Association of Anti-TNF with Decreased Survival in Steroid Refractory Ipilimumab and Anti-PD1–Treated Patients in the Dutch Melanoma Treatment Registry

Abstract

Purpose: Unleashing the immune system by PD-1 and/or CTLA-4 blockade can cause severe immune-related toxicity necessitating immunosuppressive treatment. Whether immunosuppression for toxicity impacts survival is largely unknown.Experimental Design: Using data from the prospective nationwide Dutch Melanoma Treatment Registry (DMTR), we analyzed the association between severe toxicity and overall survival (OS) in 1,250 patients with advanced melanoma who were treated with immune checkpoint inhibitors (ICI) in first line between 2012 and 2017. Furthermore, we analyzed whether toxicity management affected survival in these patients.Results: A total of 1,250 patients were included, of whom 589 received anti-PD1 monotherapy, 576 ipilimumab, and 85 combination therapy. A total of 312 patients (25%) developed severe (grade ≥3) toxicity. Patients experiencing severe ICI toxicity had a significantly prolonged survival with a median OS of 23 months compared with 15 months for patients without severe toxicity [hazard ratio (HR adj ) ¼ 0.77; 95% confidence interval (CI), 0.63-0.93]. Among patients experiencing severe toxicity, survival was significantly decreased in patients who received anti-TNF AE steroids for steroid-refractory toxicity compared with patients who were managed with steroids only (HR adj ¼ 1.61; 95% CI, 1.03-2.51), with a median OS of 17 and 27 months, respectively.Conclusions: Patients experiencing severe ICI toxicity have a prolonged OS. However, this survival advantage is abrogated when anti-TNF is administered for steroid-refractory toxicity. Further prospective studies are needed to assess the effect of different immunosuppressive regimens on checkpoint inhibitor efficacy.

Success and failure of additional immune modulators in steroid-refractory/resistant pneumonitis related to immune checkpoint blockade

“…In addition to opportunistic infections, another theoretical risk of use of immunosuppressant is the loss of antitumor immunity. One report Open access has described poorer outcomes for patients treated with anti-TNF agents±steroids in comparison to steroids alone, 17 although this has not been described in most other cases nor obviously noted in this report. 18 In fact, preclinical data demonstrates that with anti-TNF therapy toxicity management can be uncoupled from efficacy and that TNF blockade might even have positive effects on anticancer control.…”

Biomarkers of Checkpoint Inhibitor Induced Immune-Related Adverse Events—A Comprehensive Review

“…This is not surprising, in view of the common underlying mechanism of irAEs and anti-tumor responses ( 48 ). It is important to consider that the patients at increased risk of irAEs could also be the patients deriving the most benefit from ICIs and that aggressive or early irAE management could compromise ICI efficacy ( 81 ).…”

Concomitant or delayed anti-TNF differentially impact on immune-related adverse events and antitumor efficacy after anti-CD40 therapy

“…Clinically, questions remains as to the role anti-TNF may play on promoting or suppressing the antitumor efficacy of ICIs. 41 Currently, two trials addressing this question have obtained contradictory results with one study demonstrating infliximab abrogated the survival advantage given by ICI treatment 47 while another study reported improved survival of patients with cancer. 27 Considering the known dual role of TNF in tumor development, addressing this question is of the utmost importance before generalizing the use of infliximab in the clinic.…”