Study aims to demystify the immune toxicity triggered by osimertinib-ICI co-treatment

Non-small cell lung cancer (NSCLC) accounts for the majority of lung cancer cases and remains a leading cause of cancer mortality worldwide. Epidermal growth factor receptor (EGFR) mutations are common in NSCLC and have made EGFR-targeting drugs like osimertinib a cornerstone of treatment. Immune checkpoint inhibitors have also transformed the treatment landscape by reactivating the immune system to attack tumors. Despite their promise, combining these two therapies has proven problematic. Several clinical trials were halted after reporting high incidences of severe immune-related adverse events (irAEs)—such as interstitial pneumonia and hepatitis—linked to the combination. Due to these risks and the lack of mechanistic clarity, there is an urgent need to investigate the cellular drivers of this toxicity and identify safer strategies.

A research team from Tianjin Medical University Cancer Institute & Hospital published their findings (DOI: 10.20892/j.issn.2095-3941.2024.0269) in Cancer Biology & Medicine, aiming to demystify the heightened immune toxicity triggered by osimertinib-ICI co-treatment. Through the development of a specialized mouse model mimicking irAEs seen in patients, the team pinpointed activation of the IL-6/JAK/STAT3 signaling cascade in liver macrophages as the culprit. Their results not only offer a compelling explanation for these adverse reactions but also suggest that this toxicity may be preventable through targeted pharmacological intervention.

To explore the root cause of irAEs, the researchers administered osimertinib and immune checkpoint inhibitors (ICIs) in mice, which resulted in pronounced lung and liver inflammation, increased EGFR expression on macrophages, and elevated blood levels of IL-6, ALT, and ferritin. Notably, flow cytometry revealed that EGFR expression was exclusive to macrophages, not T or NK cells. RNA sequencing confirmed the upregulation of inflammatory signaling, particularly the IL-6/JAK/STAT3 pathway, which was further validated via Western blot analysis. The turning point came when ruxolitinib, a JAK1/2 inhibitor, was introduced into the regimen—leading to a marked decrease in inflammatory cytokines despite ongoing tissue-level inflammation. This finding suggests that systemic cytokine release, rather than local tissue damage, may be a more sensitive indicator of irAEs. The study proposes that osimertinib's inhibition of EGFR phosphorylation in macrophages, when combined with ICI-induced immune activation, triggers this inflammatory cascade. These results not only clarify the pathway responsible for irAEs but also spotlight ruxolitinib as a potentially safe and effective countermeasure.

Our findings provide a crucial mechanistic link between osimertinib-ICI therapy and the dangerous cytokine surges seen in patients. By pinpointing the IL-6/JAK/STAT3 axis in liver macrophages, we not only clarify the pathogenesis of immune-related toxicity, but also suggest that targeted inhibitors like ruxolitinib can be safely integrated into cancer immunotherapy regimens. This represents a significant step toward safer combination treatments."

Dr. Xiubao Ren, corresponding author of the study

This research delivers a mechanistic blueprint for understanding and managing irAEs in EGFR-mutant NSCLC patients receiving combination therapy. By selectively inhibiting the IL-6/JAK/STAT3 pathway, clinicians may be able to protect patients from serious inflammatory reactions while preserving the anti-cancer potency of both osimertinib and ICIs. These results pave the way for future clinical trials to assess IL-6 pathway blockers as adjunct therapies in cancer immunotherapy. If successful, this strategy could significantly improve patient safety and expand the clinical utility of EGFR-TKI and ICI combination regimens.