Thinking Critically About Classifying Adverse Events: Incidence of Pancreatitis in Patients Treated With Nivolumab + Ipilimumab

J Natl Cancer Inst. 2016 Dec 31;109(4):djw260. doi: 10.1093/jnci/djw260. Print 2017 Apr.


The Common Terminology Criteria for Adverse Events (CTCAE) were developed to document the adverse effects of chemotherapy but are now also used to document immune-related adverse events (irAE). Characterization of irAE by the CTCAE has implications for determining dose-limiting toxicity (DLT) and, consequently, the recommended phase II dose (RP2D) of investigational agents. In the phase I trial of nivolumab + ipilimumab, an asymptomatic increase in lipase was the primary DLT that informed the RP2D. We performed a retrospective study of 119 patients with melanoma who were treated at Memorial Sloan Kettering Cancer Center with the combination of nivolumab + ipilimumab to investigate the relationship between asymptomatic grade 3 or higher increases in amylase and/or lipase and pancreatitis, a known irAE. Of the 119 patients, there were only two cases of pancreatitis, representing 20% of patients with grade 3 or higher amylase, 6.3% of patients with grade 3 or higher lipase, and 20% of patients with grade 3 or higher elevations of both enzymes. The application of the CTCAE, especially in grading independent lab values, should be considered carefully in clinical trials of novel immunotherapeutic agents.

MeSH terms

  • Amylases / blood*
  • Antibodies, Monoclonal / administration & dosage
  • Antineoplastic Combined Chemotherapy Protocols / adverse effects*
  • Clinical Trials, Phase I as Topic
  • Clinical Trials, Phase II as Topic
  • Female
  • Humans
  • Ipilimumab
  • Lipase / blood*
  • Male
  • Melanoma / drug therapy*
  • Nivolumab
  • Pancreatitis / blood*
  • Pancreatitis / chemically induced*
  • Retrospective Studies


  • Antibodies, Monoclonal
  • Ipilimumab
  • Nivolumab
  • Lipase
  • Amylases