Clinical Outcomes And Optimal Treatment Strategy Of Epidermal Growth Factor Receptor Gene Mutated Locally Advanced Non-Small Cell Lung Cancer

Part1:Real-World Treatment Patterns and Clinical Outcomes in EGFR-Mutant Locally Advanced Lung Adenocarcinoma:A Multi-center StudyObjective:Chemoradiotherapy(CRT)is the standard care for unresectable locally advanced non-small cell lung cancer(LA-NSCLC).The optimal management of patients with epidermal growth factor receptor gene(EGFR)mutant LA-NSCLC is unclear.This study aims to evaluate the benefit of the early use of EGFR-tyrosine kinase inhibitors(TKI)in LA-NSCLC harboring EGFR mutations,either in combination with chemoradiation or radiation alone.Methods:This retrospective,multicenter cohort study assessed EGFR gene mutations and treatment outcomes among patients with unresectable stage ? lung adenocarcinoma(LAC)from 12 Chinese academic cancer institutions between January 1,2012 and December 31,2018.Patients with anaplastic lymphoma kinase(ALK)gene rearrangements were excluded.Patients were categorized into three primary treatment groups,including patients administered CRT,and EGFR-tyrosine kinase inhibitors(TKI)and radiation therapy(RT)with/without chemotherapy,or EGFR-TKI alone until tumor progression.Using Inverse probability of multiple treatment weighting(IPTW)of propensity score to account for confounding factors.The survival was estimated using the Kaplan-Meier method.Consider the competition of death event Cumulative incidence curves and Fine-Gray regression models for subdistribution hazard were then used to summarize and evaluate the first recurrences in different treatment groups.Results:EGFR mutations were present in 516/2137(24.1%)of genotyped patients.Of 511 eligible patients with EGFR mutation,245(47.9%)patients had exon 19 deletion,217(42.5%)had L858R exon,49 patients(9.6%)had uncommon mutations.Of440 patients with adequate information,104,105,and 231 patients were categorized into CRT,TKI+RT and EGFR-TKI respectively.By median 35.9 months(interquartile range,23.8-53.6)follow-up.the median PFS for CRT,TKI+RT,EGFR-TKI was 12.6,24.8 and 15.9 months(log-rank P<0.001),and the median OS was52.1,67.4 and 46.5 months(log-rank P=0.037)respectively.Compared to CRT,TK1+RT significantly improved PFS(P<0.001)and OS(P=0.035).EGFR-TKI treatment prolonged PFS(P=0.005)but not OS(P=0.875).For the EGFR uncommon mutation group,compared to EGFR-TKI,CRT and RT+TKI significantly improved PFS(P=0.022,0.042),and showed superior OS trend than the upfront TKI(P=0.487,0.065)TKI+RT was associated with a lower probability of local regional recurrence(adjusted hazard ratio[aHR],0.50;95%confidence interval[CI],0.33-0.78;P=0.002)and distant metastasis(aHR,0.57;95%CI,0.41-0.79;P=0.001).EGFR-TKI treatment alone was associated with a higher risk for local regional recurrence(HR,1.45;95%CI,1.03-2.03;P=0.031)and lower risk distant metastases(aHR,0.63;95%CI,0.44-0.89;P=0.01).IPTW analysis showed that the adjusted median PFS for groups CRT,TKI+RT,EGFR-TKI was 12.4,26.2 and 16.2 months(log-rank P<0.001)and the median OS was 51.0,67.4 and 49.3 months(log-rank P=0.084),respectively.Compared to CRT,RT+TKI with/without chemotherapy significantly improved PFS(aHR,0.40;95%CI,0.29-0.54;P<0.001)and OS(aHR,0.61;9%CI,0.38-0.98;P=0.039).EGFR-TKI treatment alone prolonged PFS(aHR,0.66,95%CI,0.50-0.87;P=0.003)but not OS(aHR,0.90;95%CI,0.62-1.32;P=0.595).TKI+RT was associated with a lower probability of local regional recurrence(aHR,0.48;95%CI,0·31-0·77;P=0.002)and distant metastasis(aHR,0.56;95%CI,0·39-0·79;P=0.001).EGFR-TKI treatment alone was associated with a higher risk for local regional recurrence(aHR,1.33;95%CI,0·95-1-87;P=0.10)and lower risk distant metastases(aHR,0.62;95%CI,0·42-0·90;P=0.013).Doubly robust IPTW analysis and multivariable Cox regression analysis yielded similar findings.Conclusions:Compared to the CRT or EGFR-TKI,First-line TKI+RT with effective control of local regional and distant diseases correlated with the longest PFS and OS in patients with EGFR-mutant unresectable LA-NSCLC.Part2:Radiation Pneumonitis after Cncurrent Target Therapy and Radiotherapy for Non-small Cell Lung CancerObjectives:Concurrent epidermal growth factor receptor-tyrosine kinase inhibitors(EGFR-TKI)with radiotherapy in patients with EGFR-mutant unresectable stage III non-small cell lung cancer(NSCLC)might improve survival.However,both treatments carry the potential risk of pneumonitis,and the dose constraints are based on limited clinical data.Our study aims to assess the outcomes and adverse events of concurrent EGFR-TKI or ALK-TKI in non-small cell lung cancer,especially focusing on lung toxicities,for this combined strategy.Methods:Between May 2012 and December 2017,patients with histologically and cytologically unresectable stage III NSCLC treated with concurrent radiotherapy and EGFR-TKI were enrolled in the retrospectively study.Between December 2015 and September 2020,patients with histologically and cytologically NSCLC with concurrent radiotherapy and ALK inhibitor also were enrolled in this study.The National Cancer Institute Common Toxicity criteria(NCICTC)version 4.0 was used to assess treatment-related toxicities,including radiation pneumonitis and fibrosis.The modified Medical Research Council(mMRC)questionnaire with grade 0-4 scales(mild to severe symptom)was used to evaluate the extent of dyspnea symptoms.The survival was assessed using Kaplan-Meier analysis.The analysis of the lung toxicity grade used logistic regression analysis.Results:Among 45 eligible patients,20(44.4%)had an EGFR mutation and 44(97.8%)received 50-66 Gy of radiotherapy.The median follow-up was 62.7 months(IQR,51.4-74.2).The median progression free survival and overall survival for patients with EGFR-mutations were 27.9(95%CI,18.7-37.2)and of 49.7(95%Cl,27.7-71.8)months,and 13.8(95%CI,8.8-18.9)and 31.1(95%CI,9.8-52.4)months for EGFR wild-type/unknown patients.Seventeen patients(37.7%)developed radiation pneumonitis(14 grade 2,3 grade 3):In 16 patients,pneumonitis occurred within the radiation field and one patient had bilateral pneumonitis.The median time from the initial radiotherapy to pneumonitis was 74(range,42-156)days.Logistic regression analysis revealed a trend between the time of EGFR-TKI and the development of G2 pneumonitis.For late toxicity,only two patients had G2 fibrosis.The daily dyspnea symptoms of patients.with G2+pneumonitis recovered significantly after the phase of pneumonitis(P=0.007).Of the 9 adenocarcinoma patients treated with ALK inhibitors,9 patients had an ALK rearrangement,the median age was 39 years old(range 30-57),and received dose was 53.75-60Gy radiotherapy,1 patient received 60Gy/10F,4 patients received radiotherapy combined with ALK-TKI first-line therapy,and 5 patients received?2-line salvage radiotherapy.After a median follow-up of 19.5 months(IQR,17.3-25.9),3 patients(33.3%)developed tumor progression after treatment,and all patients was alive,with 7 patients(77.8%)developing grade 2 radiation pneumonitis and no grade 3 or higher occurred.The median time from the start of radiotherapy to pneumonitis was 72 days(range,47-151 days),with pneumonia occurring in the radiation field.Conclusions:Combined EGFR-TKI and radiotherapy showed favorable survival in EGFR-mutant patients with inoperable LA-NSCLC,with a 6.7%incidence of grade 3+radiation pneumonitis/pneumonitis and without higher grade increase.Mild radiation pneumonitis was significantly increased in patients receiving radiotherapy with ALK-TKI,despite no moderate to severe pneumonia(grade 3-5)occurred.Radiotherapy combined with EGFR-TKI/ALK-TKI was warrant for further study.