Abstract 1177: The chronology of immune-related adverse events (irAEs)-mechanistic implications

Abstract

Abstract Immune Oncology (IO) is a novel component of the oncology armamentarium given its distinct mechanism of action, and by extension, unique mechanisms of toxicity (Tx). To recognize these unusual Txs, the term irAEs was popularized in clinical trials. Most organs have been involved by irAEs and autoimmunity has been implicated commonly by practicing oncologists. The onset of irAEs has not been studied well, however. We reasoned that autoimmune phenomena would be expected early after IO, since this is the timeframe within which T-cells expand to exert their effects on tumor and other ‘self’ tissues. It follows that if autoimmunity is the sole mechanism of irAEs, such toxicities should be reported early. Mechanism(s) of irARs may prove important for IO duration discussions. In some cases, tumor antigenic epitopes may mimic self-tissues, and in such cases irAEs develop early after initiation of IO. We hypothesized that irAEs have distinct chronology: earlier events representing autoimmunity (unavoidable); later events reflecting an intercurrent exposure to an antigen (e.g., virus) and therefore are avoidable by limiting duration of IO. Methods: We reviewed published IO monotherapy trials if individual patient data (swimmers’ plot) were reported. We derived the timing and frequency of Tx. We used therapy discontinuation without progressive disease as a surrogate for Tx if reported before the planned 24 months IO therapy.Results: Table depicts the data on included clinical trialsConclusion: The emergence of irAEs after IO extends over a protracted periods with 86% of events occurring beyond 4 months of IO. Though responses occasionally develop late after IO, for Tx consideration, T-cell expansion starts within days of IO initiation, and if autoimmunity is the mediator of Tx, irAEs would emerge only early. Our results suggest dual mechanisms and provide one more impetus to consider shortening IO duration. Tumor Author Discontinued IO (n) Months of IO Discontinuation 0-2 3-4 5-6 7-8 9-10 11-12 13-14 15-16 17-18 19-20 21-22 NSCLC Topalian 12 1 1 4 1 1 3 1 Dart 11 3 4 3 1 Warburton 56 2 2 7 8 7 22 1 3 1 2 1 Melanoma Topalian 13 4 1 2 1 2 2 1 Weber 2 1 1 Demetriou 66 8 4 6 5 6 10 6 10 6 5 RCC Topalian 3 1 2 Total 163 14 10 15 25 14 38 9 15 10 11 2 8% 6% 9% 15% 8% 23% 5% 9% 6% 7% 1% Citation Format: Farah Mazahreh, Haya Safar, Liyan Mazahreh, A. Mazin Safar. The chronology of immune-related adverse events (irAEs)-mechanistic implications [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1177.