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Adobe Flash Player is required to view this feature. If you are using an operating system that does not support Flash, we are working to bring you alternative formats. Original Article Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma James Larkin, M. Download Kernel on this page. D., Ph.D., Vanna Chiarion-Sileni, M.D., Rene Gonzalez, M.D., Jean Jacques Grob, M.D., C. Lance Cowey, M.D., Christopher D. Lao, M.D., M.P.H., Dirk Schadendorf, M.D., Reinhard Dummer, M.D., Michael Smylie, M.D., Piotr Rutkowski, M.D., Ph.D., Pier F.

Ferrucci, M.D., Andrew Hill, M.D., John Wagstaff, M.D., Matteo S. Carlino, M.D., John B. Haanen, M.D., Michele Maio, M.D., Ph.D., Ivan Marquez-Rodas, M.D., Ph.D., Grant A. McArthur, M.D., Paolo A. Ascierto, M.D., Georgina V. Long, M.D., Margaret K. Callahan, M.D., Ph.D., Michael A.

Postow, M.D., Kenneth Grossmann, M.D., Mario Sznol, M.D., Brigitte Dreno, M.D., Lars Bastholt, M.D., Arvin Yang, M.D., Ph.D., Linda M. Rollin, Ph.D., Christine Horak, Ph.D., F. Stephen Hodi, M.D., and Jedd D. Wolchok, M.D., Ph.D. N Engl J Med 2015; 373:23-34 DOI: 10.1056/NEJMoa1504030. Results The median progression-free survival was 11.5 months (95% confidence interval [CI], 8.9 to 16.7) with nivolumab plus ipilimumab, as compared with 2.9 months (95% CI, 2.8 to 3.4) with ipilimumab (hazard ratio for death or disease progression, 0.42; 99.5% CI, 0.31 to 0.57; P. Figure 1 Progression-free Survival.

Panel A shows the Kaplan–Meier curves for progression-free survival in the intention-to-treat population. Patients were followed for a minimum of 9 months.

The median progression-free survival was 6.9 months (95% CI, 4.3 to 9.5) in the nivolumab group, 11.5 months (95% CI, 8.9 to 16.7) in the nivolumab-plus-ipilimumab group, and 2.9 months (95% CI, 2.8 to 3.4) in the ipilimumab group. Significantly longer progression-free survival was observed in the nivolumab-plus-ipilimumab group than in the ipilimumab group (hazard ratio for death or disease progression, 0.42; 99.5% CI, 0.31 to 0.57; P. Figure 2 Tumor-Burden Change in Target Lesions.

The waterfall plots show the maximum change from baseline in the sum of the reference diameters of the target lesion in patients receiving nivolumab (Panel A), nivolumab plus ipilimumab (Panel B), or ipilimumab (Panel C). Data are shown for all the patients who had target lesions evaluated at baseline and who underwent at least one tumor assessment during treatment.

The percentage increase was truncated at 100% (rectangles). Asterisks indicate patients who had a response to treatment according to the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1. The horizontal dashed lines indicate a 30% reduction in the tumor burden in the target lesion, and the vertical dashed lines indicate the inflection point for the nivolumab-plus-ipilimumab group. The change in tumor burden was defined as the percentage decrease in the sum of the reference diameters of the target lesion from baseline to nadir, observed up until the date of progression, as assessed by the investigator per RECIST, version 1.1, the date of subsequent anticancer therapy (including tumor-directed radiotherapy and tumor-directed surgery), or death, whichever occurred first. Considerable progress in the treatment of metastatic melanoma has been made in the past 5 years, with the approval of immune checkpoint–blocking antibodies and, in parallel, agents targeting aberrant signaling in the 40 to 50% of melanomas with BRAF mutations.

Ipilimumab, an anti–cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) antibody, acts to up-regulate antitumor immunity and was the first agent to be associated with an improvement in overall survival in a phase 3 study involving patients with metastatic melanoma. Ipilimumab was associated with responses in 10% and 15% of patients; approximately 20% of treated patients had long-term survival. Two anti–programmed death 1 (PD-1) antibodies, nivolumab and pembrolizumab, were approved by the Food and Drug Administration in 2014 for the treatment of metastatic melanoma after progression during ipilimumab treatment and, in patients with BRAF-mutated melanoma, after progression during treatment with a BRAF inhibitor.