Treatment Strategy Refinement For Advanced Non-small Cell Lung Cancer In Different Subgroups

Part ?:Comparing first-line treatment patterns and clinical outcomes of patients with pan-negative advanced non-squamous non-small cell lung cancerBackground:Platinum-based chemotherapy is standard first-line treatment for patients with advanced pan-negative non-squamous(non-Sq)non-small cell lung cancer(NSCLC)However,identifying the chemotherapy regimens from which such patients will derive the most benefit remains unknown.Therefore,this study aimed to explore which chemotherapy regimens were advantageous for those patients.Methods:A retrospective study was conducted on 114 patients with advanced non-Sq NSCLC using platinum-based chemotherapy as first-line treatment between Jan 2013 and Dec 2015.The study evaluated the most common first-line regimens including pemetrexed/platinum,paclitaxel/carboplatin,gemcitabine/platinum,and vinorelbine/cisplatin.The primary endpoint was progression free survival(PFS),and secondary endpoints were the objective response rate(ORR)and disease control rate(DCR).Univariate and multivariate logistic analysis was carried out using SPSS version 16.0.Results:Sixty of 114 patients underwent pemetrexed/platinum(PP)regimens and the other 54 patients received non-pemetrexed plus platinum(NPP)regimens.The median PFS was significantly longer for the PP group than the NPP group(7.2 months[95%Cl:5.3-9.1]vs.4.9 months[95%CI:3.2-6.6],P=0.031).The The DCR of the PP regimen was better than that of the NPP regimen(90.0%vs,74.1%,P=0.026).Smoking status was an independent predictor of PFS(RR=2.1,95%CI:1.4-3.3,P=0.001)in a final multivariate Cox regression model.Conclusions:A PP regimen tends to be more beneficial than a NPP regimen for patients with pan-negative advanced non-Sq NSCLC.Smoking status may be a valuable predictor for the selection of a chemotherapy regimen in such patients.Part ?:Heterogeneous Response to First-generation Tyrosine Kinase Inhibitors in Non-Small-Cell Lung Cancer with Different EGFR exon 19 Mutation VariantsBackground:Epidermal growth factor receptor(EGFR)exon 19 deletions(19 dels)contain a large number of variants and account for approximately 50%of all EGFR mutations.Variants of EGFR exon 19dels have not been distinguished in previously published trials despite differences in deletion and insertion locations.The therapeutic response of patients with EGFR exon 19 dels to first-generation tyrosine kinase inhibitors(TKIs)and the mechanisms of disease progression have not yet been noted.Methods:Between July 2011 and June 2019,the clinical outcomes of 195 patients harboring EGFR 19 mutations who received first-generation EGFR-TKIs were retrospectively analyzed.Results:A total of 195 patients,twenty of EGFR 19 deletion variants were identified.126 patients(64.6%)who had 19 deletions starting on E746,62(31.8%)exhibited a deletion from L747 and 7(3.6%)started from the beginning of T751 or S752.The median PFS was significantly different between groups(P<0.001).Patients harboring exon 19 del starting on T751 or S752 had the shortest median PFS(2.9 months,95%CI:1.6-4.3months),followed by those with E746 group(11.4months,95%CI:9.8-13.1months)and L747 group(17.2months,95%CI:11.6-22.8months).140 patients who had progressed were analyzed.EGFR 19dels harboring T751 or S752 were associated with a low incidence of T790M mutation(16.7%).Conclusions:Deletion location with or without amino acid insertion/substitution might affect first-generation efficacy and EGFR 19 variant differences should be considered when make a decision on EGFR-TKIs.Part ?:Sequential therapy according to distinct disease progression patterns in advanced ALK-positive non-small-cell lung cancer after crizotinib treatmentBackground:Crizotinib is recommended as first-line therapy for advanced anaplastic lymphoma kinase(ALK)-positive non-small-cell lung cancer(NSCLC).Despite its initial efficacy,patients ultimately acquired resistance to Crizotinib within 1 year.In such patients,the optimal sequential therapy after Crizotinib treatment remains unknown.This study explored which sequential therapy option confers the greatest benefit.Methods:138 patients with advanced ALK-positive NSCLC resistant to crizotinib were studied.Based on patterns of disease progression of metastases,patients were divided into 3 groups:brain progression,non-liver progression,and liver progression.Sequential therapies included crizotinib continuation plus local therapy,next-generation ALK inhibitors(ALKi),and chemotherapy.The primary endpoint was overall survival(OS)from the time of crizotinib resistance to death or last follow-up.Results:The 138 patients included 64 cases with progression in brain,57 cases in non-liver sites and 17 cases in liver.A significant difference in OS was observed between the distinct progression pattern(median OS,25.4 months in brain,15.8 months in non-liver,and 10.8 months in liver,respectively,P=0.020).The difference in OS between sequential therapies was statistically significant in the non-liver progression group(median OS,27.6months with next-generation ALK,13.3 months with crizotinib continuation,and 10.8months with chemotherapy,respectively,P=0.019).And no significant differences in OS were found in patients with progression in liver(P=0.061).Conclusions:Crizotinib continuation together with local therapy might be a feasible strategy for patients with progression in brain beyond Crizotinib resistance,as well as next-generation ALKi's.Next-generation ALKi's tended to provide a survival benefit in patients with non-liver progression.Part ?:Crizotinib versus platinum-based chemotherapy as first-line treatment for advanced non-small cell lung cancer with different ROS1 fusion variantsBackground:ROS1 gene fusion represents a specific subtype of non-small-cell lung cancer(NSCLC).Crizotinib is recommended for ROS1-positive NSCLC due to its favorable outcome in published clinical trials.However,due to the low incidence of ROS-1-positive NSCLC,there is limited information on real-world clinical outcomes in patients treated with either Crizotinib or platinum-based doublet chemotherapy.Methods:Outcomes were recorded in 102 patients with stage ?b or ? NSCLC who were treated at 4 Chinese hospitals between April,2010 and June,2019.Result:Of the 102 patients followed,71.6%were females,81.4%were non-smokers,and 98.0%had adenocarcinoma.First-line treatment with crizotinib achieved a significantly longer median progression-free survival(PFS)compared with platinum-based chemotherapy(14.9 months vs 8.5 months,respectively;P<0.001).Next-generation sequencing(NGS)identified 61 patients who had ROS1 fusion variants,including CD74(n=33)and non-CD74(n=28)variants.In patients harboring CD74 fusion variants,the median PFS with first-line crizotinib treatment was significantly longer than in those harboring non-CD74 fusion variants(20.1 months vs 12.0 months,respectively;P=0.046).However,in patients treated with platinum-based chemotherapy,there was no significant difference in PFS between the CD74 and non-CD74 variant groups(8.6 months vs 4.3 months,respectively;P=0.115).Overall survival(OS)was not reached.Conclusion:First-line therapy with Crizotinib is more beneficial than platinum-based chemotherapy in patients with advanced NSCLC with different ROS1 fusion variants.Patients harboring CD7474 fusion variants appear to response better to Crizotinib.