“In the combination arm, the majority are off all treatment, and the median time off treatment was 18 months. This, along with the information about response in those with or without a BRAF mutation, is good evidence for us to use in the clinic to support why we might or might not use one approach over the other. It is by far the most mature data set for combination therapy,” emphasized Dr Shoushtari.

Previous work pooling phase 1 to phase 3 studies using the combination found similar results,2 and compared  those who stopped therapy early due to toxicity and those who did not. This work has found that the progression-free survival (PFS) and overall survival (OS) were similar in both groups after 1 year. The new research shows similar results, but with a longer follow-up time.

“The combined use of nivolumab plus ipilimumab is effective yet toxic, so as a field we continue to work on balancing these [aspects] for patients. This continues to give us some reassurance that you can stop treatment for severe side effects and still get potential long-term benefit,” said Dr Shoushtari.

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Treatment of metastatic melanoma is undoubtedly a modern-day success story, with approximately 50% of patients now surviving for 5 years or more after diagnosis, up from approximately 10% just a decade ago. But immune checkpoint inhibition is far from the only strategy that has helped boost these numbers. Viral therapies such as T-VEC3 and newer bespoke neoantigen approaches4 are also being developed, with the hope that survival rates will increase even further.

So, what role will immune checkpoint inhibitors have going forward?

“I look forward to seeing Phase 3 randomized data for other approaches, such as combining BRAF- plus MEK-targeted therapy with PD-1 blockade and combining PD-1 blockade with T-VEC,” said Dr Shoushtari.

The big question that remains, however, is: Why do some patients initially respond to this combination therapy and then stop responding, and some never respond at all? Even with nivolumab and ipilimumab combination therapy for advanced melanoma, metastases at different anatomical sites seem to have varied sensitivity to the drugs.5 Predicting this sensitivity or resistance may be the next big step up in survival from advanced melanoma treated with immunotherapies.

“Even for those ones where anti–PD-1 is approved, only a small proportion of patients respond, indicating that anti–PD-1 checkpoint is only 1 of the mechanisms that a tumor uses to evade the immune system. The ultimate goal is when we have a patient in the clinic, we can use screening tests to find out what their mechanisms of immune resistance are,” said Dr Hu-Lieskovan. “But we aren’t there yet.”


  1. Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Five-year survival with combined nivolumab and ipilimumab in advanced melanoma. N Engl J Med. 2019;381(16):1535-1546.
  2. Schadendorf D, Hodi FS, Robert C, et al. Pooled analysis of long-term survival data from phase II and phase III trials of ipilimumab in unresectable or metastatic melanoma. J Clin Oncol. 2015;33(17):1889-1894.
  3. Forster V. TVEC for advanced melanoma yields stunning results in 3-center study. Cancer Therapy Advisor. Published March 20, 2019. Accessed November 6, 2019.
  4. Forster V. Personalized cancer vaccine NEO-PV-01 shows promise in early trials in advanced melanoma. Cancer Therapy Advisor. Posted May 23, 2019. Accessed November 6, 2019.
  5. Pires da Silva I, Lo S, Quek C, et al. Site‐specific response patterns, pseudoprogression, and acquired resistance in patients with melanoma treated with ipilimumab combined with anti–PD‐1 therapy [published online October 4, 2019]. Cancer. doi: 10.1200/JCO.2014.56.2736