Immune-related adverse events predict the therapeutic efficacy of anti–PD-1 antibodies in cancer patients

Abstract Background Cancer immune therapy has shown remarkable benefit in the treatment of a range of cancer types, although it may initiate autoimmune-related disorders in some patients. We have attempted to establish whether the incidence of irAEs after the use of anti–PD-1 antibodies nivolumab or pembrolizumab in advanced malignancies is associated with anti–PD-1 treatment efficacy. Patients and methods We studied patients treated with single-agent nivolumab or pembrolizumab for advanced cancer. irAEs (immune-related adverse events) were identified clinically and graded as per the Common Terminology Criteria for Adverse Events version 4.0. Efficacy was evaluated with objective response rate (ORR, immune-Response Evaluation Criteria in Solid Tumours [RECIST] criteria) progression-free survival (PFS) and overall survival (OS). Tests were performed to determine the association between irAEs and ORR, PFS or OS. Results We identified 106 patients. Primary diagnoses were lung cancer ( n  = 77), melanoma ( n  = 8), head and neck carcinoma ( n  = 7), renal carcinoma ( n  = 5), Hodgkin's lymphoma ( n  = 3), urothelial carcinoma ( n  = 3) and gallbladder adenocarcinoma, hepatocellular carcinoma and Merkel cell carcinoma ( n  = 1 each). IrAEs were observed in 40 patients (37.7%). The most frequent irAEs were hypothyroidism ( n  = 15), nephritis ( n  = 5) and hyperthyroidism ( n  = 4). Objective response was observed in 44 patients (41.5%), and median PFS was 5.5 months (0.5–31 months). Thirty-three of the 40 patients with irAEs had objective response (82.5%) in contrast with 11 of the 66 cases without irAEs (16.6%) (OR 23.5, P P  = 0.016). OS in patients with irAEs was 32 months and 22 in those without irAEs, without statistically significant differences. Conclusion In advanced cancer treated with single-agent anti–PD-1 antibodies, patients with irAEs showed a markedly improved efficacy over patients without irAEs (ORR of 82.5% and PFS of 10 months vs ORR of 16.6% and PFS of 3 months). Future studies of anti–PD-1 immune-therapy should address this association to explore the underlying biological mechanisms of efficacy.