In an uncontrolled phase 1 trial, patients with advanced melanoma treated with nivolumab had favorable rates of overall survival and responses that persisted for weeks to months after drug discontinuation, with low rates of serious adverse events (AEs).1
Nivolumab is an immunomodulator that targets the programmed cell death 1 (PD-1) pathway, an immune checkpoint that regulates the autoimmune action of activated T cells so as to protect normal tissue. Tumor cells can co-opt PD-1, using it to evade T-cell attack. Blocking PD-1 reveals tumor cells to the immune system, allowing nivolumab to target them more effectively.
The study included 107 patients with advanced melanoma, 62% of whom had received at least two prior systemic treatments.
Median overall survival in the study group was 16.8 months and 1- and 2-year survival rates were 62% and 43%, respectively.
Overall survival was considerably better than the median progression-free survival (PFS) of 3.7 months, suggesting that early disease progression in some patients treated with nivolumab can evolve to stable disease or regression, according to the study authors. PFS was 36% at 1 year and 27% at 2 years.
Among the 33 patients with objective tumor regression, estimated median response duration was 2 years.
Benefits Seen Even After Discontinuation
The researchers were impressed by the persistence of response after discontinuation of nivolumab. Among the 17 patients who withdrew from therapy for reasons other than disease progression, 12 (71%) maintained responses for 16 to 56 weeks after withdrawal.
Persistent tumor regression and stable disease in a substantial proportion of patients “suggests that PD-1 blockade may reset the immune equilibrium between tumor and host,” the study authors wrote. The findings “are consistent with a mechanism by which an effective tumor-selective immune memory response may have been established in some patients, similar to immune memory against specific infectious organisms after antigen exposure.”
Nivolumab was generally well tolerated. Treatment-related AEs were reported in 54% of patients, most commonly skin disorders (36%), gastrointestinal events (18%), and endocrinopathies (5%). The most common AE was fatigue (32%). There were no treatment-related deaths. Most AEs occurred during the first 6 months of treatment and there were no signs of cumulative toxicity.
In an editorial accompanying the report, Geraldine O’Sullivan Coyne, MD, Ravi A. Madan, MD, and James L. Gulley, MD, of the National Cancer Institute suggested that nivolumab may eventually be found to be as effective against metastatic melanoma as ipilimumab, but with a more favorable safety profile.2
“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,” they 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.”
- Topalian SL, Sznol M, McDermott DF, et al. Survival, durable tumor remission, and long-term safety in patients with advanced melanoma receiving nivolumab. J Clin Oncol. 2014;32(10):1020-1031.
- Coyne GO, Madan RA, Gulley JL. Nivolumab: promising survival signal coupled with limited toxicity raises expectations. J Clin Oncol. 2014;32(10):986-988.