The Efficacy Of First-Generation EGFR-TKIs Combined With Chemotherapy As First-line Treatment In Lung Adenocarcinoma With EGFR Classical Mutations

BackgroundNon-small cell lung cancer(NSCLC)is the main pathological type of lung cancer which has the highest morbidity and mortality in all malignant tumor.And lung adenocarcinoma is the most common in NSCLC.For many years,first-line chemotherapy that pemetrexed associated with platinum is the standard therapy of advanced lung adenocarcinoma.Some researchs show that 50.2%of the patients with advanced lung adenocarcinoma have sensitive EGFR mutations.Common clinical EGFR-TKIs include the first-generation EGFR-TKIs,gefitinib,erlotinib,icotinib,the second-generation EGFR-TKIs,afatinib,dacomitnib and the third-generation EGFR-TKIs,osimertinib.Almost all NSCLC patients with EGFR mutations invariably develop acquired resistance to EGFR-TKIs,usually within 1 to 2 years.T790M mutation is the main mechanism of the acquired resistance to EGFR-TKIs,osimertinib can overcome it.However,resistance to osimertinib has also been reported,and the resistance mechanism is more complex.For NSCLC patients who are likely to develop acquired EGFR-TKIs resistance,there is an urgent need to adopt effective and safe methods to overcome the resistance or delay its appearance in order to extend the survival as much as possible and access to a wide range of treatment options.As pemetrexed and EGFR-TKIs have different mechanisms of anti-tumor and minimally overlapping toxicity profiles,it is hypothesized that their combination might provide synergistic anti-tumor activity accompanied by acceptable toxicity.Some preclinical studies also confirmed that gefitinib combined with pemetrexed can delay the appearance of gefitinib resistance.Therefore EGFR-TKIs combined with chemotherapy has become a potential treatment and become the focus.However,the relevant clinical trials are few and the results are controversial,so a unified conclusion has not been reached at present.So more clinical studies are needed to evaluate the clinical efficacy of EGFR-TKIs combined with chemotherapy.ObjectiveTo evaluate the efficacy and safety of first-generation EGFR-TKIs,gefitinib and icotinib,combined with chemotherapy as first-line treatment in lung adenocarcinorria patients with EGFR classical mutations and to analyze the difference in efficacy between the two classical mutations in subgroup.MethodsThe data that patients with advanced(stage ⅢB or Ⅳ)lung adenocarcinoma with EGFR classic mutations and negative for other gene mutations who were admitted to the Oncology Department of the First Affiliated Hospital of Zhengzhou University from January 2017 to December 2020 were retrospectively analyzed.According to the criteria,102 eligible patients were selected and divided into two groups according to different treatment plans.The A group was the first-generation EGFR-TKIs combined with chemotherapy(68 cases),and the B group was the first-generation EGFR-TKIs alone.Patients were divided into two subgroups,EGFR19Del mutation and EGFR21L858R mutation,according to the type of gene mutation.Patients in group A were treated with oral first-generation EGFR-TKIs combined with pemetrexed and platinum with 4-6 cycles,and first-generation EGFR-TKIs was given in the maintenance treatment phase;patients in group B were given oral first-generation EGFR-TKIs alone.The treatments of the two groups were continued until the patient developed disease progression or intolerable adverse reactions or death.CT was used to evaluate the clinical efficacy every 2 cycles of chemotherapy.Blood routine test and liver and kidney function test should be tested on the day before the chemotherapy and on 7th and 14th day in each cycle of chemotherapy.Follow-up was conducted through hospital or outpatient re-examination and telephone communication to evaluate the efficacy and obtain the relevant data of adverse reactions.The primary endpoints of the study are PFS and the 12-month PFS rate,and the secondary endpoints are ORR and DCR.Chi-square test or Fisher’s exact probability method were used to compare the count data;the Kaplan-Meier method is used to draw the survival curve,and the Log-rank test is used to compare the survival rate,P<0.05 means the difference is statistically significant.Results1.Clinicopathological characteristics:There is a balanced comparability among patients in different treatment groups in terms of gender,age,smoking status,clinical stage,baseline brain metastasis,and mutation type.2.The clinical efficacy and adverse reactions of the two treatments in all patients:PFS:The PFS of the first-generation EGFR-TKIs combined with chemotherapy is longer than that of the first-generation EGFR-TKIs alone(13.0 months vs.8.85 months,P=0.003<0.05);The 12-month PFS rate(52.94%vs 32.35%,P=0.049<0.05)and ORR(47.06%vs 26.47%,P=0.046<0.05)of combination therapy is higher than the first-generation EGFR-TKIs alone;The DCR of the two treatments are similar(97.06%vs 91.18%,P>0.05).Adverse reactions:The incidence of gastrointestinal reactions in the combination therapy is higher than that of the first-generation EGFR-TKIs(35.29%vs 14.71%,P=0.03<0.05);≥3 grade gastrointestinal reactions did not occur in the two groups;other adverse reactions include bone marrow suppression,≥3 grade myelosuppression,liver function damage,>3 grade liver function damage are similar in the two groups(P>0.05).3.The clinical efficacy of the two treatments in patients with different EGFR mutation types:Patients with EGFR 19Del mutation:the PFS of the combination therapy is longer than that of the first-generation EGFR-TKIs alone(16.5 months vs 10.6 months,P=0.035<0.05);The 12-month PFS rate,ORR,and DCR of the two treatments are similar(all P>0.05).Patients with EGFR 21L858R mutation:The PFS of the combination therapy is longer than that of the first-generation EGFR-TKIs alone(9.0 months vs 8.0 months,P=0.021<0.05);The 12-month PFS rate,ORR,and DCR of the two treatments are similar(all P>0.05).4.Differences in efficacy caused by different mutation types:The first-generation EGFR-TKIs combined chemotherapy:The PFS in patients with EGFR 19Del mutation is longer than 21L858R mutation(16.5 months vs 9.0 months,P=0.0003<0.05);The 12 months PFS rate in 19Del group is higher than that of 21L858R group(70.27%vs 32.26%,P=0.002<0.05);the ORR and DCR of 19Del group and 21L858R group are similar(all P>0.05);The first-generation EGFR-TKIs monotherapy:The PFS of patients with EGFR 19Del mutation is longer than that of 21L858R mutation(10.6 months vs 8.0 months,P=0.012<0.05);The 12-month PFS rate,ORR and DCR of the 19Del group and 21L858R group are similar(all P>0.05).Conclusions1.In patients with lung adenocarcinoma with classic EGFR mutations,whether 19Del mutation or 21L858R mutation,the first-generation EGFR-TKIs combined with chemotherapy as first-line treatment prolongs the progression-free survival time with an acceptable toxicity profile than the first-generation EGFR-TKIs alone.2.The progression-free survival of EGFR 19Del-mutate lung adenocarcinoma patients is longer than that of patients with EGFR 21L858R mutation,regardless of first-line combination therapy or first-line first-generation EGFR-TKIs monotherapy.