Using Combination Therapy

As researchers continue to look for biomarkers to predict which patients with melanoma will benefit most from combination therapy, Dr Sullivan said there are currently a few scenarios where combination makes the most sense.

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First, combination therapy is useful in patients who have disease that is growing rapidly and clinical criteria indicate they may not survive 6 months.

“With these patients I do not want to guess and hope that they are going to benefit from which ever drug I would decide to give first, and then find out 2.5 months later that they are dying and it is too late to give them anything else,” Dr Sullivan said. “They do not have time to get 1 drug for 3 months and then another drug for an additional 3 months.”

Another population that seems to benefit from combination therapy is patients with brain metastases, Dr Sullivan said.

Data presented at the 2017 American Society of Clinical Oncology (ASCO) Annual Meeting by investigators from the University of Texas MD Anderson Cancer Center in Houston, Texas, showed high response rates to combination immunotherapy in patients with metastatic melanoma with brain metastases.3 In CheckMate-204, patients were treated with CTLA-4 inhibitor ipilimumab and PD-1 inhibitor nivolumab and 54% had brain metastases shrinkage, including 16 patients with a complete response.

Considering Adverse Events

One of the drawbacks of widely applying combination immunotherapy is a risk for increased adverse events. In the CheckMate-069 trial, adverse events were higher with combination treatment compared with ipilimumab monotherapy. In CheckMate-067, which compared combination nivolumab plus ipilimumab with ipilimumab alone in treatment-naive patients, the combination modestly improved overall survival compared with monotherapy, but was associated with increased toxicity.4 Grade 3/4 adverse events occured in 68.7% of patients assigned the combination and 36.4% had any grade treatment-related adverse events that led to discontinuation.

A recent phase 1 study examined use of standard-dose pembrolizumab in combination with reduced-dose ipilimumab and showed that the combination was highly active with a tolerable toxicity profile.5 With a minimum follow-up of 17 months, grade 3/4 adverse events occurred in only 45% of patients and only 14% of patients assigned to the combination had treatment-related adverse events that led to discontinuation.

“One of the problems with these drugs is that because of their wide safety threshold we are probably using both drugs vastly in excess of what we really need,” Dr Daud said. “If you look across the board at head and neck cancer, lung cancer, or renal cancer, they get by with a lower dose of ipilimumab. If the role of ipilimumab is not to bring in fresh new T cells, but instead to boost the activity of T cells that are already present, we probably only need a little bit of ipilimumab to avoid driving the autoimmune side effects that are a real problem with these combinations.”

Dr Sullivan agreed that the use of reduced-dose ipilimumab appeared to mute the toxicity signal a bit, but added that because it is only early data, clinicians still do not have randomized data to help them understand whether these combination approaches will be preferable to single-agent therapy for minimizing adverse events.


  1. Postow MA, Chesney J, Pavlick AC, et al. Nivolumuab and ipilimumab versus ipilimumab in untreated melanoma. N Engl J Med. 2015;372:2006-2007. doi: 10.1056/NEJMoa1414428
  2. Loo K, Tsai KK, Mahuron K, et al. Partially exhausted cytotoxic lymphocytes within the tumor microenvironment predict response to mono or combination immunotherapy. JCI Insight. 2017;2(14). [Epub ahead of print] doi: 10.1172/jci.insight.93433
  3. The University of Texas MD Anderson Cancer Center. Two combination therapies shrink melanoma brain metastases in more than half of patients. Published June 4, 2017. Accessed August 23, 2017.
  4. Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med. 2015; 373: -34. doi: 10.1056/NEJMoa1504030
  5. Long GV, Atkinson V, Cebon JS, et al. Standard-dose pembrolizumab in combination with reduced-dose ipilimumab for patients with advanced melanoma (KEYNOTE-029): an open-label, phase 1b trial.  Lancet Oncol. 2017 Jul 17. [Epub ahead of print] doi: 10.1016/S1470-2045(17)30428-X