Efficacy and safety of utidelone for the treatment of patients with locally advanced or metastatic non-small-cell lung cancer who have failed standard second-line treatment:A phase 2 clinical trial(BG01-1801)

Background:Chemotherapy remains the standard-of-care for many patients with locally advanced or metastatic non-small-cell lung cancer(NSCLC),but acquired resistance presents challenges.The aim of this open-label,multicenter phase 2 clinical trial was to determine the efficacy and safety of utidelone,a novel genetically engineered epothilone analog and microtubule-stabilizing agent,as a third-or later-line treatment for locally advanced ormetastatic NSCLC.Methods:Patients who had failed standard second-line treatment(including platinum-containing chemotherapy or targeted therapy)received utidelone(40 mg/m?via intravenous injection daily,day 1-5)every 21 days.The primary endpoint was the objective response rate(ORR).Secondary endpoints were the duration of response(DoR),progression-free survival(PFS),overall survival(OS),and safety.Results:From March 12,2019 to January 18,2021,26 pretreated patients with locally advanced or metastatic NSCLC(100%of patients had received prior platinum and 65.4%patients had received prior taxane treatment)were enrolled(80.8%of patients had adenocarcinoma).At baseline,nine(34.6%)patients had received secondline treatment,10(38.5%)patients had received third-line treatment,and seven(26.9%)patients had received fourth-or later-line treatment.By the data cut-off date of August 10,2021,the median follow-up was 7.49 months(range,1.4-26.7 months).The ORR was 15.4%(95%confidence interval[CI],4.4%-34.9%)in the intention-totreat(ITT)cohort(N=26)and 19.0%(95%CI,5.4%-41.9%)in the per-protocol(PP)cohort(N=21).The disease control rate was 69.2%(95%CI,48.2%-85.7%)and 81.0%(95%CI,58.1%-94.6%)in the ITT and PP cohorts,respectively.The median DoR was 4.1 months(95%CI,3.1-5.1 months)in the ITT cohort.The median PFS was 4.37 months(95%CI,2.50-5.29 months)in the ITT cohort and 4.37 months(95%CI,2.50-9.76 months)in the PP cohort.The median OS was not reached,and the 12-month OS rate was 69%(95%CI,45.1%-84.1%).Grade 3/4 treatment-emergent adverse events occurred in 38.5%of patients,and the most common was peripheral neuropathy(23.1%,all Grade 3),which was manageable with dose modifications.Conclusions:In this clinical trial,utidelone showed promising efficacy and had a manageable safety profile.Furtherclinical studies arewarranted to confirm its role in NSCLC treatment.Trial registration:No.NCT03693547;https://classic.clinicaltrials.gov.

转移性非小细胞肺癌的化学治疗现状与进展

近年来,吸烟、污染以及油烟等导致肺癌的发病率及病死率迅速增长。非小细胞肺癌起病隐匿,发展迅速,预后差,患者初诊时多数即发生转移(IV期),失去手术机会,化疗是其主要的治疗方法,目的在于延长生存期、提高生活质量。目前临床应用的化疗药物主要是铂类以及第三代细胞毒药物。基于功能基因组学和蛋白组学的个体化治疗,为每一位肺癌患者设计最佳治疗策略是2l世纪临床发展的方向和理想的治疗模式。本文就转移性非小细胞肺癌的化学治疗现状与进展作一文献综述。

Organ-specific efficacy in advanced non-small cell lung cancer patients treated with first-line single-agent immune checkpoint inhibitors

Background:Response to immune checkpoint inhibitors(ICIs)is affected by multiple factors.This study aimed to explore whether sites of metastasis are associated with clinical outcomes of ICIs in advanced non-small-cell lung cancer(NSCLC)patients.Methods::The data of NSCLC patients with high programmed death-ligand 1 expression and good performance status receiving first-line ICIs monotherapy from Guangdong Provincial People’s Hospital between May 2019 and July 2020 were retrospectively analyzed.Metastatic sites included liver,bone,brain,adrenal gland,pleura,and contralateral lung.Progression-free survival(PFS)and overall survival(OS)were compared between different metastatic sites and metastatic burden by the Kaplan-Meier method.Organ-specific disease control rate(OSDCR)of different individual metastatic sites was evaluated.Results:Forty NSCLC patients meeting the criteria were identified.The presence of liver metastasis was significantly associated with shorter PFS(3.1 vs.15.5 months,P=0.0005)and OS(11.1 months vs.not reached,P=0.0016).Besides,patients with bone metastasis tend to get shorter PFS(4.2 vs.15.5 months,P=0.0532)rather than OS(P=0.6086).Moreover,the application of local treatment could numerically prolong PFS in patients with brain metastasis(15.5 vs.4.3 months,P=0.1894).More metastatic organs involved were associated with inferior PFS(P=0.0052)but not OS(P=0.0791).The presence of liver metastasis or bone metastasis was associated with more metastatic organs(Phi[φ]:0.516,P=0.001).The highest OSDCR was observed in lung(15/17),and the lowest in the liver(1/4).Conclusions:Metastases in different anatomical locations may be associated with different clinical outcomes and local tumor response to ICIs in NSCLC.ICIs monotherapy shows limited efficacy in patients with liver and bone metastasis,thus patients with this type of metastasis might require more aggressive combination strategies.