Abstract 151P
Background
Immune related adverse events (irAEs) can possess a major challenge in patient symptom burden and risk of fatalities. In addition, it is a barrier for the development of multi-agent immunotherapy regimen. Management of these irAEs using corticosteroids as first-line therapy may have detrimental impact on cancer outcomes and worsen survival. We have previously demonstrated that interleukin-6 (IL-6) plays a role in the pathogenesis of irAEs in tumor resistance. Based on this data, we conducted this trial to assess the safety and efficacy of IL-6 blockade, using Tocilizumab, in combination with ipilimumab and nivolumab in melanoma patients.
Methods
Phase II clinical study to evaluate the safety and efficacy of the triplet therapy in melanoma (n=35). Pts received subcutaneous tocilizumab 162 mg bi-monthly for up to 12 weeks plus ipi 3mg/kg + nivo 1mg/kg every 3 weeks. The primary endpoints: 1) assess the frequency ofgrade 3/4 irAEs; 2) objective response rate (ORR); and 3) assess biomarker analysis from tumor, blood and inflamed tissue.
Results
A total of 25 melanoma patients were enrolled; duration of treatment ranged from 6 to 41 weeks. Eleven patients (44%) had grade 3/4 irAEs; median time to onset was 8.3 weeks (2.7-17.3). This included colitis (20%), hepatitis (16%), pancreatitis (8%), and fibromyalgia rheumatica-like and type I diabetes (4% each) and led to study disconsolation in 4% but no treatment-related deaths. The ORR was 60% (44% in patients with elevated LDH). Our longitudinal immune analysis from tumor tissue demonstrates increase infiltration of immune cells Th1, Th17, and CD8 cells. Furthermore, gene expression data exhibits enrichment of IL-1, IL-6, and IL-17 pathways in patients with high grade toxicity post treatment.
Conclusions
Our preliminary data showed a trend to mitigate irAEs with the triplet therapy with no negative impact on tumor immunity. Furthermore, exploratory biomarker analysis suggests that we are not sufficiently blocking the IL-6/Th17 pathway with the current dosing of Tocilizumab. The protocol will enroll a new cohort of patients with increased Tocilizumab administration.
Legal entity responsible for the study
A. Diab.
Funding
MD Anderson.
Disclosure
A. Diab: Financial Interests, Institutional, Sponsor/Funding: Bristol Myers. All other authors have declared no conflicts of interest.