Prognostic Analysis Of Adjuvant Targeted Therapy For EGFR-positive ⅠA Stage Invasive Lung Adenocarcinoma After Complete Resection

Research background and purposeTumor metastasis can occur in the early stage.Lung adenocarcinoma is a common pathological type of non-small cell lung cancer(NSCLC),and early hematogenous metastasis is common.Complete resection is the standard ttreatment for early stage lung cancer.However,the 5-year overall survival(OS)rate of patients with postoperative stage IA NSCLC is from 77% to 92%,and the 5-year recurrence rate is 10-30% after surgery,the rate of 2-year disease-free survival(DFS)rate after operation is about 70-80%.The risk of recurrence and metastasis in patients with EGFR positive stage IA NSCLC was similar to that in stage IB patients.It is speculated that some patients with lung cancer may have distant micro-metastasis at the time of surgery,which were not in the real "early stage".Compared with stage I squamous cell carcinoma,lung adenocarcinoma has a poor long-term prognosis.At present,the 5-year OS rate of adenocarcinoma in situ(AIS)and micro-invasive adenocarcinoma(MIA)both are 100%,AIS been classified as precancerous lesion in the 2021 edition of WHO lung tumor classification,while MIA still remains.It is suggested that the appearance of invasive components is the main cause of histological heterogeneity in early satge adenocarcinoma,with the increase of invasive components,significantly increased risk of recurrence and metastasis.In summary,invasive adenocarcinoma is the main factor leading to the decreased survival rate of patients with stage IA.TNM stage of tumor alone cannot well predict the recurrence and metastasis of stage I lung adenocarcinoma.There are many risk factors show significant impact on the early recurrenceand metastasis of stage IA invasive adenocarcinoma after surgery,such as minimal residual disease(MRD),tumor vessel invasion(TVI),epithelial-mesenchymal transformation(EMT),tumor spread through air space(STAS),micropapillary and solid components≥5% in the tumor.How to identify the patients with recurrent high-risk stage IA lung adenocarcinoma as soon as possible and further improve the five-year OS rate of the population is an urgent clinical problem.Epidermal growth factor receptor(EGFR)is the most common type of driving gene mutation in lung adenocarcinoma.The benefits of epidermal growth factor receptor tyrosine kinase inhibitors(EGFR-TKIs)applied to EGFR mutant NSCLC have been gradually confirmed from advanced stage to stage IB.At present,the ADAURA2 study,a large-scale international clinical study of adjuvant osimertinib treatment after surgery for stage IA2-IA3 non-small cell lung cancer,has also been launched.Compared with chemotherapy,EGFR-TKIs has higher effective rate and lower side effects.The survival status of EGFR-positive mutation stage IA invasive lung adenocarcinoma may be improved by adjuvant targeted therapy after completeresection.In this paper,we selected the patients with EGFR-positive mutation and pathological type of invasive lung adenocarcinoma as the high-risk group for postoperative recurrence of stage IA lung adenocarcinoma,and retrospectively analyzed the efficacy and safety of adjuvant targeted therapy for EGFR-positive IA stage invasive lung adenocarcinoma after complete resection.Research methodsThe clinical data of patients who were hospitalized in our hospital from January 1,2016 to September 30,2022 were collected.The clinical baseline of the above two groups of patients was consistent.In order to further balance the baseline consistency of each clinical feature,reduce the additive effect of each clinical feature,we selected age,sex,smoking history,pathological grade of IASLC,clinical stage,type of gene mutation,STAS,and postoperative chemotherapy as covariates for 1:1 use of propensity Score Matching(PSM).The observation was treated with EGFR-TKIs before tumor recurrence and metastasis,and postoperative chemotherapy was allowed.The control group was not treated with EGFR-TKIs or only received chemotherapy before tumor recurrence and metastasis.Disease-free survival(DFS)as the primary endpoint,DFS is defined as the time from postoperative to disease recurrence or metastasis.The clinical characteristics,postoperative treatment plan and efficacy,median disease-free survival(median DFS)and safety of the above patients were sorted and analyzed.The safety analysis was conducted according to the Common Terminology Criteria for Adverse Events(CTCAE)version 5.0.Research results1.The follow-up date ended on September 30,2022.A total of 82 patients were included,and 34 pairs of observation group and control group were matched at 1:1 by PSM.After matching,the median follow-up time of observation group and control group was 22.43months(Range,8.57-56.39)and 22.16 months(Range,7.14-51.00),respectively.A total of 13 patients had endpoint events,including 3 cases(8.8%)in the observation group and 10 cases(29.4%)in the control group.No lymph node metastasis was found in the 13 patients after intraoperative lymph node dissection and re-examination by pathologists.2.The 2-year DFS rate and 3-year DFS rate in the observation group and the control group were 97% vs.71% and 89% vs.71%,respectively.The median DFS of the observation group was not reached,and the median DFS of the control group was 44.50 months(95%CI24.51-64.49;p=0.014),HR=0.22(95%CI 0.06-0.81;p=0.023).The risk of metastasis of postoperative adjuvant EGFR-TKIs therapy was reduced by 78.0%,and the difference was statistically significant.3.A total of 13 of the overall patients received postoperative adjuvant chemotherapy,of which 6 patients in the observation group(17.6%)and 7 patients in the control group(20.6%)received 1-6 cycles of platinum-containing adjuvantchemotherapy.Among the patients who received postoperative chemotherapy in the observation group and the control group,1 patient(16.7%)and 3 patients(42.9%)relapsed.Too few patients received adjuvant chemotherapy after operation and failed to perform further survival analysis.After excluding the influence of chemotherapy,the median DFS of observation group and control group was not reached and 44.50 months(95%CI 16.62-72.38;p=0.03),HR=0.15(95%CI 0.03-0.87;p=0.034),respectively.Postoperative adjuvant EGFR-TKIs therapy alone reduced the risk of metastasis,and the difference was statistically significant.4.DFS subgroup analysis: IASLC grade 1,IASLC grade 3,STAS positive,other EGFR mutation types except Ex19 del and L858 R mutation could not get effective results because of the small number of DFS events.The rest of the results showed that the overall population benefited from postoperative targeted therapy(HR=0.22),IASLC grade 2(HR=0.18,95%CI0.04-0.84;p=0.01),STAS negative(HR=0.23,95%CI 0.06-0.85;p=0.03)and no postoperative chemotherapy(HR=0.20,95% CI 0.04-0.99;p=0.05)subgroups benefited statistically from postoperative adjuvant targeted therapy,while other subgroups did not show independent protective efficacy in this study.5.Safety analysis: Adverse drug reactions occurred in 15 patients(44.1%)in the observation group.Most of them were CTCAE grade 1-2 adverse reactions,mainly: skin damage such as rash,pruritus,nail infection,oral ulcers;gastrointestinal manifestations such as diarrhoea,bloating,nausea and liver function abnormalities,and most of the patients’ symptoms subsided or remitted after a short period of symptomatic treatment(e.g.sun protection,protection of wounds,anti-diarrhoea,et al.).Analysis conclusionPostoperative adjuvant EGFR-TKIs therapy in patients with EGFR-postive IA stage invasive lung adenocarcinoma can prolong the 2-year and 3-year disease-free survival rate,and reduce the risk of postoperative metastasis.