AP Versus DP Chemotherapy Regimen As Second-line Therapy In EGFR-TKIs Treated Advanced Non-small-cell Lung Cancer Patients With EGFR Mutations

Objective:Non-small-cell lung cancer(NSCLC)accounts for 85% of lung cancer,and is often diagnosed at an advanced stage.With first-line platinum-based chemotherapy regimens,median survival is 7 – 8 months.Targeted therapies are actively being developed to improve efficacy in activating EGFR mutation patients of NSCLC.EGFR-activating mutations correlated with a 70% TKI treatment response rate and a striking PFS prolongation for patients receiving gefitinib or erlotinib.NCCN guideline recommended EGFR-TKI as first-line therapy for advanced and EGFR mutation patients of NSCLC.A retrospective analysis shows that second-line pemetrexed singlet therapy provides significantly prolonged PFS compared to second-line docetaxel+platinum chemotherapy for NSCLC patients with EGFR mutations who failed first-line EGFR-TKI.To date,no clinical studies have been reported to evaluate the efficacy and safety of DP or AP regimen therapy in EGFR TKI treated NSCLC patients.We consider it particularly important to investigate the comparative effectiveness and safety of docetaxel-based versus pemetrexed-based doublet as second-line therapy in EGFR TKI treated NSCLC patients with EGFR mutations.Patients and methods:1 Patients The information of 198 EGFR mutation positive advanced NSCLC patients was collected from the West China Hospital of Sichuan University,the Second Peoples Hospital of Sichuan province and Enshi Tujia and Miao Autonomous Prefecture Central Hospital.The study protocol was approved by the Institutional Review Board of Enshi Tujia and Miao Autonomous Prefecture Central Hospital.Patients were eligible for inclusion in this study at the age of 18 or older,had confirmed advanced NSCLC(stage IV),activating EGFR mutations consisting of microdeletion in exon 19 or an L858 R point mutation in exon 21,received first-line EGFR-TKIs treatment and at least 1 measurable tumor lesions as evaluated by imaging detection.Exclusion Criteria: 1.Any evidence of severe or uncontrolled systemic diseases(unstable respiratory,cardiac,hepatic,or renal disease or uncontrolled infection).2.Any pregnant or lactating woman.3.Severehypersensitivity to docetaxel,cisplatin,carboplatin,and pemetrexed.2 Treatment Among the 198 patients,69 NSCLC patients with EGFR mutations who failed first-line TKI were enrolled.Thirty-eight patients treated with a DP regimen(docetaxel/cisplatin,n=17;docetaxel/carboplatin,n=21)and 31 patients were treated using AP regimen(pemetrexed/carboplatin,n=30;pemetrexed/cisplatin,n=1).Docetaxel(75mg/m2),pemetrexed(500mg/m2),cisplatin(75mg/m2)or carboplatin(AUC=5)on day 1,repeated every 3 weeks.All chemotherapy drugs were administered intravenously.3 Treatment assessments The primary index was progression-free survival after second-line chemotherapy.PFS was defined as the lapse of time between the start of DP/AP regimen therapy and progressive disease under the chemotherapy or death.The secondary index was overall survival(OS)in such patients.OS was defined as the lapse of time between the start of DP/AP regimen therapy and death of any cause.During treatment,tumor response was assessed every 2 months.Tumor response was performed using Response Evaluation Criteria in Solid Tumors(RECIST 1.1)criteria.Safety and tolerability were assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events(NCI-CTCAE)version 4.0.PFS and OS were assessed using the Kaplan-Meier method and compared between risk groups using the log-rank test.P values less than 0.05 were considered to be statistically significant.The statistical software SPSS16.0(SPSS Inc.,Chicago,Illinois)was used for all the statistical analysis.Results:1 Patient characteristics A total of 69 patients participated in this retrospective study.All patients were positive for EGFR mutation at the central laboratory in each treatment group.The majority of patients were male(60.8%),had PS scores of 0-1(85.5%),and had histological diagnoses of adenocarcinoma(97.1%).Among the 69 patients,36 patients with bone metastases,18 patients with brain metastases,5 patients with adrenal metastases,2 patients with liver metastases.38 patients treated with a DP regimen(docetaxel/cisplatin,n=17;docetaxel/carboplatin,n=21)and 31 patients treated with a AP regimen(pemetrexed/carboplatin,n=30;pemetrexed /cisplatin,n=1).2 Response to chemotherapy Overall response rate was closing in the two arms(DP regimen vs AP regimen: 15.79% vs 19.35%;p = 0.473).No complete responses were observed in both arms,while six(15.79%)and seven(19.35%)patients achieved a partial response(PR),in the docetaxel-based doublet and pemetrexed-based doublet respectively.More patients in the DP group had progressive disease(PD)compared with AP group;PD was observed in 28(73.7%)and 19(61.3%)patients,respectively(p = 0.720).Median progression-free survival was 3.5 months in the DP group and 5.1 months in the AP group(HR 1.457;95% CI:0.8904 to 2.7204;p=0.0029).In addition,the median OS was 7.9 months for DP group and 9.8 months for AP doublet group(HR0.6101;95% CI: 0.3375 to 1.103;p=0.1019).The results suggested that AP regimen treatment resulted in significantly longer progression-free survival than DP regimen therapy.3 Adverse effect All the 69 patients were evaluated for hematotoxicity.In this retrospective study,28(73.7%)and 10(32.2%)patients experienced grade 3 or 4hematotoxicity in the DP and AP group respectively.No significant differences were observed between the two arms in terms of hematological toxicity,with the exception of leucopenia which was more pronounced in the DP group(p=0.0045).No significant differences were observed between the two arms in terms of other adverse effect such as nausea/vomiting,diarrhea,fatigue,rash.Conclusion:Our findings in this study indicated that the AP regimen was superior to DP regimen in NSCLC patients with EGFR mutations who failed first-line EGFR TKI.AP regimen treatment resulted in significantly longer progression-free survival than DP regimen therapy.There were no differences among the two groups on overall survival.