Pharmacovigilance Assessment of Immune-Mediated Reactions Reported for Checkpoint Inhibitor Cancer Immunotherapies

Ipilimumab, pembrolizumab, and nivolumab are checkpoint inhibitors (CPI) that activate T cell-mediated immune response. CPI can provide durable benefits to some cancer patients with melanoma, renal cell cancer, non-small cell lung cancer, and a growing list of other cancers. However, CPI treatment is also associated with adverse immune-mediated reactions (IMR) that can be life-threatening. This pharmacovigilance analysis aims to characterize IMR signals in relation to CPI treatment.

Retrospective pharmacovigilance disproportionality analysis.

FDA Adverse Event Reporting System (FAERS).

Adverse event reports submitted to FAERS between 2011 and 2015 were analyzed. CPI were identified by generic names, and IMR were identified by MedDRA Preferred Terms. Empirical Bayes Geometric Means with corresponding 95% confidence interval (EB05-EB95) were calculated as CPI-IMR association metrics. Signals were defined as metrics with EB05≥2.0. Overall, 1,018 IMR events were submitted for CPI, corresponding to 76% for ipilimumab, 15% for nivolumab, and 9% for pembrolizumab. The period of data collection precluded data on the most recently approved CPI agents. IMR comprised of 51% colitis, 16% endocrinopathies, 12% pneumonitis, 11% hepatitis, 4% infusion-related reactions, 3% nephritis, and 3% other IMR. Colitis contributed to 63% and 41% of IMR for ipilimumab and nivolumab, respectively. Pneumonitis and hepatitis contributed to majority of IMR for pembrolizumab, for which nephritis and infusion-related reactions were not reported. Signals of IMR were detected for CPI as a class (EB05=12.4) and individual agents: ipilimumab (EB05=13.2), nivolumab (EB05=15.0), and pembrolizumab (EB05=7.3). Colitis and pneumonitis had the strongest signals for CPI (EB05=45.6 and EB05=17.6, respectively). Colitis was the strongest signal for ipilimumab (EB05=54.2), and pneumonitis was the strongest signal for nivolumab (EB05=48.0) and pembrolizumab (EB05=21.8).

Cancer immunotherapy with CPI is associated with a multitude of IMR, especially colitis and pneumonitis. Individual CPI had variable IMR signals, and pharmacoepidemiologic studies are required to evaluate the identified signals. This article is protected by copyright. All rights reserved.

Pharmacotherapy. 2017 Sep 26 [Epub ahead of print]

Ayad K Ali, David E Watson

Global Patient Safety, Eli Lilly and Company, Indianapolis, IN, USA., Toxicology, Eli Lilly and Company, Indianapolis, IN, USA.