IL-6 blockade for prophylaxis and management of immune-related adverse events (irAEs) with anti-PD-1 based immunotherapy.

Abstract

9553 Background: Immune checkpoint inhibitors (ICIs) have activity across many tumor types, but activation of the immune system may also lead to significant, often steroid-refractory irAEs. We sought to determine the activity of tocilizumab, an anti-IL6R monoclonal antibody (mAb), in treatment or prevention of auto-immune irAE in ICI-treated patients (pts). Methods: Institutional databases from 2 melanoma centers were reviewed for pts treated with ICIs and tocilizumab. Treatment and melanoma outcomes were prospectively assessed. Longitudinal assessment of c-reactive protein (CRP) and assessment of clinical improvement (defined as irAE resolution to grade ≤1 CTCAEv5) or prophylaxis (absence of flare, defined as ≥ grade 2) were utilized to evaluate the benefit of tocilizumab. Paired Wilcoxon rank test was used to compare CRP levels prior to ICI administration, at the onset of irAEs and after tocilizumab administration. Results: 22 pts were identified. 2 pts were treated prophylactically (pre-existing dermatomyositis [n = 1] and giant cell arteritis [GCA, n = 1]) before the administration of PD1. 20 pts were treated for management of irAEs due to PD1 +/-CTLA4 (multiple concurrent irAEs [n = 3], steroid refractory irAES [hepatitis & pancreatitis, n = 2], steroid+anti-TNFα refractory colitis [n = 2], steroid+other immunosuppressive-refractory hepatitis [n = 1], cytokine release syndrome-related AEs [n = 6], musculoskeletal irAEs [n = 6]). 15 (68.2%) pts with irAEs required hospitalization and of those, 13 (86.7%) received tocilizumab whilst inpatient. Median time to irAE onset from ICI start was 48 days (range 8-786) and from irAE onset to tocilizumab administration 32 days (range 1-192). Median time to irAE resolution from tocilizumab administration was 7 days (range 1-799). Clinical improvement/benefit was demonstrated in 21/22 patients; one patient with ir-hepatitis did not respond. Median CRP prior to ICI administration was 32mg/L (range 0.3-99), at the onset of irAE 49.5mg/L (range 0.3-251, p = 0.055) and after the tocilizumab administration 18mg/L (range 0.3-18, p = 0.0015). Tocilizumab was well tolerated with self-limiting and transient toxicities in 17 (77.3%) patients. There were two grade 4 events; gastrointestinal tract perforation and Fournier gangrene, the latter unrelated to tocilizumab. Two (9%) patients died due to melanoma. From start of ICI, median progression-free survival (PFS) was 5.88 months and median overall survival (OS) was not reached. Conclusions: Tocilizumab was a well-tolerated and effective steroid-sparing treatment for both management of irAEs, as well as prevention of a flare of pre-existing auto-immune disorders during ICI administration. Prospective trials to evaluate its efficacy and impact on cancer outcomes compared with standard strategies are required.