Synergistic effect of canakinumab with epidermal growth factor receptor tyrosine kinase inhibitors versus with chemotherapy for non-small cell lung cancer

Interleukin-1β (IL-1β) is one of the critical proinflammatory cytokines that trigger a series of inflammatory mediators, promoting the tumor microenvironment (TME) and tumor progression (1). In the Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS), a randomized clinical trial designed to evaluate the use of canakinumab in patients with atherosclerosis (2), IL-1β blockade with canakinumab was initially reported to remarkably decrease the incidence and mortality of lung cancer. Moreover, analysis of circulating tumor DNA and soluble inflammatory biomarkers of patients in CANTOS further confirmed the importance of IL-1β-mediated protumor inflammation in lung cancer (3). This unexpected finding stimulated a series of clinical trials of canakinumab combined with immune checkpoint blockade or chemotherapy aimed at repurposing canakinumab for treating patients with non-small cell lung cancer (NSCLC).

The Canakinumab as Adjuvant Therapy in Patients with Completely Resected Non-Small Cell Lung Cancer-A (CANOPY-A), a phase III, randomized, double-blind, multicenter study of canakinumab as adjuvant therapy in patients with NSCLC (4), recently reported failure of the therapy. C-reactive protein and IL-6 levels decreased in the canakinumab group, but this group showed no correlation with differential clinical outcomes (4). However, the failure of CANOPY-A is not an isolated occurrence and rather represents one of several terminated trials of canakinumab combined with chemotherapy or/and immunotherapy that were reported to fail in meeting the primary efficacy endpoints, including two large-scale phase III clinical trials in the advanced or metastatic setting (5-7).

This repeated failure has generated considerable discussion on the reliability and validity of CANTOS; however, another potential explanation is that chemotherapy or immunotherapy may not be an effective pairing with canakinumab in patients with lung cancer. It was recently found that fine particulate matter (PM2.5) could cause release of IL-1β, leading to a progenitor-like cell state within epidermal growth factor receptor (EGFR)-mutant lung alveolar type II epithelial cells, thereby promoting tumorigenesis. This reported interaction between IL-1β and EGFR gene mutations in lung cancer may offer new insights into potential avenues of treatment (8). It is possible that IL-1β blockade may be effective in lung cancer treatment in the presence of oncogenic driver mutations, which means that canakinumab may perform better when combined with EGFR tyrosine kinase inhibitors (TKIs) than when combined with chemotherapy or immunotherapy. Thus far, no trials have evaluated the efficacy of canakinumab combined with EGFR-TKIs in treating patients with NSCLC. This study thus provides a new direction for the investigation of EGFR-TKI combination therapy modalities and may warrant subsequent clinical exploration.

Acknowledgments

Funding: None.

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