Effectiveness and Tolerability of First-Line Afatinib for Advanced EGFR-Mutant Non-Small Cell Lung Cancer in Vietnam

Background: We aimed to evaluate the effectiveness and tolerability of Afatinib as first-line treatment of advanced epidermal growth factor receptor (EGFR) mutant non small cell lung cancer (NSCLC) in a real-world setting. Patients and methods: This is a retrospective study of Vietnamese patients  with advanced EGFR-mutant NSCLC treated with first-line afatinib at the National Cancer Hospital from 1st January 2018 to 31st October 2020. Patients’ demographic, clinical and treatment data were captured. Objective response rate (ORR), disease control rate (DCR), time to treatment failure (TTF) and tolerability were evaluated. We used Kaplan-Meier curve and log-rank test for survival, and Cox regression model for multivariate analysis. Results: A total of 44 patients were included. Common EGFR mutations (Del 19/L858R) were detected in 61% patients. Fifty percent of patients with uncommon mutations had compound mutations of G719X, L861Q and S768I. The ORR was 75% while DCR rate was 98%. The median TTF was 12.3 months (95% CI: 7.2-17.3); the mTTFs were 12.3 and 10.8 months for patients with common and uncommon mutations (p = 0.001), respectively, and 14.0 and 7.5 months for patients with Del 19 and L858R mutations (p = 0.067), respectively. Afatinib 30 mg once daily was the most common starting (77%) and maintenance (64%) doses. The mTTFs were 12.3 and 7.5 months for patients with 30 mg starting dose vs 40 mg dose (p = 0.256), respectively. Diarrhea, skin rash, paronychia and fatigue were observed in 32%, 30%, 25% and 9%, respectively. There was no grade 4 toxicity except three patients with grade 3 paronychia. Conclusions: First-line afatinib is beneficial for Vietnamese patients with advanced EGFR-mutant NSCLC with a good response rate and prolonged TTF with manageable adverse event profile. Baseline brain metastasis status and starting doses do not significantly impact TTF.     

Real-World Testing Practices,Treatment Patterns and Clinical Outcomes in Patients from Central Eastern Europe with EGFR-Mutated Advanced Non-Small Cell Lung Cancer: A Retrospective Chart Review Study (REFLECT)

The targeted therapy with tyrosine kinase inhibitors (TKIs) against the epidermal growth factor receptor mutation (EGFRm) in advanced non-small cell lung cancer (NSCLC) changed the treatment paradigm. REFLECT study ({"type":"clinical-trial","attrs":{"text":"NCT04031898","term_id":"NCT04031898"}}NCT04031898) explored EGFR/T790M testing and treatment patterns in EGFRm NSCLC patients receiving first- or second-generation (1G/2G) EGFR TKIs as front-line (1L) in eight countries. Pooled data from Central Eastern Europe (CEE) countries from this study (Bulgaria, Poland, Romania, Slovenia) are presented here. This physician-led chart review study was conducted in patients with confirmed-EGFRm NSCLC initiating 1L 1G/2G EGFR TKIs between 2015–2018. The CEE cohort included 389 patients receiving 1L erlotinib (37%), afatinib (34%), and gefitinib (29%). Overall, 320 (82%) patients discontinued 1L, and 298 (77%) progression events were registered. Median progression free survival on 1L TKIs was 14.0 (95% CI: 12.6–15.6) months. Median overall survival from 1L start was 26.6 (95% CI: 24.1–29.0) months. Attrition rate between 1L and next line was 30%. Among patients with 1L progression, 200 (67%) were tested for T790M and 58% were positive. This first CEE analysis of treatments and outcomes in EGFRm NSCLC patients highlights the importance of using the most efficacious therapies currently available in 1L to reduce attrition and improve patient outcomes.     

Real-World Efficacy and Tolerability of Brigatinib in Patients with Non-Small Cell Lung Cancer with Prior ALK-TKIs in the United States

BackgroundReal-world evidence for brigatinib, a next-generation anaplastic lymphoma kinase-tyrosine kinase inhibitor (ALK-TKI) used in ALK-rearranged non-small cell lung cancer, is scarce. This retrospective study evaluated real-world brigatinib utilization in the US post other ALK-TKIs.Materials and MethodsAdults with ≥1 brigatinib claim (index date) between 1 April 2017 and 30 September 2020 in the IQVIA longitudinal pharmacy claims database were followed until dose reduction, discontinuation, or end of follow-up. Patients had ≥12 months pre– and ≥1-month post–index observations.ResultsA total of 413 patients treated with brigatinib were analyzed. Over 80% received ≥1 prior ALK-TKI; alectinib and crizotinib were the most common (58.8% and 51.3% patients, respectively). The median follow-up was 8.4 months. The median time to treatment discontinuation (TTD) for brigatinib was 10.3 months (95% CI, 8.2-15.0), with 45% remaining on therapy at 12 months. The TTD was shortest (~8 months) in patients receiving both crizotinib and alectinib and longest in patients who received alectinib only prior to brigatinib (11.8 months). Adherence was high, with 92.7% of patients having a medication possession ratio of >80%. The mean dose compliance score was 1.0. Most patients reached the brigatinib dose of 180 mg/day (77%); 13.2% of patients had a dose reduction, with 89.3% and 84.6% continuing 180 mg/day therapy at 3 and 6 months, respectively.ConclusionsBrigatinib appears to be effective and well-tolerated in the real-world ALK+ NSCLC population in the US, showing benefit in patients after a next-generation ALK-TKI. Notably, dose reduction rates appeared markedly less than those seen in trials when most trial-related dose reductions were for asymptomatic laboratory abnormalities.     

Vinorelbine in Non-Small Cell Lung Cancer: Real-World Data From a Single-Institution Experience

The use of vinorelbine as a single agent or in combination regimens in non-small cell lung cancer (NSCLC) is associated with satisfactory clinical activity. However, the role of vinorelbine-based chemotherapy in chemonaive locally advanced unresectable or metastatic NSCLC patients, according to real-world treatment patterns, has still not been widely explored. Eighty-one patients treated at a single institution were retrospectively analyzed. Thirty-seven received standard first-line single-agent vinorelbine, and 44 received vinorelbine plus platinum drugs, based on physician’s choice; 61.7% were older than 70 years, and 60.5% were affected by 2 comorbidities. Sixty-three patients were evaluable for objective response: 22% achieved partial response and 41% stable disease. Median progression-free survival (PFS) was 5.4 months. A benefit in PFS was observed in patients treated with combinations vs. single-agent vinorelbine (6.7 vs. 3.5 months, p=0.043). Median overall survival (OS) was 10.4 months without a statistically significant difference between treatments (12.4 vs. 7.5 months). In 55 stage IV patients, OS was positively correlated with combination regimens, M1a stage, or 2 metastatic lesions. Grade 3–4 toxicity occurred in 33% of patients, and dose reduction in 11%. A statistically significant higher incidence of toxicity was observed in patients receiving combinations, in women, in patients younger than 75 years, or patients with metastases. In this real-word analysis, we confirmed the efficacy and tolerability of vinorelbine as a single agent or combined with platinums in patients usually underrepresented in controlled clinical trials. Single-agent vinorelbine may represent a suitable option in elderly or unfit NSCLC patients and warrants investigation as a potential drug candidate for immunochemotherapy combination regimens.     

Real-World Treatment Patterns,Clinical Outcomes,and Health Care Resource Utilization in Extensive-Stage Small Cell Lung Cancer in Canada

The prognosis for extensive-stage small cell lung cancer (ES-SCLC) is poor. Real-world evidence can highlight the unmet clinical need within this population. We conducted a population-based cohort study of ES-SCLC patients diagnosed in a large Canadian province (2010–2018) using electronic medical records and administrative claims data. In all, 1941 ES-SCLC patients were included, of which 476 (25%) were recurrent cases. Median age at diagnosis was 70 years (range: 39–94) and 50.2% were men. Of the 1941 ES-SCLC patients, 29.5% received chemotherapy and radiotherapy, 17.0% chemotherapy alone, 8.7% radiotherapy alone, and 44.8% received best supportive care. Chemotherapy was initiated by 46.5%, 8.5%, and 1.4% of first-, second-, and third-line patients, with lower uptake for recurrent cases. Median survival from first-, second-, and third-line chemotherapy was 7.82 months (95% CI: 7.50–8.22), 5.72 months (95% CI: 4.90–6.87), and 3.83 months (95% CI: 2.99–4.60). Among patients who received first-line therapy, the 2-year and 5-year survival was 7.3% (95% CI: 5.7–9.2) and 2.9% (95% CI: 1.8–4.5). In conclusion, initiation of first-line treatment in ES-SCLC was low with significant attrition in subsequent lines. These results underscore the need for effective front-line treatments and highlight the potential for novel therapies to improve patient outcomes.     

Uncommon EGFR Compound Mutations in Non-Small Cell Lung Cancer (NSCLC): A Systematic Review of Available Evidence

Compound epidermal growth factor receptor (EGFR) mutations represent a heterogeneous subgroup of non-small cell lung cancer (NSCLC) patients with uncommon EGFR mutations. We conducted a systematic review to investigate the available data on this patients’ subgroup. Overall, we found a high heterogeneity in the incidence of compound mutations (4–26% of total EGFR mutant cases), which is dependent on the different testing methods adopted and the specific mutations considered. In addition, the relative incidence of distinct compound subclasses identified is reported with extreme variability in different studies. Preclinical and clinical data, excluding de novo EGFR exon 20 p.T790M compound mutations, show good responses with EGFR tyrosine kinase inhibitors (TKIs) (combined common mutations: response rate (RR) ≥ 75% with either first- or second-generation TKIs; combined common plus uncommon: RR 40–80% and 100% with first-generation TKIs and afatinib, respectively; combined uncommon: RR 20–70%, ~80% and ~75% with first-generation TKIs, afatinib and osimertinib, respectively). Overall, data are consistent in supporting the use of EGFR TKIs in treating compound EGFR mutations, taking into account different sensitivity profile of accompanying EGFR mutations for selecting the most adequate EGFR TKI for individual patients.     

Multicenter Real-World Study on Effectiveness and Early Discontinuation Predictors in Patients With Non-small Cell Lung Cancer Receiving Nivolumab

BackgroundReal-world (RW) evidence on nivolumab in pretreated patients with non-small cell lung cancer (NSCLC) by matching data from administrative health flows (AHFs) and clinical records (CRs) may close the gap between pivotal trials and clinical practice.MethodsThis multicenter RW study aims at investigating median time to treatment discontinuation (mTTD), overall survival (mOS) of nivolumab in pretreated patients with NSCLC both from AHF and CR; clinical-pathological features predictive of early treatment discontinuation (etd), budget impact (BI), and cost-effectiveness analysis were investigated; mOS in patients receiving nivolumab and docetaxel was assessed.ResultsOverall, 237 patients with NSCLC treated with nivolumab were identified from AHFs; mTTD and mOS were 4.2 and 9.8 months, respectively; 141 (59%) received at least 6 treatment cycles, 96 (41%) received < 6 (etd). Median overall survival in patients with and without etd were 3.3 and 19.6 months, respectively (P < .0001). Higher number, longer duration, and higher cost of hospitalizations were observed in etd cases. Clinical records were available for 162 patients treated with nivolumab (cohort 1) and 83 with docetaxel (cohort 2). Median time to treatment discontinuation was 4.8 and 2.6 months, respectively (P < .0001); risk of death was significantly higher in cohort 2 or cohort 1 with etd compared with cohort 1 without etd (P < .0001). Predictors of etd were body mass index <25, Eastern Cooperative Oncology Group performance status >1, neutrophile-to-lymphocyte ratio >2.91, and concomitant treatment with antibiotics and glucocorticoids. The incremental cost-effectiveness ratio of nivolumab was 3323.64 euros ($3757.37) in all patients and 2805.75 euros ($3171.47) for patients without etd. Finally, the BI gap (real-theoretical) was 857 188 euros ($969 050.18).ConclusionWe defined predictors and prognostic-economic impact of nivolumab in etd patients.     

Cell Free EGFR mRNA Expression and Implications for Survival and Metastasis in Non-Small Cell Lung Cancer Cases

Background: NSCLC is a disease involving uncontrolled cell growth, which could result in metastases intonearby tissues beyond the lungs. Materials and Methods: The aim of the present study was to analyze the influenceof epidermal growth factor receptor (EGFR) gene expression on metastasis and survival in NSCLC patients.The present case-control study included 100 cases of NSCLC patients and 100 age and sex matched controls.EGFR gene expression was analyzed by quantitative real time PCR using serum RNA. Association with NSCLCpatient survival was analyzed by the Kaplan-Meier method. Results: We analyzed EGFR gene expression andobserved mean increased gene expression of 13.5 fold in NSCLC patients. Values reflected overall survival ofpatients with a median of 15.8 months in the cases of <13 fold increased gene expression vs 6.7 months with >13fold increased EGFR gene expression (p=0.005). Distant metastatic patients with <13 fold increased EGFR geneexpression had 7.9 months of median survival time while>13 fold increased EGFR gene expression had only 5months of median survival time (p=0.03). Non metastatic patients with <13 fold increased EGFR gene expressionhad 18 months of median survival time as compared to only 7.1 months with >13 fold increased expression.Conclusions: Higher cell free EGFR mRNA expression may play an important role in causing distant metastasesand reducing overall survival of NSCLC patients in the Indian population.     

细胞周期蛋白D_1在非小细胞肺癌中表达的临床意义

目的　探讨非小细胞肺癌 (NSCLC)中细胞周期蛋白D1(CyclinD1)的表达及其临床意义。方法　用鼠抗人CyclinD1单克隆抗体(DCS/6 )对 89例石蜡包埋的原发性NSCLC组织进行免疫组化染色 ,并与 2 0例肺炎性病变比较。结果　CyclinD1在肺鳞癌、腺癌、大细胞癌中都有较高的表达 ,其阳性率分别为 6 0 .5 %、6 1.0 %、40 .0 % ;而在肺炎性病变中 ,则全部阴性。在肺鳞癌、腺癌中 ,肿块直径≥ 3cm、有淋巴结转移或远处转移者 ,其CyclinD1阳性率较高 (P <0 .0 5 ) ,且与临床分期有关 ,Ⅲ～Ⅳ期癌中的阳性率高于Ⅰ～Ⅱ期癌 (P <0 .0 5 )。结论　CyclinD1的过表达与NSCLC的发生、发展和预后等密切相关 ,对NSCLC的诊断、治疗有一定的指导意义 ,可作为一个诊断及预后指标。     

Evolution of Systemic Treatment Uptake and Survival in Advanced Non-Small Cell Lung Cancer

Background: Non-small cell lung cancer (NSCLC) commonly presents at advanced stage. We previously reported systemic treatment uptake in stage IV NSCLC climbing from 55% (2009–2012) to 62% (2015–2017). Since then, first-line immunotherapy and 2nd/3rd generation tyrosine kinase inhibitors (TKIs) have emerged as standards of care. We explored whether treatment rates continued to rise and studied outcomes. Methods: We reviewed all cases of de novo stage IIIB/IIIC/IV NSCLC seen in out-patient medical oncology consultation at our institution between 2009–2012 (cohort A), 2015–2017 (cohort B), and June–December 2018 (cohort C). We compared rates of systemic treatment, molecular testing, targeted therapy, and immune checkpoint inhibitor (ICI) use. We compared survival in the overall, treated/untreated, younger and elderly population in cohort A vs. cohort B + C (=cohort D). Results: Cohorts A, B, and C included 528, 463, and 93 patients, respectively. Overall, 66% received any systemic therapy in cohort C, compared to 62% in cohort B and 55% in cohort A. Across three time periods, first-line chemotherapy rates fell (93, 76, 46%) while rates of first-line targeted therapy (5, 16, 15%) and ICI (0, 2, 36%) rose. Among molecular subtypes, first-line targeted treatment in EGFR-positive patients (63, 94, 100%) and anaplastic lymphoma kinase (ALK)-positive patients (0, 91, 100%) rose. Survival improved in all subgroups in cohort D vs. cohort A, except for patients ≥ 70 years and the untreated population. Conclusions: Systemic treatment rose across three time periods, reflecting the introduction of rapid diagnostic pathways, reflex molecular testing, ICI, and targeted therapies. Survival outcomes of advanced NSCLC patients have significantly improved.     

Systematic Analysis of Icotinib Treatment for Patients with Non-Small Cell Lung Cancer

Purpose: This analysis was conducted to evaluate the efficacy and safety of icotinib based regimens in treatingpatients with non-small cell lung cancer (NSCLC). Methods: Clinical studies evaluating the efficacy and safetyof icotinib-based regimens with regard to response and safety for patients with NSCLC were identified usinga predefined search strategy. Pooled response rates of treatment were calculated. Results: With icotinib-basedregimens, 7 clinical studies which including 5,985 Chinese patients with NSCLC were considered eligible forinclusion. The pooled analysis suggested that, in all patients, the positive reponse rate was 30.1% (1,803/5,985)with icotinib-based regimens. Mild skin itching, rashes and diarrhea were the main side effects. No grade III orIV renal or liver toxicity was observed. No treatment-related death occurred in patients treated with icotinibbasedregimens. Conclusions: This evidence based analysis suggests that icotinib based regimens are associatedwith mild response rate and acceptable toxicity for treating Chinese patients with NSCLC.     

非小细胞肺癌和肺结核中血清BCAR1水平的临床意义

探讨血清BCAR1水平在非小细胞肺癌和肺结核中的临床意义。方法：采用酶联免疫试剂方法（ELISA）检测2009年3月至2010年5月期间65例非小细胞肺癌（NSCLC）,26例肺良性肿瘤（炎性假瘤15例、错构瘤7例、纤维瘤4例）,30例肺结核患者（结核瘤17例,空洞型肺结核13例）,40例正常人血清BCAR1水平。结果：NSCLC组血清BCAR1水平高于肺良性肿瘤组和正常对照组（P<0.001）,而与肺结核组无显著差异（P>0.05）;血清BCAR1水平与性别、年龄和淋巴结转移无关（P>0.05）;与鳞癌和腺癌病理类型无关（P>0.05）,支气管肺泡癌BCAR1血清水平低于其它类型NSCLC（P=0.02）;BCAR1血清水平随着临床分期增加有逐渐递增的趋势;BCAR1血清水平在切除肿瘤后其血清水平降低;肺结核组BCAR1血清水平高于正常对照组和肺良性肿瘤组（P<0.001）,与结核病变的直径呈正相关（rs=0.92,P<0.001）,切除结核病变后其血清水平下降,空洞型肺结核血清中BCAR1水平高于结核瘤（P<0.001）;肺良性肿瘤组和正常对照组血清BCAR1水平无显著性差异（P>0.05）。结论：血清BCAR1可以作为NSCLC和肺结核诊断、了解病情进展和判断治疗效果新指标。     

248例N0期非小细胞肺癌的预后因素分析

目的:回顾性分析248例N0期非小细胞肺癌的预后因素。方法:本文选取1994年1月～1997年7月间行根治性切除的248例N0期非小细胞肺癌,采用Kaplan-Meier法绘制生存曲线(Log-Rank检验)和COX多因素回归对该组病例的预后因素进行分析。结果:术中同侧肺门和纵隔淋巴结清扫超过6枚的病例生存率高于6枚以下的病例(P=0.005);术后生存率随T1、T2、T3和T4依次明显递减(P<0.001);术后化疗组病例的生存期高于非化疗组(P=0.016);鳞癌和腺癌的生存率高于其他病理类型(P=0.002)。结论:纵隔淋巴结的清扫数量、术后化疗与否、肿瘤的T分期和病理类型是影响N0期非小细胞肺癌预后的主要因素,而性别、术后放疗、术后免疫治疗、手术方式等对预后无明显影响。     

Src inhibitors act through different mechanisms in Non-Small Cell Lung Cancer models depending on EGFR and RAS mutational status

Resistance to the EGFR tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib, often related to Ras or secondary EGFR mutations, is a relevant clinical issue in Non-Small Cell Lung Cancer (NSCLC). Although Src TK has been involved in such resistance, clinical development of its inhibitors has been so far limited.To better define the molecular targets of the Src TKIs saracatinib, dasatinib and bosutinib, we used a variety of in vitro/in vivo studies.Kinase assays supported by docking analysis demonstrated that all the compounds directly inhibit EGFR TK variants. However, in live cells only saracatinib efficiently reduced EGFR activation, while dasatinib was the most effective agent in inhibiting Src TK. Consistently, a pronounced anti-proliferative effect was achieved with saracatinib, in EGFR mutant cells, or with dasatinib, in wt EGFR/Ras mutant cells, poorly dependent on EGFR and erlotinib-resistant. We then identified the most effective drug combinations to overcome resistance to EGFR inhibitors, both in vitro and in nude mice: in T790M EGFR erlotinib-resistant cells, saracatinib with the anti-EGFR mAb cetuximab; in Ras mutant erlotinib-resistant models, dasatinib with the MEK inhibitor selumetinib.Src inhibitors may act with different mechanisms in NSCLCs, depending on EGFR/Ras mutational profile, and may be integrated with EGFR or MEK inhibitors for different cohorts of NSCLCs.     

易瑞沙治疗化疗失败的晚期非小细胞肺癌

目的观察易瑞沙治疗化疗失败晚期非小细胞肺癌的疗效和不良反应。方法易瑞沙每天口服250mg治疗化疗失败的30例晚期非小细胞肺癌,1个月以后进行疗效评价,无进展者继续服用,之后每个月行CT检查评价疗效并临床密切观察,病情进展或不能耐受相关毒性者则停止使用易瑞沙。结果30例均可评价疗效,无CR者,PR6例(20.0%),SD14例(46.7%),PD10例(33.3%)。有效率(CR PR)为20.0%,疾病控制率(CR PR SD)66.7%,全组中位无进展生存期为3.0个月(0.7～29.0个月),中位生存期6.4个月(1.7～39.0个月)。主要不良反应包括皮疹22例,腹泻2例。没有患者因毒性不能耐受而停药。结论易瑞沙对化疗失败的晚期非小细胞肺癌具有一定疗效,不良反应轻微。     

晚期非小细胞肺癌治疗策略

肺癌是临床最常见的恶性肿瘤之一,非小细胞肺癌约占肺癌的80%,由于肿瘤具有隐匿性特点,确诊时大约2/3患者已属晚期。随着医学的发展与新药的研发应用,晚期非小细胞肺癌的疗效有所提升,但仍不十分令人满意,临床中急需在一线、二线、维持以及中医药等综合治疗中,逐步优化治疗策略,使患者生存更加获益。