Clinical Outcome And Resistance Mechanism Of Osimertinib In EGFR-mutated Advanced Non-Small-Cell Lung Cancer

Part I Efficacy and safety of osimertinib in patients with pretreated advanced non-small cell lung cancerBackground:Osimertinib is an oral,irreversible third-generation epidermal growth factor receptor(EGFR)tyrosine kinase inhibitor(TKI).The results of several clinical trials demonstrated its efficacy in patients with non-small-cell lung cancer(NSCLC)harboring EGFR sensitizing mutations and T790M resistance mutations,while the real-world data of osimertinib in Chinese patients was lacking.Our study aimed to assess the efficacy and safety of osimertinib in patients with pretreated NSCLC in the real-world setting.Methods:Ninety-four patients with pretreated advanced EGFR-mutated NSCLC who received osimertinib between Mar 1,2017 and Jul 1,2018 were retrospectively collected.Primary endpoints were disease control rate(DCR)and progression-free survival(PFS).Secondary objectives included objective response rate(ORR),duration of response(DoR),and safety.Results:A total of 94 patients were included.In evaluable for response analysis set(n=91),overall ORR was 47.3%,and DCR was 90.1%.Median DoR in responding patients was 12.5 months(95%CI,10.7-14.3).Median PFS was 8.6 months(95%CI,7.2-10.0)in overall population,8.5 months(95%CI,7.4-9.6)in 2nd line group,and 9.1 months(95%CI,6.6-11.6)in?3rd line group.For subgroup analysis,DCR and median PFS were 91.9%and 8.6 months(95%CI,7.2-10.0)in patients with detectable T790M mutation at baseline,respectively,while 80.0%and 3.2 months(95%CI,0.5-5.9)for those without.Median PFS was significantly longer for T790M-positive patients co-occurring with exon19del than with L858R mutation(17.9 months vs.7.3 months;P<0.001).Among 45 patients with metastases to the central nervous system(CNS),median systemic PFS was 8.8 months(95%Cl,6.9-10.7),while intracranial time to progression(iTTP)was not reached.Safety profile was acceptable in our study patients,no adverse events(AEs)related deaths was observed.Conclusions:Osimertinib was highly active in patients with pretreated advanced NSCLC who harbored EGFR T790M mutation,with manageable side-effects.Part II Acquired resistance to osimertinib in patients with advanced non-small cell lung cancer:Mechanisms and clinical outcomesBackground:Osimertinib,a third-generation epidermal growth factor receptor tyrosine-kinase inhibitor(EGFR-TKI),has demonstrated substantial clinical benefit in patients with non-small cell lung cancer(NSCLC)who resistant to early-generation EGFR-TKIs and acquired T790M mutation.However,resistance to osimertinib ultimately occurs after approximately 10 months according to prospective clinical research.The aim of our study was to identify mechanism of resistance to osimertinib and correlate it with the clinical outcomes.Methods:We retrospectively analyzed patients with advanced NSCLC who received osimertinib for T790M-mutated acquired resistance to prior EGFR-TKI between Mar 1,2017 and Dec 31,2018.Patients with paired molecular data of pre-osimertinib and after resistance development,and was not confirmed with SCLC transformation were included in the molecular analysis set.The data cutoff was May 14,2019.Results:Of the 49 patients evaluated in the molecular analysis set,24 patients maintained T790M mutation,while 25 patients performed T790M-loss.Molecular modification was identified in 27 of 49 patients,including EGFR acquired mutations(C797S,C796S,G796S,V802I,V834L,E758D and G724S),non-EGFR dependent mutations(PIK3CA,ALK,BRAF,KRAS and TP53),EGFR amplification and MET amplification.At data cutoff,median progression-free survival(PFS)was 9.3 months(95%Cl,4.9,13.7)in the T790M-retained group,compared with 7.8 months(95%CI,5.4,10.2)in the T790M-loss population(P=0.053).Median PFS was significantly longer in patients with EGFR-dependent resistance mechanism(13.5 months[95%CI,9.1,17.9])than in those with bypass activation(8.2 months[95%CI,3.6,12.8];P=0.007).Conclusions:Our study demonstrated heterogeneous mechanisms of resistance to osimertinib in Chinese patients with advanced NSCLC.Patients who maintained T790M mutation or with EGFR-dependent resistance mechanism have a longer clinical benefit.Part III Clinical modality of osimertinib resistance and subsequent management analysis in patients with advanced non-small cell lung cancerBackground:Third-generation epidermal growth factor receptor(EGFR)tyrosine kinase inhibitor(TKI)osimertinib has become the standard treatment in patients with pretreated non-small cell lung cancer(NSCLC)who developed T790M resistance mutation.However,no standard treatment after osimertinib failure has been established.The aim of our study was to explore clinical resistance modality of osimertinib and assess the survival benefit of post-progression treatment in the real-world setting.Methods:Between Mar 1,2017 and Jul 1,2018,medical data of patients with advanced NSCLC who developed resistance to osimertinib were retrospectively collected in our cancer center.Results:A total of 65 patients were analyzed.Clinical resistance modality varied among patients:15(23.1%)with local progression,29(44.6%)with gradual progression and 21(32.3%)with dramatic progression.As for site of osimertinib failure,most patients performed intrathoracic progression only(40/65,61.5%),while only 10(15.4%)cases presented intracranial failure alone.After evidence of progressive disease(PD),20 patients(30.8%)received subsequent chemotherapy,and showed a trend of longer median overall-survival(OS)compared to those with non-chemotherapy regimen(25.0 months vs.11.8 months,P=0.106).Thirty-nine patients(60.0%)continued osimertinib beyond progression with median post-progression treatment duration of 4.1 months.No significant difference of median OS in osimertinib-continued and osimertinib-discontinued groups(18.9 months vs.15.1 months,P=0.802)was found.For subgroup analysis,OS was in favor of chemotherapy in patients performed dramatic progression,but was immature in patients with local or gradual progression.Conclusions:Chemotherapy was an effective option after osimertinib failure in advance NSCLC.Continuation of osimertinib beyond progression did not provide survival benefit in non-selected patients.