PracticeUpdate: In your view, which development that occurred in 2013 in melanoma research could have the most significant impact on clinical practice?

Dr. Kirshner: The reporting of the results of additional clinical trials of antibodies against the programmed death 1 (PD-1) receptor and ligand (PD-L1).

The most striking of these studies was presented at ASCO 2013 and promptly published by Wolchok et al in The New England Journal of Medicine in July.¹ Metastatic melanoma patients treated with the combination of ipilimumab and nivolumab had a disease control rate of over 65%! The majority of responses were major and are predicted to be durable.

Additional reports of T-cell checkpoint inhibition presented at ASCO add to the growing body of evidence that inhibitors of CTLA-4, PD-1, and PD-L1 are effective treatments for melanoma, with a number of long-term survivors. Patients progressing on ipilimumab can respond to nivolumab or even to retreatment with the same drug and schedule.

PracticeUpdate: What specific changes have you observed or do you foresee as a result of this development?

Dr. Kirshner: I expect FDA approval of nivolumab in the next year and the approval of even more checkpoint inhibitors in the near future.

PracticeUpdate: Would you put this development into historical perspective for the practicing physician?

Dr. Kirshner: Not too long ago, treatment options for metastatic melanoma were very limited. Responses to chemotherapy are poor, in general, and toxicity can be substantial. Immunotherapy (interferon and IL-2) is toxic, for the most part, but occasional durable responses were seen, usually in patients with more limited disease.

T-cell checkpoint inhibitors have a different mode of action than prior treatments (blocking inhibition activates T cells for more effective immune destruction of the metastases). These are the most active treatments for metastatic melanoma to date, and toxicities are manageable.

PracticeUpdate: Would you sum up in a single sentence why you chose this development as the top story of the past year?

Dr. Kirshner: The development of new T-cell checkpoint inhibitors (specifically anti-PD-1 and anti-PD-L1) not only adds to the armamentarium of treatments for advanced melanoma, but there are reasons to believe that these drugs will be active in a wide range of malignancies that would respond to immunotherapy.

Reference

1. Wolchok JD, Kluger H, Callahan MK, et al. Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med. 2013;369(2):122-133.