Predictive Factors And Acquired Resistance For EGFR-TKI Plus Bevacizumab As First-line Treatment In Patients With EGFR Mutant Non-small Cell Lung Cancer

Objective: Two phase 3 clinical studies,NEJ026 and CTONG1509,have consistently demonstrated better anti-tumor activity of adding bevacizumab to erlotinib regimen in the treatment of patients with epidermal growth factor receptor(EGFR)-mutant advanced non-squamous non-small-cell lung cancer(NSCLC);however,the subset of patients that benefits more with the addition of bevacizumab to their EGFR-TKIs regimen still remains to be identified.In this study,we aimed to investigate the clinical and molecular factors that affect the efficacy of first-generation EGFR-TKIs regimen with or without bevacizumab as first-line treatment of patients with EGFR-mutant NSCLC.Methods: A total of 176 patients with EGFR-mutant stage IIIB-IV relapsed or metastatic NSCLC and underwent next generation sequencing(NGS)with 168-gene panel prior to treatment between Jan 2015 to May2020 with the patients identified using Propensity Score Matching(Ratio of 1:1).Cohort T included 88 patients treated with first-generation EGFR-TKI gefitinib or erlotinib;while cohort A+T consisted of 88 patients treated with EGFR-TKI gefitinib or erlotinib combined with bevacizumab.The gene mutations in 176 patients were detected with high throughput sequencing.We retrospectively analyzed the clinical data,baseline and progression gene mutation of all patients to evaluate the clinical efficacy and potential drug resistance mechanism.Results: Baseline clinical characteristics were not significantly different between Cohort T and A+T.Patients treated with A + T had significantly longer progression-free survival(PFS)and overall survival(OS)(median PFS:14.0 months vs 10.5 months,P=0.0002;Median OS:37.0 vs 26.0 months,P=0.0418).As compared to the T group,PFS was significantly longer among patients who received A+T and harbored L858 R mutation(m PFS: 13.9 vs 10.5months,P=0.012)and TP53mutation(m PFS: 15.0 vs 8.0 months,P<0.001;m OS: 57.0 vs 19.0 months,P=0.002).Nomogram was constructed by Cox multivariate analysis.After dividing patients into low-risk and high-risk two groups,the nomogram was cross validated to demonstrate that the treatment of A + T could eliminate the negative impact of poor prognostic factors on efficacy.At progression,EGFR T790 M,detected from 34% in the A+T group,was the major resistance mechanism in A+T group.No statistical difference was found between the acquired resistance mechanisms of the two groups(P=0.787).Conclusion: Our study demonstrated that EGFR-TKI combined with bevacizumab therapy significantly improved the PFS and OS.And in patients with EGFR L858 R mutation,the PFS of A+T group was longer than that of T group,while in patients with EGFR with tumor suppressor gene mutation,the median PFS and OS also longer than that of T group.The T790 M mutation was the most common acquired resistance mechanism,whether treated with EGFR-TKI therapy or EGFR-TKI combined with bevacizumab.