Treatment Of Advanced EGFR-mutant Non-small-cell Lung Cancer:A Single-center Experience

Part 1:Efficacy of EGFR-TKI plus thoracic SBRT in patients with advanced EGFR-mutant non–small-cell lung cancer Background:Tyrosine kinase inhibitor(TKI)has been the standard of care for advanced nonsmall-cell lung cancers(NSCLC)harboring epidermal growth factor receptor(EGFR)mutation,but these tumors invariably develop drug resistance.As progression most frequently advances in sites of original disease,this retrospective study aimed to evaluate the efficacy of EGFR-TKI with thoracic stereotactic body radiation therapy(SBRT)in patients with advanced EGFR-mutant NSCLC.Methods:Patients with advanced NSCLC harboring positive EGFR mutations after initial TKI therapy for at least 8 weeks were eligible for SBRT between August 2016 and February 2019.Eligible patients were treated with thoracic SBRT,and TKI were administered for the duration of SBRT and continued after SBRT until they were considered ineffective.The control group was treated with TKI monotherapy.Propensity score matching(PSM)was used to account for differences in baseline characteristics.Overall survival(OS),progression-free survival(PFS)and treatment safety were evaluated.Results:Two hundred and fifty patients were included in the study population.Among them,210 patients received TKI alone,and 40 patients received TKI with SBRT.Baseline characteristics were not significantly different between the two cohorts after PSM.The median PFS was 18.5 months in the TKI + SBRT group compared to 9.6months in the TKI group(p<0.001).An influence on OS has not yet been shown(p=0.73).In multivariate analysis,a Cox regression model showed that SBRT was an independent statistically significant positive predictor of better PFS,with a hazard ratio(HR)of 0.50(p= 0.002).The addition of thoracic SBRT to TKI for advanced NSCLC patients with EGFR mutations was well tolerated without severe toxicities.There were no grade 4 to 5 toxicities in either cohort.Conclusion:Real world data prove that TKI plus thoracic SBRT significantly extend PFS in patients with advanced EGFR-mutant NSCLC with tolerable toxicity.Therefore,thoracic SBRT might be a suitable addition to TKI in patients with EGFR-mutant NSCLC.The optimal options for thoracic SBRT in advanced EGFR-mutant NSCLC need to be prospectively investigated to obtain more convincing evidence.Part 2: Efficacy of osimertinib for preventing leptomeningeal metastasis derived from advanced EGFR-mutated non-small-cell lung cancerBackground:Leptomeningeal metastasis(LM)is one of the severe complications of advanced NSCLC and typically occurs in 3-5% of patients.However,its incidence is higher in subgroups of patients with targetable molecular driver mutations and occurs in 9.4% of patients with EGFR mutations.This retrospective study aimed to investigate the potential use of osimertinib for preventing LM in patients with advanced EGFRmutated NSCLC.Methods:Patients with advanced NSCLC harboring EGFR mutations who underwent TKI therapy for at least 8 weeks between September 2016 and September 2019 were eligible for this study based on inclusion criteria.All included patients were divided into two groups based on whether they received osimertinib,the osimertinib group and the control group(patients not treated with osimertinib).PSM was used to account for differences in baseline characteristics.The cumulative incidence of LM was evaluated.Results:A total of 304 patients were included in the study population.Among them,116 patients received osimertinib,and 188 did not.A total of 112 patients remained in each group after PSM,and the baseline characteristics were not significantly different between the two cohorts.LM developed in 11 patients(9.82%)in the osimertinib group and 24 patients(21.42%)in the control group(HR 0.38,95% confidence interval 0.19-0.79,p=0.009).Multivariate analysis indicated that osimertinib was an independent,statistically significant predictor for determining the risk for LM,with an HR of 0.33(p=0.042).Conclusion:Our study demonstrates that osimertinib can significantly reduce the incidence of LM in patients with advanced NSCLC harboring EGFR mutations.Given this result,osimertinib should be encouraged in clinical practice for specific patient populations.Part 3: Advanced non-small-cell lung cancer with uncommon EGFR fusion mutations: A report of two casesBackground:The identification of the molecular events that drive cancer transformation is essential to the development of targeted agents that improve the clinical outcome of lung cancer.Many studies have reported genomic driver mutations in NSCLC.However,EGFR fusions are rare genomic events in NSCLC.Clinical support and evidence to guide management are absent for NSCLC patients harboring EGFR fusion.Case presentation:We provide valuable information for two NSCLC patients with novel EGFR fusion gene including one case with kinesin family member 5B(KIF5B)-EGFR fusion and another case with acquired vesicular overexpressed in cancer pro-survival protein 1(VOPP1)-EGFR fusion.Firstly,we report a case of KIF5B-EGFR fusion in NSCLC responding to TKI.A 50-year-old male underwent left upper lobectomy followed by 4 cycles of adjuvant chemotherapy for pathological stage IA3 lung adenocarcinoma.The tumor tissue was subjected to next-generation sequencing(NGS)and showed a KIF5B-EGFR fusion.When cancer recurrence occurred thirteen months later,the patient received afatinib(40 mg,qd)and a partial response was observed,which resulted in an 11-month PFS.In another case,we describe a 69-year-old female who received right upper lobectomy and was diagnosed with pathological stage IIIA lung adenocarcinoma harboring EGFR L858 R.Twenty months later she had recurrent disease in the liver,lung,and bone,and was treated with icotinib.A novel VOPP1-EGFR fusion gene coexistent with T790 M were identified by NGS using pericardial effusion and blood samples after icotinib treatment.Subsequently,the patient was switched to osimertinib treatment,which resulted in a PFS interval of more than 11 months.Conclusion:This study provides a meaningful reference for the treatment of NSCLC patients harboring EGFR fusion mutations including one case with KIF5B-EGFR fusion who responded well to afatinib and another case with acquired VOPP1-EGFR fusion after icotinib treatment.NGS technologies provide a reliable diagnostic tool for the identification of novel fusion partner genes for EGFR in patients with NSCLC.