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

ABSTRACT

STUDY OBJECTIVE: Ipilimumab, pembrolizumab, and nivolumab are checkpoint inhibitors (CPIs) 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, or a growing list of other cancers. However, CPI treatment is also associated with adverse immune-mediated reactions (IMRs) that can be life-threatening. This pharmacovigilance analysis aims to characterize IMR signals in relation to CPI treatment. DESIGN: Retrospective pharmacovigilance disproportionality analysis. DATA SOURCE U.S. Food and Drug Administration Adverse Event Reporting System (FAERS). MEASUREMENTS AND MAIN RESULTS: Adverse event reports submitted to FAERS between 2011 and 2015 were analyzed. CPIs were identified by generic names, and IMRs were identified by MedDRA Preferred Terms. Empirical Bayes geometric means with corresponding 95% confidence intervals (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 CPIs, 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. IMRs consisted of 51% colitis, 16% endocrinopathies, 12% pneumonitis, 11% hepatitis, 4% infusion-related reactions, 3% nephritis, and 3% other IMRs. Colitis contributed to 63% and 41% of IMRs for ipilimumab and nivolumab, respectively. Pneumonitis and hepatitis contributed to a majority of IMRs for pembrolizumab, for which nephritis and infusion-related reactions were not reported. Signals of IMRs were detected for CPIs 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 CPIs (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). CONCLUSION: Cancer immunotherapy with CPIs is associated with a multitude of IMRs, especially colitis and pneumonitis. Individual CPIs had variable IMR signals, and pharmacoepidemiologic studies are required to evaluate the identified signals.