Associations between immune checkpoint inhibitor response, immune-related adverse events, and steroid use in RADIOHEAD: a prospective pan-tumor cohort study

Abstract

Background: Immune checkpoint inhibitors (ICIs) have led to enduring responses in subsets of patients with cancer. However, these responses carry the risk of immune-related adverse events (irAEs), which can diminish the overall benefit of ICI treatment. While associations between irAE development and overall survival have been increasingly documented, there is a need for further understanding of these connections in large prospective real-world cohorts.

Methods: The Resistance Drivers for Immuno-Oncology Patients Interrogated by Harmonized Molecular Datasets (RADIOHEAD) study, a pan-tumor, prospective cohort of 1,070 individuals undergoing standard of care first-line ICI treatment, aims to identify factors driving irAEs and clinical response. Clinical data and longitudinal blood samples were collected prospectively at multiple time points from 49 community-based oncology clinics across the USA. Structured, harmonized clinical data underwent unbiased statistical analysis to uncover predictors of real-world overall survival (rwOS) and risk factors for irAEs.

Results: Across 1,070 participants' treatment courses, RADIOHEAD accumulated over 4,500 clinical data points. Patients experiencing any irAE (25.4%, n=272) exhibited significantly improved rwOS in the pan-tumor cohort (n=1,028, HR=0.41, 95% CI=(0.31, 0.55)). This association persisted when adjusting for age and metastatic disease in multivariate time-dependent Cox proportional hazard analysis, and was consistent across major tumor subtypes, including lung cancer and melanoma. Skin and endocrine irAEs of any grade were strongly associated with improved rwOS (Cox proportional hazard analysis, skin, p=2.03e-05; endocrine, p=0.0006). In this real-world cohort, the irAE rate appeared lower than those reported in clinical trials. Patients receiving corticosteroids prior to initiation of ICI treatment had significantly worse survival outcomes than non-users (HR 1.37, p=0.0054), with a stronger association with systemic steroid use (HR 1.75, p=0.0022). The risk of irAE was increased by exposure to combination immunotherapy relative to monotherapy (OR 4.17, p=2.8e-7), zoster vaccine (OR 2.4, p=5.2e-05), and decreased by prior chemotherapy (OR 1.69, p=0.0005).

Conclusion: The RADIOHEAD cohort is a well-powered, real-world cohort that clearly demonstrates the association between irAE development with improved response and baseline steroid use with worse response to ICI treatment after adjustment for survival bias.

Keywords: Immune Checkpoint Inhibitors; Immune related adverse event - irAE; Immunotherapy.

Figure 1. Immune-related adverse events and impact on survival outcome. (A) Distribution of observed irAEs; (B) Most frequently observed irAEs; (C) Kaplan-Meier survival analysis of all patients in the RADIOHEAD cohort with confirmed alive or dead (including hospice) status for any irAE incidence. Statistical significance for this association is shown for both a Cox proportional hazards model adjusted for age (p) and time-dependent Cox proportional hazard model adjusting for age and metastatic disease (p(time dependent)); (D) Kaplan-Meier survival analysis of patients with lung cancer (NSCLC and SCLC) with confirmed alive or dead (including hospice) status for any irAE incidence. Again, significance from both analytic approaches is shown; (E) Kaplan-Meier survival analysis of patients with melanoma with confirmed alive or dead (including hospice) status for any irAE incidence. Again, significance from both analytic approaches is shown. AI, adrenal insufficiency; IrAE; immune-related adverse event; NSCLC, non-small cell lung cancer; RADIOHEAD, Resistance Drivers for Immuno-Oncology Patients Interrogated by Harmonized Molecular Datasets; SCLC, small cell lung cancer; SIRS, systemic inflammatory response syndrome.

Figure 2. Univariate risk analysis for survival outcomes. (A) Univariate Cox survival graph for age-adjusted clinical risk factors, directionality of the arrow indicates association with either improved or worse survival. HRs are provided for variables if nominally significant (p<0.05 prior to adjustment for multiple comparisons, gray dashed line) or significant after adjusting for multiple comparisons (Bonferroni adjusted, purple dashed line); (B) Kaplan-Meier survival analysis of all patients for any skin or subcutaneous tissue irAE incidence. As in figure 1, statistical significance for this association is shown for both a Cox proportional hazards model adjusted for age (p) and time-dependent Cox proportional hazard model adjusting for age and metastatic disease (p(time dependent)); (C) Kaplan-Meier survival analysis of all patients for any endocrine irAE incidence. Again, significance from both analytic approaches is shown; (D) Kaplan-Meier survival analysis of all patients for baseline corticosteroid use and route of administration. Time-dependent Cox proportional hazards not done as the use of the steroid preceded ICI initiation. ICI, immune checkpoint inhibitor; irAE, immune-related adverse event; MSK, musculoskeletal; PD-1, programmed cell death protein-1; PD-L1, programmed death-ligand 1.

Figure 3. Univariate risk analysis for irAE occurrences. Univariate predictors of any irAE incidence (pink arrow) and any severe Grade III–IV irAE (purple arrow); directionality of the arrow indicates association with higher or lower risk of irAE. ORs are provided for variables if nominally significant (p<0.05 prior to adjustment, gray dashed line) or significant after adjusting for multiple comparisons (Bonferroni adjusted, purple dashed line). IrAE, immune-related adverse event; PD-1, programmed cell death protein-1; PD-L1, programmed death-ligand 1.