A Systematic Review of Cases of Diabetes Mellitus following Immune Checkpoint Inhibitor Therapy for Cancer

Introduction: Immune checkpoint inhibitors (ICI) [anti-PD-1, anti-PD-L1, and anti-CTLA-4] are novel drugs increasingly used to treat solid tumor malignancies. Immune-related adverse events (irAE) occur with such therapy. We conducted a systematic review of case reports on endocrine irAE following ICI therapy. Here, we focus on the diabetes mellitus (DM) irAE case reports. Method: In July 2017 we searched Medline, Embase, Cochrane Central Register and Web of Science for articles related to endocrine irAE and ICI. From 815 citations retrieved, 241 mentioned DM. From these, 32 articles reported 43 cases (had close temporal relationship of immunotherapy and development of DM IrAEs and clinical, biochemical, and/or treatment data). A hand-search in Jan 2018 found 8 more papers with 8 cases. These 51 cases were reviewed independently by 2 co-authors for quality of data, using a standardized form. Results: Thirty-five patients presented in DKA (21 with fulminant T1DM), 15 with hyperglycemia, and 1 with lab data not reported (NR). The median age of the 31 males and 20 females was 63 years. Median time to onset of DM was 7 weeks after treatment initiation. Anti-GAD65, IA2, or ZnT8 were positive in 53% and negative or NR in 47%. Top 2 cancer treated were melanoma (n=23) and non-small cell lung cancer (n=11). The ICIs used were anti-PD-I (n=34); anti-PD-L1 (n=4); anti-PD-1 + CTLA-4 (n=7); and anti-CTLA-4 then anti-PD-1 (n=6). When DM occurred, ICI was stopped in 16, continued in 12, and NR in 23. At onset, 3 cases with known T2DM continued with oral meds, but all were treated with insulin and fluids. All patients recovered - 38 remained on insulin, 1 stopped insulin 81 days after ICI was stopped; and 12 NR. Conclusion: Reported cases of T1DM irAE are rising - 9 in 2015, 13 in 2016 and 28 in 2017. Most (69%) presented in DKA. All were treated with anti-PD-1/PD-L1 drugs with the majority on monotherapy. All recovered and 38 were insulin-dependent. Endocrinologists and oncologists should collaborate in managing such patients. Disclosure K.R. Mizokami-Stout: None. R. Gianchandani: None. M. MacEachern: None. R.M. Iyengar: None. S. Yentz: None. L. Shen: None. B.G. Redman: None. M. Tan: Other Relationship; Self; Eli Lilly and Company.