Fluorouracil and bevacizumab plus anakinra for patients with metastatic colorectal cancer refractory to standard therapies (IRAFU): a single-arm phase 2 study

Abstract

In preclinical models, IL-1β inhibition could enhance the efficacy of fluorouracil (5-FU). In this phase 2 study, we assessed the activity and safety of 5-FU plus bevacizumab and anakinra (an IL-1β and α inhibitor) in patients with metastatic colorectal (mCRC) refractory to chemotherapy and anti-angiogenic therapy.Eligible patients had unresectable mCRC; were refractory or intolerant to fluoropyrimidine, irinotecan, oxaliplatin, anti-VEGF therapy, and anti-EGFR therapy (for tumors with wild-type KRAS). Patients were treated with a simplified acid folinic plus 5-FU regimen and bevacizumab (5 mg/kg) both administered by intravenous infusion for 30 min every 2 weeks. Anakinra (100 mg) was injected subcutaneously once daily. The primary endpoint was the 2-month response rate determined upon CHOI criteria.Thirty two patients with metastatic colorectal cancer were enrolled. Five patients demonstrated response (Choi criteria) and 22 patients had stable disease as the best 2-month overall response. Median progression-free and overall survival were 5.4 (95% CI, 3.6–6.6) and 14.5 months (95% CI, 9–20.6) respectively. Twenty patients experienced grade 3 toxicity. No grade 4 or 5 toxicity related to therapy occurred. The most common grade 3 adverse events were neutropenia in 8 (25%) patients, digestive side effects in 7 (21.9%) patients and hypertension in 6 (18.75%) patients. No treatment-related deaths or serious adverse events were reported.5-FU plus bevacizumab and anakinra has promising activity and a manageable safety profile, suggesting that this combination might become a potential treatment option for patients with refractory mCRC.

Interleukin-1 and Related Cytokines in the Regulation of Inflammation and Immunity

“…A 10-year trial of daily Anakinra with weekly low dose dexamethasone in 47 patients with smoldering myeloma resulted in significantly increased survival (Lust et al, 2009;Lust et al, 2016). Improved survival has been reported when Anakinra is added to the standard of therapy with fluorouracil in advanced metastatic colorectal cancer (Isambert et al, 2018), hormone negative breast cancer , and in advanced pancreatic cancer (Becerra et al, 2018;Whiteley et al, 2016). In pre-clinical studies, Anakinra also abated chimeric antigen receptor (CAR)-T-cell-induced cytokine release syndrome and neurotoxicity (Giavridis et al, 2018;Norelli et al, 2018).…”

Current perspectives on the interleukin‐1 family as targets for inflammatory disease

“…Anakinra, which neutralizes both IL‐1 ligands, has been reported to inhibit colon tumour growth in preclinical studies and has been investigated as a therapy across various malignancies. In metastatic colorectal cancer patients, anakinra administration was reported to provide significant survival benefit and improved quality of life scores, when added to standard‐of‐care chemotherapy for colorectal cancer . However, in such settings the relative short half‐life of anakinra and requirement for continuous administration is problematic and can hinder patient adherence, prompting investigation of anti‐IL‐1 neutralising antibodies .…”

An Interleukin-1 Signature in Breast Cancer Treated with Interleukin-1 Receptor Blockade: Implications for Treating Cytokine Release Syndrome of Checkpoint Inhibitors

“…The combination of anakinra plus chemotherapy was not associated with any adverse events such as serious infection. Similar to the trial of anti-IL1α in patients with metastatic colorectal cancer (9), some patients with breast cancer reported reduced pain and increased quality of life on anakinra plus chemotherapy and in other studies, anakinra reduced the “sickness syndromes” of chemotherapy used to treat metastatic colorectal cancer but also increased overall survival (3). Three of the 11 patients in the Palucka trial are still alive (1).…”

“…Anakinra is increasingly used as adjunct therapy to reduce the inflammation of metastatic cancer. A trial in metastatic colorectal cancer showed significant survival benefit when anakinra was added to standard-of-care chemotherapy for colorectal cancer (3) and patients with pancreatic cancer also benefit when anakinra is added to chemotherapy (4). Moreover, in these trials, the patients report improved quality-of-life scores with the use of anakinra.…”

“…To increase the efficacy of checkpoint inhibitors, some trials add chemotherapy which increases the toxicity. Because anakinra is administered as an adjunct with chemotherapy (1, 3, 4), can anakinra be considered a safe checkpoint inhibitor? The concept that IL1 blockade itself provides for checkpoint inhibition is supported by the canakinumab trial data (6).…”