CheckMate-067 details the varying risk of toxicities between monotherapy and dual regimens. In this study, close to 40% of patients in the combination arm discontinued compared with only 12% to 16% of patients receiving monotherapy. Most of these patients discontinued therapy during the induction phase.

These patients did not, however, have worse outcomes.10 The median PFS was similar between patients who discontinued therapy secondary to adverse events (8.4 months) compared with those who continued treatment (10.8 months). This finding may support the notion that a more severe reaction to dual therapy may signify a significant immune-mediated response to the underlying melanoma.

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The optimal time to resume nivolumab or ipilimumab after significant adverse events following both single and dual therapy is, for now, undetermined. Management, furthermore, depends on the type and grade of toxicity. In general, patients with grade 1 toxicity can continue treatment, while those with grade 2 to 4 events should have their dose withheld. Patients with grade 2 toxicities can potentially be managed with steroids and reinitiate treatment after about 1 month. Patients who develop grade 4 toxicities should have their immunotherapy permanently withheld.

The management of toxicities and re-initiation of medication should, however, be made on a case by case basis, and must take the patient’s entire clinical presentation into account.11 Additional studies are needed to develop evidence-based algorithms for managing toxicities associated with these agents.


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  2. Snyder A, Makarov V, Merghoub T, et al. Genetic basis for clinical response to CTLA-4 blockade in melanoma. N Engl J Med. 2014;371(23):2189-99.
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  5. Schachter J, Ribas A, Long GV, et al. Pembrolizumab versus ipilimumab for advanced melanoma: final overall survival results of a multicentre, randomised, open-label phase 3 study (KEYNOTE-006). Lancet. 2017;390(10105):1853-62.
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  7. Opdivo prescribing information. Bristol-Myers Squibb website. Updated January 2018. Accessed January 2018.
  8. Keytruda prescribing information. Merck & Co website. Updated November 2017. Accessed January 2018.
  9. Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med. 2015;373(1):23-34.
  10. Schadendorf D, Wolchok JD, Hodi FS, et al. Efficacy and safety outcomes in patients with advanced melanoma who discontinued treatment with nivolumab and ipilimumab because of adverse events: a pooled analysis of randomized phase II and III trials. J Clin Oncol. 2017;35(34):3807-14.
  11. Immune mediated adverse reactions management guide. Opdivo website. Accessed February 2018.