PMID- 28973656 OWN - NLM STAT- MEDLINE DCOM- 20190905 LR - 20220410 IS - 2374-2445 (Electronic) IS - 2374-2437 (Print) IS - 2374-2437 (Linking) VI - 4 IP - 2 DP - 2018 Feb 1 TI - Incidence of Endocrine Dysfunction Following the Use of Different Immune Checkpoint Inhibitor Regimens: A Systematic Review and Meta-analysis. PG - 173-182 LID - 10.1001/jamaoncol.2017.3064 [doi] AB - IMPORTANCE: If not promptly recognized, endocrine dysfunction can be life threatening. The incidence and risk of developing such adverse events (AEs) following the use of immune checkpoint inhibitor (ICI) regimens are unknown. OBJECTIVE: To compare the incidence and risk of endocrine AEs following treatment with US Food and Drug Administration-approved ICI regimens. DATA SOURCES: A PubMed search through July 18, 2016, using the following keywords was performed: "ipilimumab," "MDX-010," "nivolumab," "BMS-963558," "pembrolizumab," "MK-3475," "atezolizumab," "MPDL3280A," and "phase." STUDY SELECTION: Thirty-eight randomized clinical trials evaluating the usage of these ICIs for treatment of advanced solid tumors were identified, resulting in a total of 7551 patients who were eligible for a meta-analysis. Regimens were categorized by class into monotherapy with a PD-1 (programmed cell death protein 1) inhibitor, a CTLA-4 (cytotoxic T-lymphocyte-associated protein-4) inhibitor, or a PD-L1 (programmed cell death 1 ligand 1) inhibitor, and combination therapy with PD-1 plus CTLA-4 inhibitors. DATA EXTRACTION AND SYNTHESIS: The data were extracted by 1 primary reviewer (R.B.-S.) and then independently reviewed by 2 secondary reviewers (W.T.B. and A.C.G.-C.) following Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. Inferences on the incidence of AEs were made using log-odds random effects models. MAIN OUTCOMES AND MEASURES: Incidence of all-grade hypothyroidism, hyperthyroidism, hypophysitis, primary adrenal insufficiency, and insulin-deficient diabetes. RESULTS: Overall, 38 randomized clinical trials comprising 7551 patients were included in this systematic review and meta-analysis. The incidence of both hypothyroidism and hyperthyroidism was highest in patients receiving combination therapy. Patients on the combination regimen were significantly more likely to experience hypothyroidism (odds ratio [OR], 3.81; 95% CI, 2.10-6.91, P < .001) and hyperthyroidism (OR, 4.27; 95% CI, 2.05-8.90; P = .001) than patients on ipilimumab. Compared with patients on ipilimumab, those on PD-1 inhibitors had a higher risk of developing hypothyroidism (OR, 1.89; 95% CI, 1.17-3.05; P = .03). The risk of hyperthyroidism, but not hypothyroidism, was significantly greater with PD-1 than with PD-L1 inhibitors (OR, 5.36; 95% CI, 2.04-14.08; P = .002). While patients who received PD-1 inhibitors were significantly less likely to experience hypophysitis than those receiving ipilimumab (OR, 0.29; 95% CI, 0.18-0.49; P < .001), those who received combination therapy were significantly more likely to develop it (OR, 2.2; 95% CI, 1.39-3.60; P = .001). For primary adrenal insufficiency and insulin-deficient diabetes no statistical inferences were made due to the smaller number of events. CONCLUSIONS AND RELEVANCE: Our study provides more precise data on the incidence of endocrine dysfunctions among patients receiving ICI regimens. Patients on combination therapy are at increased risk of thyroid dysfunction and hypophysitis. FAU - Barroso-Sousa, Romualdo AU - Barroso-Sousa R AD - Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. FAU - Barry, William T AU - Barry WT AD - Department of Biostatistics and Computation Biology, Dana-Farber Cancer Institute, Boston, Massachusetts. FAU - Garrido-Castro, Ana C AU - Garrido-Castro AC AD - Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. FAU - Hodi, F Stephen AU - Hodi FS AD - Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. FAU - Min, Le AU - Min L AD - Division of Endocrinology, Diabetes, and Hypertension, Brigham and Women's Hospital, Boston, Massachusetts. FAU - Krop, Ian E AU - Krop IE AD - Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. FAU - Tolaney, Sara M AU - Tolaney SM AD - Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. LA - eng PT - Journal Article PT - Meta-Analysis PT - Systematic Review PL - United States TA - JAMA Oncol JT - JAMA oncology JID - 101652861 RN - 0 (Antibodies, Monoclonal) RN - 0 (Antineoplastic Agents, Immunological) RN - 0 (Protein Kinase Inhibitors) SB - IM CIN - JAMA Oncol. 2018 Sep 1;4(9):1295. PMID: 29955774 CIN - JAMA Oncol. 2018 Sep 1;4(9):1295-1296. PMID: 29955794 MH - Antibodies, Monoclonal/*adverse effects MH - Antineoplastic Agents, Immunological/*adverse effects MH - *Cell Cycle Checkpoints/drug effects/immunology MH - Endocrine Glands/drug effects/physiopathology MH - Endocrine System Diseases/*chemically induced/*epidemiology MH - Humans MH - Immunotherapy/adverse effects MH - Incidence MH - Neoplasms/drug therapy/epidemiology MH - Protein Kinase Inhibitors/*adverse effects MH - Randomized Controlled Trials as Topic/statistics & numerical data PMC - PMC5838579 COIS- Conflict of Interest Disclosures: Dr Hodi reports receiving research support from Bristol-Myers Squibb and serving as a consultant to MERCK, Novartis, and EMD Serono. Dr Krop reports receiving research support from Genentech. Dr Tolaney reports receiving research support from MERCK, Bristol-Myers Squibb, and Genetech. No other disclosures are reported. EDAT- 2017/10/04 06:00 MHDA- 2019/09/07 06:00 PMCR- 2018/09/28 CRDT- 2017/10/04 06:00 PHST- 2017/10/04 06:00 [pubmed] PHST- 2019/09/07 06:00 [medline] PHST- 2017/10/04 06:00 [entrez] PHST- 2018/09/28 00:00 [pmc-release] AID - 2655010 [pii] AID - coi170065 [pii] AID - 10.1001/jamaoncol.2017.3064 [doi] PST - ppublish SO - JAMA Oncol. 2018 Feb 1;4(2):173-182. doi: 10.1001/jamaoncol.2017.3064.