Selective immune suppression using interleukin-6 receptor inhibitors for management of immune-related adverse events

Abstract

Background: Management of immune-related adverse events (irAEs) is important as they cause treatment interruption or discontinuation, more often seen with combination immune checkpoint inhibitor (ICI) therapy. Here, we retrospectively evaluated the safety and effectiveness of anti-interleukin-6 receptor (anti-IL-6R) as therapy for irAEs.

Methods: We performed a retrospective multicenter study evaluating patients diagnosed with de novo irAEs or flare of pre-existing autoimmune disease following ICI and were treated with anti-IL-6R. Our objectives were to assess the improvement of irAEs as well as the overall tumor response rate (ORR) before and after anti-IL-6R treatment.

Results: We identified a total of 92 patients who received therapeutic anti-IL-6R antibodies (tocilizumab or sarilumab). Median age was 61 years, 63% were men, 69% received anti-programmed cell death protein-1 (PD-1) antibodies alone, and 26% patients were treated with the combination of anti-cytotoxic T lymphocyte antigen-4 and anti-PD-1 antibodies. Cancer types were primarily melanoma (46%), genitourinary cancer (35%), and lung cancer (8%). Indications for using anti-IL-6R antibodies included inflammatory arthritis (73%), hepatitis/cholangitis (7%), myositis/myocarditis/myasthenia gravis (5%), polymyalgia rheumatica (4%), and one patient each with autoimmune scleroderma, nephritis, colitis, pneumonitis and central nervous system vasculitis. Notably, 88% of patients had received corticosteroids, and 36% received other disease-modifying antirheumatic drugs (DMARDs) as first-line therapies, but without adequate improvement. After initiation of anti-IL-6R (as first-line or post-corticosteroids and DMARDs), 73% of patients showed resolution or change to ≤grade 1 of irAEs after a median of 2.0 months from initiation of anti-IL-6R therapy. Six patients (7%) stopped anti-IL-6R due to adverse events. Of 70 evaluable patients by RECIST (Response Evaluation Criteria in Solid Tumors) V.1.1 criteria; the ORR was 66% prior versus 66% after anti-IL-6R (95% CI, 54% to 77%), with 8% higher complete response rate. Of 34 evaluable patients with melanoma, the ORR was 56% prior and increased to 68% after anti-IL-6R (p=0.04).

Conclusion: Targeting IL-6R could be an effective approach to treat several irAE types without hindering antitumor immunity. This study supports ongoing clinical trials evaluating the safety and efficacy of tocilizumab (anti-IL-6R antibody) in combination with ICIs (NCT04940299, NCT03999749).

Keywords: autoimmunity; cytokines; immune checkpoint inhibitors.

Figure 1

A patient with metastatic melanoma. (A) Baseline maximal intensity projection (MIP) PET images showing FDG avid left lung nodules. Note the hypermetabolic FDG uptake at the left knee joint is consistent with arthritis (dotted arrow). (B) MIP PET image at 6 months after initiation of pembrolizumab shows near complete resolution of metabolic activity of left pulmonary metastases (arrow). Note the increase in radiotracer uptake at the left knee joint (dotted arrow). (C) MIP PET image at 1 month after concomitant therapy with anti-IL-6R and pembrolizumab shows persistent near complete resolution of metabolic activity of left pulmonary metastases (arrow). Note the decrease in metabolic activity at the left knee joint (dotted arrow). (D) MIP PET image at 4 months after cessation of both anti-IL-6R and pembrolizumab shows persistent near complete resolution of metabolic activity of left pulmonary metastases. There is further decrease in metabolic activity at the left knee joint (dotted arrow). (E) MIP PET image at 7 months after cessation of ICI shows persistent near complete resolution of metabolic activity of left pulmonary metastases (arrow). The physiologic metabolic activity at the left knee joint (dotted arrow) consistent with resolution of arthritis. anti-IL-6R, anti-interleukin-6 receptor; FDG, F-fluorodeoxyglucose; ICI, immune checkpoint inhibitor; PET, positron emission tomography;

Figure 2

A patient with non-small cell lung cancer. (A) Baseline contrast-enhanced CT image showing unremarkable appearance of the liver. (B) Contrast-enhanced CT image at about 1 year after immune checkpoint inhibitor (ipilimumab and nivolumab) initiation showing periportal cuffing (solid arrows), thickening and avid enhancement of the common bile duct and the gallbladder wall (dotted arrows) and pericholecystic fluid (arrowhead). (C) 5-min delayed post-contrast gradient spoiled echo image showing periportal cuffing (arrows) and avid enhancement of the gallbladder wall (arrowhead), these findings are consistent with cholangitis. (D) 5-min delayed post-contrast gradient spoiled echo image 3 months after initiation of anti-IL-6R therapy showing resolution of periportal enhancement but there is persistent irregularity and mild dilatation of the intrahepatic biliary ducts (arrows). Avid enhancement of the gallbladder wall has also resolved (arrowhead). anti-IL-6R, anti-interleukin-6 receptor; ICI, immune checkpoint inhibitor.

Figure 3

A patient with malignant melanoma. (A) Maximal intensity projection (MIP) images of concurrent cranial CT angiography at 7 months after immune checkpoint inhibitor (ipilimumab and nivolumab) initiation show multiple sites of intracranial arterial narrowing and/or occlusion involving the right posterior cerebral artery (white arrow), left middle cerebral artery and both anterior cerebral arteries (black arrowheads). This multi vascular pattern of involvement is suggestive of vasculitis. (B) Diffusion-weighted image, corresponding apparent diffusion coefficient (ADC) map, and fluid-attenuated inversion recovery (FLAIR) 3 months after initiation of anti-IL-6R therapy show normalization of ADC signal and development of high signal intensity foci on FLAIR (arrows) without corresponding diffusion restriction, in keeping with chronic infarcts. (C) MIP images of cranial CT angiography after anti-IL-6R therapy show recanalization with persistent narrowing of the right posterior cerebral artery (white arrow), persistent narrowing of the left middle cerebral artery, and recanalization of the anterior cerebral arteries (black arrowheads). anti-IL-6R, anti-interleukin-6 receptor.

Figure 4

(A) The best overall response rate to ICI therapy in patients with melanoma treated with anti-IL-6R. (B) Overall survival from ICI initiation: median follow-up from ICI initiation 23 months (95% CI, 20 to 27). anti-IL-6R, anti-interleukin-6 receptor; CR, complete response; ICI, immune checkpoint inhibitor; PD, progressive disease; PR, partial response; SD, stable disease.