Effect Of Different Systemic Therapy On The Prognosis Of Lung Adenocarcinoma Patients With Negative Driver Genes And Symptomatic Brain Metastases

Purpose:When advanced lung adenocarcinoma patients had symptomatic brain metastases,craniocerebral radiotherapy is needed to control the growth of brain metastases and alleviate symptoms.In addition to craniocerebral radiotherapy,patients with negative driver genes must receive systemic therapy such as chemotherapy,anti-angiogenic therapy or immune checkpoint inhibitor(ICI).The objective of this study was to explore the effect of different systemic therapy on the prognosis of lung adenocarcinoma patients with negative driver genes and symptomatic brain metastases,explore the optimal treatment and guide clinical selection.Methods:Lung adenocarcinoma patients with negative driver genes and symptomatic brain metastases who received craniocerebral radiotherapy at first diagnosis,were collected retrospectively.According to different first-line systemic treatment regimens,patients were divided into chemotherapy group,bevacizumab plus chemotherapy group(bevacizumab+chemotherapy group),ICI plus chemotherapy group(ICI+chemotherapy group)and ICI plus bevacizumab plus chemotherapy group(ICI+bevacizumab+chemotherapy group).Chi-square test was used to compare the efficacy and safety.Kaplan-Meier plotted the survival curve and Log-rank test was used for statistical analysis.Results:A total of 136 patients were enrolled from January 2019 to August 2021,with 31,52,31,and 22 patients in the four groups,respectively.The median age of patients was 62 years old,all patients had 70≤Karnofsky performance status(KPS)≤ 90,97 patients had ≤4 brain metastases.Lung-molecular graded prognostic assessment(Lung-mol GPA)was 1.5-2.0 or 2.5-3.0 in 83.8%patients.Only 41 patients were tested for programmed cell death receptor ligand-1(PD-L1)tumor cell proportion score(TPS),of which 73.2%(30 patients)had PD-L1 TPS≥1%.Baseline characteristics,including PD-L1 TPS levels(p=0.190)et al.,were not different among the four groups.Until May 1st,2022,the median follow-up time was 22.8 months.There was no difference in objective response rate(ORR)(p=0.202)and disease control rate(DCR)(p=0.217)of intracranial lesions among the four groups.ORR and DCR in the chemotherapy group were lower than those in the other three groups,but there was no difference in ORR(p=0.559)and DCR(p=0.140)among the bevacizumab+chemotherapy group,ICI+chemotherapy group,and ICI+ bevacizumab+ chemotherapy group.Intracranial progression-free survival(iPFS),progression-free survival(PFS),and overall survival(OS)in chemotherapy group were the shortest.iPFS and PFS were longest in ICI+bevacizumab+chemotherapy group.Compared with bevacizumab+ chemotherapy group,iPFS of ICI+bevacizumab+chemotherapy group was 19.4 months(19.4 vs.14.7 months,HR=0.470,p=0.030),PFS was 12.8 months(12.8 vs.8.8 months,HR=0.526,p=0.038).Compared with ICI+chemotherapy group,HR of iPFS in ICI+ bevacizumab+ chemotherapy group was 0.429(19.4 vs.17.0 months,p=0.033),HR of PFS was 0.493(12.8 vs.10.3 months,p=0.049).However,there was no significant difference in iPFS and PFS between bevacizumab+chemotherapy group and ICI+chemotherapy group.There was also no difference in OS among bevacizumab+chemotherapy group,ICI+chemotherapy group,and ICI+bevacizumab+chemotherapy group.Lung-mol GPA was an independent prognostic factor of PFS in ICI+bevacizumab+chemotherapy group.In terms of safety,treatment-related adverse events(TRAEs)and grades 3 to 4 TRAEs were not different among four groups.Conclusions:For lung adenocarcinoma patients with negative driver gene and symptomatic brain metastases at first diagnosis,compared with chemotherapy,bevacizumab+chemotherapy,and ICI+chemotherapy,the combination therapy of ICI+bevacizumab+chemotherapy can provide longer iPFS and PFS when patients receive craniocerebral radiotherapy.Lung-mol GPA is an independent prognostic factor of PFS.Patients who receive chemotherapy alone have worse efficacy and shorter survival than other patients who receive combination regimens.The safety of the four groups was similar.