Dynamics of clinical biomarkers as predictors of immunotherapy (IT) benefit in metastatic melanoma (MM) patients (pts) treated in reference institution

Background: Baseline LDH and derived neutrophil–lymphocyte ratio (dNLR) are markers of response to IT. Cutaneous immune-related adverse events (irAEs) are also associated with improved outcomes in MM patients. We hypothesized whether dynamic shifts in LDH, dNLR and incidence of irAEs may impact prognosis of MM pts treated with IT. Methods: We analyzed 52 MM pts treated at VHIO with single agent IT Anti-PD-1 (Nivolumab or Pembrolizumab) or Anti-CTLA-4 (Ipilimumab) outside clinical trials. DNLR and LDH were collected at baseline and after cycle 2 of IT. IrAEs were assessed with CTCAE v.4.0. Primary endpoint was immunotherapy overall survival (IOS). A cutoff value of dNLR ≥2.5 and LDH ≥1.5xULN was set by the maximization of the log-rank test. Changes in dNLR, LDH and incidence of irAEs were correlated with IOS. Results: Out of 52 pts, median age was 62.8 years, 49 (96%) ECOG ≤1, treated with Ipilimumab 14 (27%), Nivolumab 20 (38%) or Pembrolizumab 18 (35%). BRAF mutation was present in 19 (37%) pts. Median prior lines were 1 (0-3) and median follow-up was 14.4 months. Baseline dNLR ≥2.5 and LDH ≥1.5xULN were associated with worse IOS (HR: 5.7; 2.2 – 14.3; p < 0.001 and HR: 1.9; 0.8 – 4.2; p = 0.13, respectively). At cycle 2 assessment, dNLR ≥2.5 and LDH ≥1.5xULN also resulted in worse IOS (HR: 29.2; 7.4 – 114.6; p < 0.001 and HR: 3.9; 1.5 – 10.1; p < 0.01 respectively). Importantly, pts switching from either high dNLR to low dNLR (HR: 0.14; 0.03 – 0.74; p = 0.02) or high LDH, to low LDH (HR: 0.08; 0.01 – 0.68; p = 0.02) had significantly better IOS than those with high scores at cycle 2. In addition, significantly longer IOS was also observed for ≥G2 irAEs development (HR: 0.2; 0.05 – 0.89; p = 0.03) in a survival model adjusted for time-dependent covariates. Conclusions: LDH and dNLR at baseline may impact on prognosis, however in our cohort both cycle 2 measures and shifts from baseline to cycle 2 scores better defined IOS in MM pts. These results suggest that laboratory changes may help indentify “super-responders” or “hyperprogressors” and therefore optimize intrapatient prognostic estimations. We also identified irAEs as a strong predictor of long-term improved outcomes. Legal entity responsible for the study: VHIO. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.