The impact of emotional distress on pathologic response and survival after neoadjuvant combination immune checkpoint blockade (ICB) in high-risk stage III melanoma.
Authors: Reijers Irene L.M. , Fraterman Itske , Dimitriadis Petros , Broeks Annegien , Gonzalez Maria , Menzies Alexander M. , Kapiteijn Ellen , Van Der Veldt Astrid Aplonia Maria , Suijkerbuijk Karijn , Hospers Geke , Long Georgina V. , Blank Christian U. , van de Poll-Franse Lonneke 
Published: June 2023

9558 Background: Neoadjuvant ICB has been shown to induce high pathologic response rates in high-risk stage III melanoma, outperforming adjuvant ICB with respect to survival benefit. Biomarkers that have been shown to predict ICB efficacy, including the interferon-gamma (IFN-γ) signature and tumor mutational burden (TMB), do not completely explain why some patients (pts) fail to benefit from neoadjuvant ICB. Emerging evidence in preclinical and clinical studies suggests that emotional distress (ED) negatively affects tumor progression and anti-tumor immune responses, mediated by β-adrenergic and glucocorticoid signaling. Here, we investigate the association between ED prior to neoadjuvant ICB and pathologic response and survival in pts with stage III melanoma treated in the PRADO trial. Methods: PRADO tested neoadjuvant ipilimumab + nivolumab followed by a response-directed surgical and adjuvant treatment regimen in stage III melanoma pts. The European Organization for Research and Treatment of Cancer (EORTC) scale for emotional functioning was used to identify pts with ED, based on established clinically relevant thresholds. Association between ED and pathologic response or survival was assessed using multivariable logistic or Cox regression analysis. Potential effects of ED on the tumor and its microenvironment were examined in baseline tumor biopsies using RNA sequencing. Results: Pts who completed the baseline EORTC questionnaire were included and defined as pts with ED (n = 28) or without ED (n = 60). Baseline characteristics, IFN-γ signature expression and TMB were comparable. Pts with ED showed a trend towards achieving less major pathologic responses (MPR; ≤10% viable tumor) compared to pts without ED (46% vs 65%, p = 0.099). Multivariable analysis showed a significant association between ED and MPR (OR 0.20, p = 0.043) when adjusted for age, sex, IFN-γ signature (OR 9.36, p = 0.002) and TMB (OR 13.21, p = 0.003). Pts with ED also had a significantly lower relapse-free survival (RFS) compared to pts without ED (2-year RFS 74% vs 91%, p = 0.011), and ED at baseline remained associated with relapse in multivariable regression (HR 3.81, p = 0.034) when adjusting for IFN-γ signature (OR 0.34, p = 0.109) and TMB (OR 1.02, p = 0.972). Analyses investigating the relation between ED with β-adrenergic and glucocorticoid signaling and factors representing anti-tumor immune responses are ongoing and will be presented at ASCO. Conclusions: Emotional distress was identified as baseline marker associated with impaired clinical outcomes after neoadjuvant combination ICB in pts with high-risk stage III melanoma. This data warrants further investigation in independent cohorts and into the potential effect of pharmacological and psychosocial interventions, e.g. adrenergic receptor blockade, on the anti-tumor immune response and patient outcomes. Clinical trial information: NCT02977052 .