Retrospective Study Of EGFR-TKI Plus Bevacizumab As Maintenance Therapy For Advanced Lung Adenocarcinoma

Background and objectiveEpidermal growth factor receptor-tyrosine kinase inhibitors(EGFR-TKIs)are the main first-line therapy for EGFR mutated advanced lung cancer.They showed greater efficacy and slighter toxicity compared with standard chemotherapy.However,EGFR-TKIs are inevitably faced with acquired drug resistance,resulting in disease progression or even death.To delay acquired drug resistance,the most commonly used strategy is first-line combination therapy.Bevacizumab is a commonly used anti-angiogenic drug in clinical practice.Many clinical trials proved that compared with EGFR-TKI monotherapy,first-line combination of bevacizumab and EGFR-TKI dramatically prolonged progression-free survival(PFS)but the incidence of grade 3 or worse adverse events also significantly increased.Maintenance therapy is a therapeutic regimen using continued or switched drug after attaining the maximum tumor response through inductive therapy.Previous trials showed that bevacizumab combined with chemotherapy as maintenance therapy increased short-term efficacy as well as survival benefit without remarkably increased drug toxicity.However,few studies focused on EGFR-TKI combined with bevacizumab as maintenance therapy for EGFR mutated advanced lung adenocarcinoma.Therefore,our study aimed to evaluate the efficacy and safety of EGFR-TKI combined with bevacizumab as maintenance therapy,trying to explore a new strategy to delay EGFR-TKI acquired drug resistance.MethodsWe collected the clinical data of 192 patients with EGFR mutated advanced lung adenocarcinoma treated in the First Affiliated Hospital of Army Military Medical University from January 2013 to December 2019.30 patients were in combination group and 162 patients were in monotherapy group.Patients in combination group were treated with EGFR-TKI plus bevacizumab after inductive therapy of EGFR-TKI,while patients in monotherapy group were treated with EGFR-TKI monotherapy.The R project for statistical computing was used for propensity score matching and patients in combination group were matched at a radio of 1:2 to patients in monotherapy group based on clinical characteristics.90 patients(30 in combination group and 60 in monotherapy group)were matched for subsequent analysis.Overall PFS,PFS after reaching stable disease(PFS1),duration of response(Do R),objective response rate(ORR),change of tumor size and safety profiles of two groups were compared.Results1.Until to the end time of observation,29 patients in combination group and all 60 patients in monotherapy group occurred disease progression.In combination group,13patients(44.8%)had disease progression only in primary lesion,12 patients(41.4%)had disease progression only in non-primary lesion and 4 patients(13.8%)had disease progression in both primary and non-primary lesions.In monotherapy group,23 patients(38.3 %)had disease progression only in primary lesion,24 patients(40.0%)had disease progression only in non-primary lesion and 13 patients(21.7%)had disease progression in both primary and non-primary lesions.The incidence of progression in non-primary lesion in combination group was less than that in monotherapy group,as were 16 patients(55.2%)versus 37 patients(61.7%).2.Median overall PFS was 17.2 months(95% CI 14.4-20.0)in combination group and11.4 months(95% CI 8.9-13.9)in monotherapy group with statistical difference(HR=0.455,95% CI 0.286-0.724,P=0.001).In combination group,patients harboring 19 deletion had prolonged short-time efficacy compared with patients harboring 21L858 R mutation,as median PFS1 were 18.1 months(95% CI 16.4-19.8)versus 13.0 months(95% CI 7.7-18.3)separately without statistical difference(HR=0.903,95% CI 0.408-1.998,P=0.800).Median PFS1 was 6.0 months(95% CI 5.8-6.2)in combination group,also significantly increased than that in monotherapy group which was 3.7 months(95% CI 3.4-4.0)with statistical difference(HR=0.524,95% CI 0.326-0.843,P=0.008).3.ORR were 76.7% versus 73.3% in two groups with no statistical difference.In combination group,3 patients didn’t get partial response(PR)during inductive therapy of EGFR-TKI but reached PR after receiving bevacizumab and 2 patients get PR during inductive therapy then reached PR again after receiving bevacizumab.4.Median Do R was 12.2 months(95% CI 7.9-16.5)in combination group and 9.8months(95% CI 8.3-11.3)in monotherapy group with statistical difference(HR=0.463,95%CI 0.266-0.807,P=0.007).5.The minimum reduction of tumor size from baseline in combination group was slightly greater than that in monotherapy group with an average reduction of 40.0% in combination group and 37.4% in monotherapy group.6.23(76.7%)patients in combination group and 41(68.3%)patients in monotherapy group had treatment-associated adverse events of any grade.The most common adverse event was skin and mucous damage in both groups,16(53%)versus 31(52%).Then was hepatic function damage,16(53%)versus 22(37%).Others included renal function damage,5(17%)versus 3(5%)and hypertension,4(13%)versus 0(0%).4(13.3%)patients in combination group and 7(11.7%)patients in monotherapy group had ≥grade 3 treatment-associated adverse events with no statistical difference.No treatment-associated death was occurred in both groupsConclusionOur study indicated that: compared with EGFR-TKI monotherapy,EGFR-TKI plus bevacizumab as maintenance therapy has greater efficacy without remarkably increased incidence rate of adverse events.It might be considered as an optimal therapeutic regimen for EGFR mutated lung adenocarcinoma and a potential strategy to delay acquired EGFR-TKI resistance.