Abstract
Over the last decade, the treatment of advanced non-small cell lung cancer (NSCLC) has undergone rapid changes with innovations in oncogene-directed therapy and immune checkpoint inhibitors. In patients with epidermal growth factor receptor (EGFR) gene mutant (EGFRm) NSCLC, newer-generation tyrosine kinase inhibitors (TKIs) are providing unparalleled survival benefit and tolerability. Unfortunately, most patients will experience disease progression and thus an urgent need exists for improved subsequent lines of therapies. The concurrent revolution in immune checkpoint inhibitor (ICI) therapy is providing novel treatment options with improved clinical outcomes in wild-type EGFR (EGFRwt) NSCLC; however, the application of ICI therapy to advanced EGFRm NSCLC patients is controversial. Early studies demonstrated the inferiority of ICI monotherapy to EGFR TKI therapy in the first line setting and inferiority to chemotherapy in the second line setting. Additionally, combination ICI and EGFR TKI therapies have demonstrated increased toxicities, and EGFR TKI therapy given after first-line ICI therapy has been correlated with severe adverse events. Nonetheless, combination therapies including dual-ICI blockade and ICI, chemotherapy, and angiogenesis inhibitor combinations are areas of active study with some intriguing signals in preliminary studies. Here, we review previous and ongoing clinical studies of ICI therapy in advanced EGFRm NSCLC. We discuss advances in understanding the differences in the tumor biology and tumor microenvironment (TME) of EGFRm NSCLC tumors that may lead to novel approaches to enhance ICI efficacy. It is our goal to equip the reader with a knowledge of current therapies, past and current clinical trials, and active avenues of research that provide the promise of novel approaches and improved outcomes for patients with advanced EGFRm NSCLC.
Highlights
Lung cancer remains the leading cause of cancer-related death in the United States with an estimated 235,760 new cases and 131,880 new deaths in 2021 [1]
non-small cell lung cancer (NSCLC) remains the deadliest malignancy on the planet. 15-67% of NSCLC tumors harbor epidermal growth factor receptor (EGFR) mutations based on geographic region, lending urgency to the development of better therapeutic strategies for EGFRm NSCLC patients
While first-line immune checkpoint inhibitor (ICI) monotherapy and ICI + EGFR tyrosine kinase inhibitors (TKIs) combination therapy in EGFRm NSCLC patients has far been disappointing, intriguing results have been obtained from trials of second-line ICI therapy combinations and multiple open research questions are under clinical investigation (Table 3)
Summary
Lung cancer remains the leading cause of cancer-related death in the United States with an estimated 235,760 new cases and 131,880 new deaths in 2021 [1]. First-generation EGFR TKIs including erlotinib and gefitinib were first approved the U.S Food and Drug Administration (FDA) in 2013 for first line use in metastatic EGFR ex19dels or L858R mutant NSCLC in 2013 after multiple studies demonstrated improved clinical outcomes compared to platinum-based chemotherapy [17, 18]. In addition to driver-mutation targeted therapies, the discovery and utilization of immune checkpoint (ICP) inhibitors in NSCLC has provided new and hopeful treatment options for many patients [27].The ICP describes an immunomodulatory process that downregulates T-cell effector responses and is mediated in part by the B7 ligand binding to the cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) receptor and the programmed cell death ligands 1 and 2 (PD-L1 and PDL2) binding to the programmed cell death protein 1 (PD-1) [28]. While the role of ICI therapy in EGFRm NSCLC is controversial, there is intriguing and hopeful evidence that certain combinations may prove beneficial, and active research is elucidating properties of EGFRm tumor biology and TME composition that we anticipate will lead to novel therapies in the near future
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