According to the World Health Organization, there are approximately 132 000 melanoma skin cancers diagnosed worldwide every year. Currently, the standard FDA approved treatment for advanced melanoma is a cytotoxic T-lymphocyte antigen blocker called ipilimumab. A second treatment, vemurafenib, also has FDA approval, despite these available therapies, the survival rate for advanced stage melanoma remains low. For patients with stage IV melanoma, the 5-year survival rate is less than 20%, strongly indicating that more treatment options are needed. Nivolumab, an antibody against the programmed death-1 (PD-1) protein, has had promising results in clinical trials for the treatment for advanced melanoma.
In melanomas, (and other tumors) levels of the molecule programmed death ligand 1 (PD-L1) are elevated. PD-L1 binds to the molecule PD-1, that is present on T-cells, resulting in a reduction of anti-tumor immunity. Blocking PD-1, thereby inhibiting the interaction between PD-L1 and PD-1, increases T-cell response and resultant anti-tumor activity.
Nivolumab, a human monoclonal antibody against the PD-1 protein, is currently in clinical trials worldwide. It works by blocking the interaction between PD-L1 and PD-1 and a recent phase I trial of nivolumab has shown efficacy in patients with advanced melanoma. In the trial, 90 patients were treated with nivolumab every 2 weeks, for 24 weeks, at varying doses. All doses of nivolumab were well tolerated, and the most common adverse events observed were fatigue and a reaction at the injection site. Promising results have also been seen when treating patients with both nivolumab and ipilimumab together. The combination had an acceptable safety profile, while inducing a tumor regression that was greater than that seen with monotherapy. Another study found that patients who were no longer responsive to ipilimumab responded to nivolumab and, conversely, patients who were no longer responsive to nivolumab responded to ipilimumab. The results of this study provide greater scope for treatment in refractory patients, supporting a combination, or even a sequencing schedule, of therapy in patients with advanced melanoma.
Phase I, phase II, and phase III clinical trials with nivolumab are underway worldwide in over 163 study locations. The studies will be assessing the safety, efficacy, and tolerability of nivolumab in patients with advanced melanoma. Additionally, there are clinical trials scheduled in which patients will be treated either with nivolumab in combination with other therapies, or in a sequential treatment strategy. These studies will determine the most effective strategies for use of nivolumab in the treatment of advanced melanoma.
WHO Skin Cancers Fact Sheet. Available from: http://www.who.int/uv/faq/skincancer/en/index1.html Last Accessed Feb 6, 2014.
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Wolchok JD, Kluger H, Callahan MK, Postow MA, Rizvi NA, Lesokhin AM, Segal NH, Ariyan CE, Gordon RA, Reed K, Burke MM, Caldwell A, Kronenberg SA, Agunwamba BU, Zhang X, Lowy I, Inzunza HD, Feely W, Horak CE, Hong Q, Korman AJ, Wigginton JM, Gupta A, Sznol M. “Nivolumab plus ipilimumab in advanced melanoma.” N Engl J Med. 2013 Jul 11;369(2):122-33.
Clinicaltrials.gov “Dose-escalation Study of Combination BMS-936558 (MDX-1106) and Ipilimumab in Subjects With Unresectable Stage III or Stage IV Malignant Melanoma” Available from: http://www.clinicaltrials.gov/ct2/show/NCT01024231?term=nivolumab+melanoma&rank=1 Last Accessed: March 5th, 2014.
Clinicaltrials.gov “Phase 3 Study of Nivolumab or Nivolumab Plus Ipilimumab Versus Ipilimumab Alone in Previously Untreated Advanced Melanoma (CheckMate 067)” Available from: http://www.clinicaltrials.gov/ct2/show/study/NCT01844505?term=nivolumab+melanoma&rank=4&show_locs=Y#locn Last Accessed: March 5th, 2014.
Clinicaltrials.gov “Multiple Class I Peptides & Montanide ISA 51 VG w Escalating Doses of Anti-PD-1 ab BMS936558” Available from: http://www.clinicaltrials.gov/ct2/show/NCT01176461?term=nivolumab+melanoma&rank=6 Last Accessed: March 5th, 2014.
Clinicaltrials.gov “Study of Nivolumab Given Sequentially With Ipilimumab in Subjects With Advanced or Metastatic Melanoma (CheckMate 064)” Available from: http://www.clinicaltrials.gov/ct2/show/NCT01783938?term=nivolumab+melanoma&rank=8 Last Accessed: March 5th, 2014.
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Written by Deborah Tallarigo, PhD