Immune-related adverse events and anti-tumor efficacy of immune checkpoint inhibitors

Abstract

Although immune checkpoint inhibitors (ICIs) have transformed the treatment landscape for patients with many advanced malignancies, only 15–60% of patients respond, leaving a broad swath of patients who do not derive benefit. Identifying biomarkers to optimally identify patients who will benefit from ICIs is a major research focus for the oncology community. Thus far, predictive biomarker research has focused on tumor signatures such as microsatellite instability, programmed death-ligand 1 (PD-L1) expression and tumor mutational burden; clinical biomarkers have been far less studied. One potential clinical biomarker for ICI response in patients is immune-related adverse event (IRAE) onset.IRAEs are thought to represent bystander effects from activated T-cells and it is plausible that patients responding to ICIs would have greater likelihood of autoimmune toxicities (e.g. due to a more competent/treatment-responsive immune system, or cross-reactivity between tumor and host tissue). Earlier studies in melanoma patients however, suggested no association between IRAE onset and anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) antibody efficacy. In contrast, a growing body of literature suggests IRAE onset is predictive of anti-programmed cell death protein 1 (PD-1) and anti-PD-L1 antibody response across a variety of solid tumors. Most of these studies report that patients who experienced IRAEs demonstrate marked improvements in progression-free survival, overall survival and overall response rate compared to those lacking toxicity.Key questions regarding the association between IRAE onset and ICI efficacy remain. The most pertinent of these involve whether the association is only relevant for patients treated with anti-PD-1 and anti-PD-L1 antibodies and whether IRAE site, severity, timing of onset and management influence ICI efficacy. Herein, we discuss the seminal studies which have begun to address these questions and have shaped the narrative about the predictive value of IRAE onset for patients on ICIs, in this review.

Immune‐related adverse events correlate with improved survival in patients with advanced mucosal melanoma treated with nivolumab: A single‐center retrospective study in Japan

“…The patients who can continue nivolumab monotherapy have the highest risk of irAE onset, while they are also the patients who are benefiting from this therapy. In addition, extremely late irAE onset is typically only observed in patients benefiting from treatment, 45 although the present study demonstrated that the irAE arising after 180 days on nivolumab monotherapy was associated with the best outcomes. Other limitations include that the study is retrospective in a single center, including lack of strict methods of timing of assessments and that the sample size was small.…”

Association of immune-related adverse events with immune checkpoint inhibitor efficacy: real or imaginary?

“…The spectrum of irAEs is broad in that they can involve various organs, and, although they are usually mild or manageable, they can be lifethreatening [2]. However, of note, evidence has suggested that these irAEs may be an early sign of ICI treatment success [3]. Indeed, numerous studies have revealed a positive association of irAEs with tumor response or extended survival in patients receiving ICI treatment.…”

Nebenwirkungen neuer onkologischer Immuntherapien

“…Umgekehrt scheint eine aufgrund von Nebenwirkungen vorzeitig erzwungene Beendigung von ICI nicht unbedingt mit einem schlechteren Ansprechen der Tumortherapie einherzugehen. Generell gibt es Signale, dass Patienten mit irAE auch ein besseres Ansprechen des Malignoms auf die Therapie aufweisen [10].…”