Perioperative immunotherapy for patients with EGFR mutant non-small cell lung cancer: Unexpected potential benefits

Abstract

Given that immunotherapy has resulted in a significant overall survival (OS) benefit in advanced-stage disease, it is of notable interest to determine the effectiveness of these agents in early-stage non-small cell lung cancer (NSCLC). The potential exists for the immunotherapeutic approach in early-stage NSCLC to mirror the paradigm seen in advanced NSCLC, wherein survival enhancements have notably benefited the majority of patients. However, their performance in early-stage epidermal growth factor receptor (EGFR) mutant NSCLC is controversial. In the limited studies that included patients with EGFR mutation status, we found unexpected, good survival benefits of perioperative immune checkpoint inhibitors (ICIs) in resectable EGFR-positive NSCLC, which is controversial with those in advanced EGFR-mutant NSCLC. It is possible because of the shift toward immunosuppression that the immune environment undergoes during tumor progression. In the early disease stages, the anti-tumor immune response can be activated with fewer hindrances. In the context of EGFR mutant tumors, intratumor genetic heterogeneity can generate treatment-sensitive and -resistant subclones. The subclonality of the resistant subclone is pivotal in therapy response, with tyrosine kinase inhibitors (TKIs) selectively controlling EGFR-mutant cell proliferation and “competitive release” potentially explaining lower pathological responses in adjuvant TKIs trials. This review delves into emerging data on perioperative treatment modalities for early-stage EGFR mutant NSCLC, exploring unique mechanisms and predictive biomarkers to guide perioperative management strategies.