Real-world Study Of Diagnosis,Treatment And Prognosis In Chinses Advanced Lung Cancer Patients With Rare Driver Mutations

Background: Harboring different driver mutations is a result of inter-tumor heterogeneity.There has been a paucity of prospective data focusing on rare driver mutations,and knowledge in this field is poor.A large-scale,real-world study would be highly valuable,however,studies in this field are sparse and sporadic and lack power.For these patients,clinical evidence is very limited,and it’s largely unknown how to optimize their clinical management.Objectives: Our study will focus on advanced non-small cell lung cancer(NSCLC)patients with rare driver mutations,performing systemic evaluation and analyzing their treatment,long-term survival,and prognosis in a real-word setting.Methods: Patients diagnosed with advanced NSCLC between 2011 and 2017 were identified in our standard database.Information involving clinicopathological parameters,treatment,and prognosis were collected.Baseline characteristics of the two groups were compared using Fisher’s exact test or χ2 test when applicable.Progressionfree survival(PFS)and overall survival(OS)were calculated by the Kaplan-Meier method and compared by log-rank text.The hazard ratio(HR)for the risk of progression or death was calculated using multivariate Cox regression model.A P value <0.05 was considered statistically significant.All the analysis was performed using Statistical Package for Social Science(SPSS,Chicago,IL,USA)22.0 version for Windows.Results: 1).In EGFR signaling pathways,complex EGFR mutations account for 3.2% of the entire EGFR mutation spectrum and comprised a variety of mutation types.PFS for patients who had 19del+21L858R(Group A,n=27),19del/21L858R+atypical mutations(Group B,n=28),double atypical mutations(Group C,n=20)and complex mutations with primary drug-resistant patterns(Group D,n=20)were 18.2 months(95% CI,12.0 months to 24.4 months),10.1 months(95% CI,6.5 months to 13.7 months),11.1 months(95% CI,6.8 months to 15.4 months)and 1.4months(95% CI,0.2 months to 2.5 months),respectively.Patients in Group D derived a statistically longer PFS(18.0 months,95% CI,15.1-20.9 months,P <0.001)and OS(25.1 months,95% CI,not calculable,P=0.02)when treated with osimertinib.2).In a real-world setting,patients with ALK rearrangement derived a median PFS and OS of 12.4 months(95% CI,10.3-14.6 months)and 45.6 months(95% CI,37.6-53.7 months)when treated with crizotinib.16.4% patients can achieve long-term survival(PFS>36 months),and 36.3% of patients were 5-year survivors.Extrathoracic metastasis before crizotinib treatment was independently associated with worse PFS(HR,1.77,95% CI,1.24-2.53,P < 0.01)and OS(HR,1.61,95% CI,1.02-2.54,P=0.04).Next-generation ALK-TKIs can reduce death risk(HR,0.33,95% CI,0.17-0.63,P < 0.01).Continuation of crizotinib alone or combined with radiotherapy may confer an extra 6.1 months benefit in terms of PFS even after RECIST PD.3).79.2% of patients show at least one treatment-involved driver mutation based on targeted next-generation sequencing.15.9% of patients changed therapeutic strategy,deriving 44.4% and 4.07 months(95% CI,2.8-5.4months)in terms of ORR and PFS.Conclusion: 1).Patients with double classical mutations had the best ORR and PFS compared with other mutation types and may benefit more from TKIs treatment.In addition,those who harbored complex mutations with classical pattern or double atypical mutations derived similar PFS compared to individuals who had a single classical mutation.Moreover,the introduction of a sensitive mutation to T790 M mutation didn’t increase the effectiveness of TKIs,and osimertinib carries a great survival benefit,and thus should be considered during the whole clinical management.2).36.3% of advanced lung adenocarcinoma patients can be clinically cured by sequential treatment with ALK-TKIs(OS > 5 years).The presence of extrathoracic metastasis before crizotinib treatment was independently associated with a worse prognosis.Switching therapeutic strategy based on RECIST criteria might lose the patients who can get durable survival benefit.3).An NGS-based clinical decision may confer a slight survival benefit for selected patients.