Immune-related adverse events are correlated with significantly improved outcome in a phase I trial population exposed to combination immunotherapy

Background Immune-related Adverse Events (IrAE) are a frequent complication of Immune Checkpoint Inhibitors (ICI) and pose a significant diagnostic and therapeutic challenge. In the early phase trial setting, IrAEs are typically underestimated as their time to onset is significantly longer than the conventional time points (usually 3-4 weeks) used to define dose-limiting toxicity (DLT). Individual IrAEs are typically rare; pooling together data from different trials may allow to better characterize the general features of these events; in the phase 1 setting, understanding the true incidence and clinical impact of IrAEs may help better define the patient population best suited for phase 1 trials. Methods We retrospectively analysed grading, outcome and type of IrAEs occurring in a large phase 1 trial unit. We explored the interaction of IrAEs with outcome variables, both in the overall population and in a landmark analysis, excluding subjects with follow-up shorter than 8 weeks to account for immortal time bias. Results 206 patients were treated with ICIs, alone (n=93) or in combination with other ICIs or targeted treatment (n=113); median followup was 237 days. 63 (30.5%) developed IrAEs of any grade. 14/206 patients (6.7%) developed G3/4 IrAE, which led to important clinical events such as ICI discontinuation (12/14, 86%) or death (2/14, 14%). At 8 wk landmark analysis, the development of any AE was significantly correlated with outcome, in terms of overall response rate (5.4 vs 26.2%, p<0.001), disease control rate (24.8 vs 54.1%, p<0.001), progression-free survival (56 vs 132 days, p<0.001) and overall survival (232 vs 515 days, p=0.0001); the occurrence of any IrAE remained an independent predictor of better survival after adjusting for age, sex and BMI (HR 0.43, p<0.001). Tumor types, prior nonsevere autoimmune disease and other factors did not exhibit significant correlation with IrAE occurrence nor survival. Conclusions IrAEs are a frequent occurrence in early phase trials and independently predicted response and survival. This correlation appeared stronger than what shown in earlier trials with single ICIs and may be due to improved efficacy of combination therapies at early stage of development.