While difficult to assess and report in trials, the approach to patient management may affect long-term survival rates in a small subset of patients. For example, patients developing severe toxicity before completion of the planned 4 cycles of the ipilimumab/nivolumab combination are not re-challenged with the combination. Although a substantial proportion of these patients may develop durable responses without additional therapy, nivolumab alone can be administered with caution after resolution of toxicity, and in a subset of patients may provide additional clinical benefit.

Disease progression in patients during or after therapy completion may be limited to a few sites only; radiation or surgery for limited progression may produce long-term recurrence-free survival. Finally, a subset of patients developing disease progression after therapy discontinuation can respond again to re-induction with the combination — possibly receiving additional survival benefit.

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Cumulative safety data from multiple trials of the ipilimumab/nivolumab combination and nivolumab alone in metastatic melanoma demonstrate substantially higher rates of grade 3 to 4 adverse events for the combination (in the range of 55% to 60%).4,5 While most severe adverse events can be managed with corticosteroids and, in some cases, secondary immune suppressive agents, a subset of patients will develop prolonged morbidity before resolution of toxicity, and in rare cases, deaths have been observed. 

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The potential for improved survival with the combination must therefore be weighed against the potential for increased toxicity when choosing therapy for individual patients. Although not definitive, the post-hoc survival analyses in subgroups could be used to inform the risk-benefit calculation when making individual treatment decisions.

It is unknown if administration of ipilimumab/nivolumab to patients with progression or suboptimal response to anti-PD-1 alone would produce equivalent overall survival compared with initial concurrent administration. Data from trials in other malignancies suggest that the toxicity of the combination may be reduced by altering the dose ratio of ipilimumab and nivolumab.

To test this question, a randomized trial (ClinicalTrials.gov Identifier: NCT02714218) comparing the approved dose and schedule to a regimen employing a higher dose of nivolumab with a lower dose of ipilimumab was initiated. If equal efficacy is achieved with lower toxicity, the addition of other promising agents to the ipilimumab/nivolumab combination may be possible to further improve overall survival.


  1. Wolchok JD, Chiarion-Sileni V, Gonzalez R, et al. Overall survival with combined nivolumab and ipilimumab in advanced melanoma. N Engl J Med. 2017;377(14):1345-56. doi: 10.1056/NEJMoa1709684
  2. Callahan MK, Kluger H, Postow MA, et al. Nivolumab plus ipilimumab in patients with advanced melanoma: updated survival, response, and safety data in a phase I dose-escalation study. J Clin Oncol. 2017 Oct 17. doi: 10.1200/JCO.2017.72.2850 [Epub ahead of print]
  3. Schadendorf D, Long GV, Stroiakovski D, et al. Three-year pooled analysis of factors associated with clinical outcomes across dabrafenib and trametinib combination therapy phase 3 randomised trials. Eur J Cancer. 2017;82:45-55. doi: 10.1016/j.ejca.2017.05.033
  4. Weber JS, Hodi FS, Wolchok JD, et al. Safety profile of nivolumab monotherapy: a pooled analysis of patients with advanced melanoma. J Clin Oncol. 2017;35(7):785-92. doi: 10.1200/JCO.2015.66.1389
  5. Sznol M, Ferrucci PF, Hogg D, et al. Pooled analysis safety profile of nivolumab and ipilimumab combination therapy in patients with advanced melanoma. J Clin Oncol. 2017 Sep 15. doi: 10.1200/JCO.2016.72.1167 [Epub ahead of print]