Abstract
Lung cancer is the leading cause of cancer-related deaths worldwide. Immune checkpoint inhibitors, including monoclonal antibodies against programmed death-1 (PD-1) and programmed death ligand-1 (PD-L1), have dramatically improved the survival and quality of life of a subset of non-small cell lung cancer (NSCLC) patients. Multiple predictive biomarkers have been proposed to select the patients who may benefit from the immune checkpoint inhibitors. EGFR-mutant NSCLC is the most prevalent molecular subtype in Asian lung cancer patients. However, patients with EGFR-mutant NSCLC show poor response to anti-PD-1/PD-L1 treatment. While small-molecule EGFR tyrosine kinase inhibitors (TKIs) are the preferred initial treatment for EGFR-mutant NSCLC, acquired drug resistance is severely limiting the long-term efficacy. However, there is currently no further effective treatment option for TKIs-refractory EGFR-mutant NSCLC patients. The reasons mediating the poor response of EGFR-mutated NSCLC patients to immunotherapy are not clear. Initial investigations revealed that EGFR-mutated NSCLC has lower PD-L1 expression and a low tumor mutational burden, thus leading to weak immunogenicity. Moreover, the use of PD-1/PD-L1 blockade prior to or concurrent with osimertinib has been reported to increase the risk of pulmonary toxicity. Furthermore, emerging evidence shows that PD-1/PD-L1 blockade in NSCLC patients can lead to hyperprogressive disease associated with dismal prognosis. However, it is difficult to predict the treatment toxicity. New biomarkers are urgently needed to predict response and toxicity associated with the use of PD-1/PD-L1 immunotherapy in EGFR-mutated NSCLC. Recently, promising data have emerged to suggest the potentiation of PD-1/PD-L1 blockade therapy by anti-angiogenic agents and a few other novel therapeutic agents. This article reviews the current investigations about the poor response of EGFR-mutated NSCLC to anti-PD-1/PD-L1 therapy, and discusses the new strategies that may be adopted in the future.
Highlights
Lung cancer is the leading cause of cancer-related deaths worldwide [1]
Tumor Mutational Burden (TMB) In a recent study investigating the impact of tumor mutational burden (TMB) on clinical outcomes of non-small cell lung cancer (NSCLC) patients treated with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), TMB was found to be remarkably lower in EGFR-mutated tumors (n = 153) than EGFR wild-type tumors (n = 1,849) [60]
We summarize the recent investigations about the use of programmed death-1 (PD-1)/programmed death ligand-1 (PD-L1) blockade therapy in EGFR-mutated NSCLC
Summary
Lung cancer is the leading cause of cancer-related deaths worldwide [1]. Non-small cell lung cancer (NSCLC) is the most common histological subtype which constitutes more than 85% of all lung cancer cases. CheckMate-057 is the first Phase III trial to report the clinical efficacy of PD-1/PD-L1 inhibitors in NSCLC patients bearing EGFR mutant tumors While this trial confirmed that patients with advanced non-squamous NSCLC and progress during or after platinum-based chemotherapy survived longer with nivolumab (an anti-PD-1 monoclonal antibody) than docetaxel, subgroup analysis revealed that there was no PFS or OS benefit in patients with activating EGFR mutation [9]. A Phase II clinical trial (NCT0287994) was conducted to evaluate the efficacy of pembrolizumab (anti-PD-1 monoclonal antibody) in TKI-naïve EGFR-mutant advanced NSCLC patients whose tumors have high PD-L1 expression [49]. Other studies have reported a lack of correlation between the expression of PD-L1 and PD-L2 in patients with different EGFR mutation status [59] With these conflicting findings, the use of PD-L1 expression alone could not adequately predict and explain why EGFR-mutant NSCLC exhibits poor response to PD-1/PD-L1 inhibitors. The study showed a significantly longer median PFS in the durvalumab cohort (16.8 months) than that in the placebo
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