Identification of Conserved Immune-Related Adverse Event Risk Factors and Clinical Outcomes in a Pan-Immunotherapy Data Mart

BackgroundCancer immunotherapy often triggers immune-related adverse events (irAEs). Analysis of irAEs in large checkpoint inhibitor (CPI) trials has enhanced their management and demonstrated their prognostic value for treatment outcome. However, data on irAEs in non-standard cancer immunotherapies (CITs) are limited, and systematic exploration is lacking. Identifying predictive biomarkers for irAEs in these therapies is still emerging and essential for improving patient care. MethodsWe established a harmonized data mart from 27 early-phase CIT trials, encompassing 14 molecules with diverse mechanisms across various cancer indications. This dataset includes 3,608 patients, both CPI-naive and CPI-experienced, with detailed information on clinical data, tumor characteristics, soluble biomarkers, and genome-wide genotyping. We examined the occurrence of different irAEs and CIT molecules concerning incidence, severity, and onset. A meta-analysis was conducted to assess the association between risk factors and the time to onset of irAEs. Finally, we explored the predictive value of irAEs for clinical outcomes, specifically measured by progression-free survival (PFS). ResultsOur analysis reveals significant variation in irAE incidence and kinetics across CIT molecules. Common irAEs include hepatitis, rash, acute kidney injuries, and hypothyroidism, with hepatitis often severe and others mild. Hepatitis is frequently associated with immunocytokine treatment, while T-cell bispecifics (TCBs) are linked to organ-specific toxicities. Hepatic metastases correlate with hepatitis but inversely with rash; elevated liver enzymes are associated with hepatitis, and high ferritin levels with acute kidney injury risk. Higher myeloid cell counts are associated with reduced rash likelihood. No tumor microenvironment (TME) associations were found, and polygenic risk scores (PGS) show limited utility in our setting. Rash correlates with improved outcomes, whereas hepatitis is associated with a poorer prognosis, independent of baseline prognostic state assessed by the Real World Prognostic score (ROPRO). ConclusionsThese findings highlight the complexity of immune toxicities in early-phase trials, emphasizing the importance of the CIT class, as well as the roles of tumor burden, metastasis sites, and systemic immune state in the development of irAEs. Additionally, the observed association between skin toxicities and improved PFS suggests that skin toxicity could serve as a marker of systemic immune activation across immunotherapy contexts. Key messagesWhat is already known on this topic[bullet] Cancer immunotherapy can induce immune-related adverse events (irAEs); their management and prognostic significance have advanced thanks to data from large checkpoint inhibitor trials. What this study adds[bullet] This study reveals the complexity of irAEs in early-phase pan-immunotherapy trials, highlighting the impact of tumor burden, metastasis sites, and systemic immune state, while identifying skin toxicity as a potential surrogate marker for improved patient outcomes. How this study might affect research, practice or policy[bullet] Our study lays a foundation for pan-immunotherapy irAE research, offering insights for clinicians and drug developers to assess risk profiles and guide the design of future trials for new immunotherapies.