of the anti-PD-1 nivolumab,” Topalian said.

The researchers enrolled 107 patients with advanced melanoma between 2008 and 2012. All patients received nivolumab every 2 weeks in 8-week treatment cycles at 0.1 mg/kg, 0.3 mg/kg, 1 mg/kg, 3 mg/kg, or 10 mg/kg for up to 96 weeks.

At 1 year, 62% of patients were alive; at 2 years, 43% were alive. The median overall survival was 16.8 months, which, according to Topalian, “compares very favorably to reports of survival in similar patients treated with other drugs.”

Thirty-one percent of patients had objective tumor regression with median response duration of 2 years. The highest response rate was in 7 of 17 (41%) patients receiving 3 mg/kg, the dose now being tested in phase III trials. Participants given that amount survived an average 20.3 months after treatment initiation.

The researchers pointed out that 17 patients discontinued therapy for reasons other than disease progression. Of these 17 patients, 71% maintained responses off-therapy for at least 16 weeks.

“The persistence of tumor regression even after stopping treatment is unusual for other forms of cancer therapy, and suggests that PD-1 pathway blockade resets the balance between the immune system and cancer in an enduring way,” Topalian said.

In an accompanying editorial, Geraldine O’Sullivan Coyne, MD, Ravi A. Madan, MD, and James L. Gulley, MD, PhD, of the National Cancer Institute, pointed out that these published data represent the longest available looking at patients with melanoma treated with an anti-PD-1 agent, and that these data, and the promising outcomes seen with other modern immunotherapy strategies, “may allow medical oncologists to have raised expectations for patients with metastatic cancer.”

“Current treatment for metastatic solid tumors, apart from rare exceptions such as testicular cancer, remains palliative, but perhaps immune checkpoint inhibitors can be part of a strategy to enhance the number of patients who can enjoy sustained, durable responses,” they wrote. “The data presented by Topalian et al suggest that nivolumab could have clinical benefits similar to those of ipilimumab, but with less toxicity.”

The most commonly reported adverse effects were fatigue (32%), rash (23%), and diarrhea (18%). Twenty-two percent of patients experienced grade 3/4 treatment-related adverse events. Of the immune-related adverse events observed in 54% of patients, the most common were skin disorders (36%), gastrointestinal events (18%), and endocrinopathies (13%). Five percent of patients had grade 3/4 immune-related adverse events.

The researchers also found that toxic side effects from nivolumab did not accumulate with continued drug administration, “which suggests the feasibility of developing combination treatment regimens,” Topalian said.

Nivolumab is now being tested in three larger, phase III trials in melanoma.