Nivolumab Delivers Durable Remissions With Low Toxicity in Advanced Melanoma

F. Stephen Hodi, MD

Nivolumab, a PD-1-specific antibody, has been shown to produce long-term remissions with limited toxicity in patients with advanced melanoma, according to results from one of the longest follow ups to examine the drug.

In the phase I analysis that was recently published in the Journal of Clinical Oncology, the objective response rate (ORR) was 31% for a median duration of two years in patients with advanced melanoma. The median overall survival (OS) in nivolumab-treated patients was 16.8 months, and 1- and 2-year survival rates were 62% and 43%, respectively.

“These are striking results for patients with metastatic melanoma,” the study’s senior author F. Stephen Hodi, MD, director of the Melanoma Treatment Center and Center for Immuno-Oncology at Dana-Farber, said in a press release. “This study provides the first demonstration of the long-term benefits this treatment approach can produce.”

In the study, representing a maximum follow-up of 4.3 years, patients with previously treated advanced melanoma (n = 107) received intravenous nivolumab in an outpatient setting every 2 weeks for up to 96 weeks. Patients treated with nivolumab experienced a median progression-free survival (PFS) of 3.7 months. PFS rates were 36% and 27% at 1 and 2 years, respectively. In the analysis, the authors pointed out that OS was significantly longer than PFS, and Kaplan-Meier curves for both flattened after 1 year of follow-up.

"The results seen here are remarkable for these patients with treatment-resistant, advanced metastatic melanoma, who had limited life expectancies when they joined the trial," says study lead-author Suzanne Topalian, MD, professor of surgery and oncology, and director of the melanoma program at Johns Hopkins.

Seventeen patients discontinued therapy for reasons other than disease progression of which 12 (71%) maintained responses off-therapy for at least 16 weeks. The side effects of the treatment were consistent with those observed in other studies of the drug. The most common adverse experiences were fatigue (32%), rash (36%), and diarrhea (18%), most of which occurred in the first six months of therapy.

In an extended analysis of 306 patients across various tumor types, the objective response rate and toxicity profiles were similar for patients treated with nivolumab. Moreover, the toxicity profile with nivolumab appears to be inline with the already approved checkpoint inhibitor ipilimumab, Geraldine O’Sullivan Coyne, MD, and colleagues from the National Cancer Institute wrote in an accompanying editorial.

“The continued demonstration of promising clinical outcomes with the use of modern immunotherapy strategies such as nivolumab may allow medical oncologists to have raised expectations for patients with metastatic cancer,” Coyne et al wrote. “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.”

Nivolumab is one of a new generation of drugs that releases the brakes on an immune system attack on cancer. The drug blocks PD-1, a protein on immune system T cells that restrains the cell from leading a charge on the tumor. By interfering with PD-1, nivolumab allows the attack to proceed.

Ongoing randomized clinical trials will further assess the impact of nivolumab therapy on survival in patients with metastatic melanoma. Clinical trials are already under way to assess a combined approach with other immune system-based therapies, such as ipilimumab.

Nivolumab is also being studied as treatment for multiple tumors types, including non-small and small cell lung cancer, renal cell carcinoma, hepatocellular carcinoma, hematologic malignancies, triple-negative breast cancer, gastric cancer, and pancreatic cancer.