COLAR: open-label clinical study of IL-6 blockade with tocilizumab for the treatment of immune checkpoint inhibitor-induced colitis and arthritis

Abstract

BackgroundImmune-related adverse events due to immune checkpoint inhibitors (ICIs) are not always effectively treated using glucocorticoids and it may negatively affect the antitumor efficacy of ICIs. Interventional studies of alternatives to glucocorticoids are lacking. We examined whether interleukin-6 blockade by tocilizumab reduced ICI-induced colitis and arthritis.Patients and methodsPatients with solid cancer experiencing Common Terminology Criteria for Adverse Events (CTCAE v5.0) grade >1 ICI-induced colitis/diarrhea (n=9), arthritis (n=9), or both (n=2) were recruited and treated with tocilizumab (8 mg/kg) every 4 weeks until worsening or unacceptable toxicity. Patients were not allowed to receive systemic glucocorticoids and other immunosuppressive drugs within the 14-day screening period. The primary endpoint was clinical improvement of colitis and arthritis, defined as ≥1 grade CTCAE reduction within 8 weeks. Secondary endpoints were improvements and glucocorticoid-free remission at week 24; safety; radiologic, endoscopic, and histological changes; and changes in plasma concentrations of C reactive protein, cytokines (IL-6, IL-8, and IL-17), and YKL-40.ResultsNineteen patients were available for efficacy analysis; one patient was excluded due to pancreatic insufficiency-induced diarrhea. Patients received treatment with pembrolizumab (n=10) or nivolumab (n=4) as monotherapy or ipilimumab and nivolumab (n=5) combined. Seven patients had been initially treated with glucocorticoids, and two of them also received infliximab. Ten patients continued ICI therapy during tocilizumab treatment. The primary endpoint was achieved in 15 of 19 (79%) patients. Additional one patient had ≥1 grade reduction at week 10, and another patient had stabilized symptoms. At week 24, ongoing improvement without glucocorticoids (n=12), including complete remission (n=10), was noted. Five patients had grades 3–4 treatment-related adverse events, which were manageable and reversible.ConclusionsTocilizumab showed promising clinical efficacy and a manageable safety profile in the treatment of ICI-induced colitis and arthritis. Our findings support the feasibility of randomized trials of immune-related adverse events.Trial registration numberNCT03601611.

Immune checkpoint Inhibitor–Induced diarrhea and Colitis: Incidence and Management. A systematic review and Meta-analysis

“…The biologic tocilizumab, an IL-6 receptor antagonist, a key drug in rheumatoid arthritis [109], has shown clinical efficacy in 79% of the cohort in a retrospective study including 34 patients with a grade 3-4 irAE (pneumonitis, 35%; serum sickness, 35%; colitis, 3%) [110]. In addition, tocilizumab has been investigated in patients with ICI-induced colitis (COLAR trial; 19 patients with colitis/arthritis) in a preliminary study published after our final search of April 21, 2021 [111]. The authors concluded that tocilizumab showed promising clinical efficacy in the treatment of ICI-induced arthritis and/or colitis, as 80% of patients with colitis had ≥ 1 grade improvement in symptoms.…”

Rheumatic Immune-Related Adverse Events due to Immune Checkpoint Inhibitors—A 2023 Update

“…Although the precise mechanism remains unclear, ICIs block negative signals on activated T cells, leading to increased autoreactive T cells and inflammatory cytokines such as tumor necrosis factor-α (TNF-α), IL-6, and IL-17 [ 62 , 63 , 64 ]. This provides the rationale for targeted inhibition of these cytokines to treat rheumatic irAEs [ 65 , 66 ]. ICIs can also induce epitope spreading, diversifying the epitope specificity of T cells [ 62 ].…”

“…As mentioned above, the use of abatacept should be avoided because of the risk of antagonizing the anti-tumor effects of ICIs [ 77 ]. There is no evidence in the literature to suggest a preference for one biologic DMARD over another: infliximab, adalimumab, etanercept, tocilizumab, and sarilumab have controlled symptoms [ 56 , 66 , 92 ].…”

Immunosuppression for immune-related adverse events during checkpoint inhibition: an intricate balance

“…Very limited clinical reports on the use of IL-6 blockade for irAEs do not show impaired ICI efficacy 111 – 114 . Stroud et al reported on 87 nivolumab treated patients, of whom 34 patients received tocilizumab (anti-IL-6R) for severe irAEs 111 .…”

“…Similarly, Dimitriou et al report a median PFS of 6 months in 22 advanced melanoma patients receiving tocilizumab 113 , which is difficult to compare given the variety of ICI regimens patients received. The COLAR study (NCT03601611) demonstrated that 6 out of 20 patients treated with tocilizumab alone for ICI colitis or arthritis had progressive disease 114 . Although a 14 day period without any immunosuppression was required prior to tocilizumab initiation, 9 of the 20 patients had received systemic corticosteroids, including 3 who had also received infliximab for any irAEs prior to tocilizumab administration 114 .…”