Programmed Death-Ligand 1 Heterogeneity and Its Impact on Benefit From Immune Checkpoint Inhibitors in NSCLC

IntroductionProgrammed death-ligand 1 (PD-L1) expression may vary in different disease sites and at different time points of the disease course. We aimed to investigate PD-L1 heterogeneity and its usefulness as a predictive value for immune checkpoint inhibitor (ICI) therapy in patients with NSCLC.MethodsPD-L1 expression was analyzed in 1398 patients with NSCLC. The predictive value of PD-L1 for ICIs in 398 patients with metastatic NSCLC was assessed.ResultsPD-L1 was significantly associated with biopsy sites (p = 0.004). Adrenal, liver, and lymph node (LN) metastases had the highest PD-L1 expression as a continuous variable and at 1% or 50% cutoff. PD-L1 expression was lower in bone and brain metastases. Among 112 patients with two specimens tested, 55 (49%) had major changes in PD-L1 falling into different clinically relevant categories (<1%, 1%–49%, ≥50%) at different time points. Previous ICI therapy was associated with significant decrease in PD-L1 compared with treatment-naive counterparts (p = 0.015). Patients with metastatic NSCLC treated with ICI (n = 398) were divided into three cohorts on the basis of biopsy sites: lung (n = 252), LN (n = 85), and distant metastasis (n = 61). Higher PD-L1 in lung or distant metastasis specimens was associated with higher response rate, longer progression-free survival, and overall survival. However, PD-L1 in LN biopsies was not associated with either response or survival.ConclusionsPD-L1 varies substantially across different anatomical sites and changes during the clinical course. PD-L1 from different biopsy sites may have different predictive values for benefit from ICIs in NSCLC.     

Predictors of the Onset of Type 1 Diabetes Obtained from Real-World Data Analysis in Cancer Patients Treated with Immune Checkpoint Inhibitors

Medications that target programmed cell death protein-1 (PD-1) have proven effective. However, blockade of PD-1/Programmed death-ligand 1(PD-L1) causes immune-related adverse events (irAEs). Characteristics of this irAE include many symptom, low in frequency, and difficulty in prevention. The key to a successful ICI-related treatment lies in the management of irAEs resulting from immune checkpoint inhibitor (ICI) treatment. Although it is difficult to predict irAE, we tried to extract features of irAE expression from analysis of real-world database. This study used data extracted from the Japan Adverse Drug Event Report (JADER) database to assess risk factors associated with serious side effects of irAE, type 1 diabetes (T1DM). The analysis targets were nivolumab, atezolizumab, durvalumab, and pembrolizumab, and the study period was from July 2014 to June 2019. Analysis of Japanese population data confirmed that being women and having melanoma were risk factors for developing ICI-related T1DM. Analysis using this database in combination with information on ICI-related T1DM provides information and guidelines that will help in the safer treatment of ICI in the future.     

Assessment of Immune-Related Interstitial Lung Disease in Patients With NSCLC Treated with Immune Checkpoint Inhibitors: A Multicenter Prospective Study

IntroductionProgrammed cell death protein 1 immune checkpoint inhibitors (ICIs) have been reported to improve the survival of patients with NSCLC. On the expansion of clinical administration for a variety of cancers, immune-related adverse events have been typically recognized to be associated with ICIs, therefore, necessitating the monitoring and management of these patients. Among immune-related adverse events, immune-related interstitial lung disease (ir-ILD) is a serious complication that interrupts treatment and can occasionally be fatal. However, no prospective studies have investigated the incidence of ir-ILD and associated risk factors for its development in the clinical setting.MethodsThis is a prospective cohort study consisting of patients with NSCLC treated with ICIs. Baseline characteristics, including laboratory data, pulmonary function tests, daily symptoms of dyspnea defined by the modified Medical Research Council, and antitumor response were assessed.ResultsAmong the 138 patients with NSCLC who received anti–programmed cell death protein 1 monotherapy, 20 patients (14.5%) had ir-ILD within median 51.5 days (interquartile range: 29–147). This was approximately three times higher than those in clinical trials. A total of 11 patients (55.0%), including all eight patients with high-grade ir-ILD (≥grade 3), developed ir-ILD within 60 days. Impaired spirometry, decreased forced vital capacity and forced expiratory volume in 1 second, and daily symptoms of dyspnea measured using the modified Medical Research Council scale were identified as risk factors for ir-ILD development. In addition, combination assessment of forced vital capacity and forced expiratory volume in 1 second successfully classified patients at risk for ir-ILD development.ConclusionsThe incidence of ir-ILD was substantially higher in the clinical setting. Assessment of spirometry and daily dyspneic symptoms before ICI treatment may be useful in monitoring and managing patients with NSCLC.     

Bevacizumab Plus Atezolizumab After Progression on Atezolizumab Monotherapy in Pretreated Patients With NSCLC: An Open-Label,Two-Stage,Phase 2 Trial

IntroductionVascular endothelial growth factor promotes an immunosuppressive tumor microenvironment that can be reverted by an antiangiogenic therapy. This two-stage, phase 2 study aimed to determine the treatment efficacy of adding bevacizumab to atezolizumab in patients with metastatic NSCLC whose disease had progressed after atezolizumab monotherapy.MethodsImmune checkpoint inhibitor–naive patients with NSCLC, without EGFR or ALK alterations, whose disease progressed after at least one line of platinum-based chemotherapy were eligible. The patients received atezolizumab 1200 mg once every 3 weeks until radiographic progression (stage I). Then, bevacizumab 15 mg/kg was combined with atezolizumab 1200 mg once every 3 weeks (stage II). The primary end point was the disease control rate (DCR) confined to stage II.ResultsA total of 42 and 24 patients were enrolled in stages I and II, respectively. Most patients had negative programmed death ligand-1 expression (71.4%) and received one or two lines of therapy (95.2%). In stage I, patients achieved a DCR of 35.7% (95% confidence interval [CI]: 21.6–52.0). In stage II, three (12.5%) and 18 (75.0%) of 24 patients had partial response and stable disease, respectively, leading to a DCR of 87.5% (95% CI: 67.6–97.3). For 24 patients enrolled in stage II, the median progression-free survival was 5.6 (95% CI: 4.1–7.1) months and the overall survival was 14.0 (95% CI: 10.7–17.4) months. Treatment-related adverse events occurred in 25% of the patients in stage II, but all were of grade 1 or 2.ConclusionsCombination of bevacizumab plus atezolizumab for patients with metastatic NSCLC whose disease had progressed after atezolizumab monotherapy was found to have a promising antitumor activity with good tolerability.     

Advanced Lung Cancer Patients’ Use of EGFR Tyrosine Kinase Inhibitors and Overall Survival: Real-World Evidence from Quebec,Canada

EGFR tyrosine kinase inhibitors (EGFR-TKIs) are breakthrough palliative treatments for advanced lung cancer patients with tumors harboring mutations in the EGFR gene. Using healthcare administrative data, three cohorts were created to describe the use of three EGFR-TKIs that are publicly funded in Quebec for specific indications (i.e., 1st-line gefitinib, 1st-line afatinib, and post-EGFR-TKI osimertinib). The main objective was to compare overall survival (OS) among patients receiving these treatments to those in previous experimental and real-world studies. The patients who received EGFR-TKIs for indications of interest between 1 April 2001, and 31 March 2019 (or 31 March 2020, for post-EGFR-TKI osimertinib) were included to estimate the Kaplan-Meier-based median OS for each cohort. An extensive literature search was conducted to include comparable studies. For the gefitinib 1st-line (n = 457), the afatinib 1st-line (n = 80), and the post-EGFR-TKI osimertinib (n = 119) cohorts, we found a median OS (in months) of 18.9 (95%CI: 16.3–21.9), 26.6 (95%CI: 13.7-NE) and 19.9 (95%CI: 17.4-NE), respectively. Out of the 20 studies that we retained from the literature review and where comparisons were feasible, 17 (85%) had similar OS results, which further confirms the value of these breakthrough therapies in real-world clinical practice.     

Real world data in the era of Immune Checkpoint Inhibitors (ICIs): Increasing evidence and future applications in lung cancer

Immune checkpoint inhibitors (ICIs) targeting programmed death 1 (PD-1) and PD-ligand 1 (PD-L1) quickly subverted the standard of treatment in Non-Small Cell Lung Cancer (NSCLC), where they were first introduced in all comers previously treated advanced/metastatic NSCLC patients and subsequently in the first line of PD-L1 selected cases of metastatic and locally advanced disease.Treatment algorithm is an evolving landscape, where the introduction of front-line ICIs, with or without chemotherapy, unavoidably influences the following treatment lines. In this context, medical oncologists are currently facing many unclear issues, which have been not clarified so far by available data.Effectiveness and safety in special populations underrepresented in clinical trials - such as elderly, poor PS, hepatitis or human immunodeficiency virus-affected patients - are only a part of the unexplored side of ICIs in the real world. Indeed, pivotal randomized clinical trials (RCTs) often lack of external validity because eligibility criteria exclude some patient subgroups commonly treated in real-world clinical practice. Similarly, cost-effectiveness and sustainability of these innovative agents are important issues to be considered in the real-world. Though affected by several limitations, real-world evidence (RWE) studies allow to collect data regarding overall treated patients in clinical practice according to local authority regulations, overcoming the intrinsic limits of RCTs.The present review focuses on RWE about ICIs in lung cancer treatment, with particular reference to special patient populations, and discusses potential application of real-world data in a potential innovative drug development model.     

非小细胞肺癌免疫治疗疗效预测的研究进展

近年来,免疫检查点抑制剂(immune checkpoint inhibitors,ICI)治疗晚期非小细胞肺癌进入了一个新纪元,但不同于靶向治疗,免疫治疗没有明确的疗效预测因子以指导临床。目前应用较多的是程序性死亡受体配体(programmed cell death ligand 1,PD-L1)表达的检测,然而多项临床试验结果提示只有约20%的NSCLC患者能从中获益。而肿瘤突变负荷(tumor mutation burden,TMB)也逐渐兴起,还有许多检测因子尚在发现中。本综述旨在探讨非小细胞肺癌中免疫治疗的疗效预测因子以更好地指导临床。     

Immune Checkpoint Inhibitors in Thoracic Malignancies: Review of the Existing Evidence by an IASLC Expert Panel and Recommendations

In the past 10 years, a deeper understanding of the immune landscape of cancers, including immune evasion processes, has allowed the development of a new class of agents. The reactivation of host antitumor immune response offers the potential for long-term survival benefit in a portion of patients with thoracic malignancies.The advent of programmed cell death protein 1/programmed death ligand-1 immune checkpoint inhibitors (ICIs), both as single agents and in combination with chemotherapy, and more recently, the combination of ICI, anti–programmed cell death protein 1, and anticytotoxic T-lymphocyte antigen 4 antibody, have led to breakthrough therapeutic advances for patients with advanced NSCLC, and to a lesser extent, patients with SCLC. Encouraging activity has recently emerged in pretreated patients with thymic carcinoma (TC). Conversely, in malignant pleural mesothelioma, pivotal positive signs of activity have not been fully confirmed in randomized trials. The additive effects of chemoradiation and immunotherapy suggested intriguing potential for therapeutic synergy with combination strategies. This has led to the introduction of ICI consolidation therapy in stage III NSCLC, creating a platform for future therapeutic developments in earlier-stage disease. Despite the definitive clinical benefit observed with ICI, primary and acquired resistance represent well-known biological phenomena, which may affect the therapeutic efficacy of these agents.The development of innovative strategies to overcome ICI resistance, standardization of new patterns of ICI progression, identification of predictive biomarkers of response, optimal treatment duration, and characterization of ICI efficacy in special populations, represent crucial issues to be adequately addressed, with the aim of improving the therapeutic benefit of ICI in patients with thoracic malignancies.In this article, an international panel of experts in the field of thoracic malignancies discussed these topics, evaluating currently available scientific evidence, with the final aim of providing clinical recommendations, which may guide oncologists in their current practice and elucidate future treatment strategies and research priorities.     

Immune checkpoints and immunotherapy in non-small cell lung cancer: Novel study progression,challenges and solutions

Lung cancer is the most common type of cancer with the highest mortality rate worldwide. Non-small cell lung cancer (NSCLC) accounts for ~85% of the total number of lung cancer cases. In the past two decades, immunotherapy has become a more promising treatment method than traditional treatments (surgery, radiotherapy and chemotherapy). Immunotherapy has been shown to improve the survival rate of patients and to have a superior effect when controlling lung cancer than traditional therapy. However, only a small number of patients can benefit from immunotherapy, and not all patients who qualify experience long-term benefits. In the clinic, the objective response rate of programmed cell death protein 1 treatment without the prior screening of patients is only 15–20%. Immunotherapy is associated with both opportunities and challenges for patients with NSCLC. The current challenges of immunotherapy include the lack of accurate biomarkers, inevitable resistance and insufficient understanding of immune checkpoints. In previous years, several methods for overcoming the challenges posed by immunotherapy have been proposed, but combination therapy is the most suitable choice. A large number of studies have shown that the combination of drugs can significantly improve their efficacy, compared with monotherapy, and that some therapeutic combinations have been approved by the Food and Drug Administration for the treatment of NSCLC. Traditional Chinese medicine (TCM) is a traditional medical practice in China that can play an important role in immunotherapy. Most agents used in TCM originate from plants, and have the advantages of low toxicity and multiple targets. In addition, TCM includes a unique class of drugs that can improve autoimmunity. Therefore, TCM may be a promising treatment method for all types of cancer.     

Atezolizumab for Pretreated Non-Small Cell Lung Cancer with Idiopathic Interstitial Pneumonia: Final Analysis of Phase II AMBITIOUS Study

BackgroundInterstitial pneumonia (IP) is a poor prognostic comorbidity in patients with non-small cell lung cancer (NSCLC) and is also a risk factor for pneumonitis. The TORG1936/AMBITIOUS trial, the first known phase II study of atezolizumab in patients with NSCLC with comorbid IP, was terminated early because of the high incidence of severe pneumonitis.MethodsThis study included patients with idiopathic chronic fibrotic IP, with a predicted forced vital capacity (%FVC) of >70%, with or without honeycomb lung, who had previously been treated for NSCLC. The patients received atezolizumab every 3 weeks. The primary endpoint was the 1-year survival rate.ResultsA total of 17 patients were registered; the median %FVC was 85.4%, and 41.2% had honeycomb lungs. The 1-year survival rate was 53.3% (95% CI, 25.9-74.6). The median overall and progression-free survival times were 15.3 months (95% CI, 3.1-not reached) and 3.2 months (95% CI, 1.2-7.4), respectively. The incidence of pneumonitis was 29.4% for all grades, and 23.5% for grade ≥3. Tumor mutational burden and any of the detected somatic mutations were not associated with efficacy or risk of pneumonitis.ConclusionAtezolizumab may be one of the treatment options for patients with NSCLC with comorbid IP, despite the high risk of developing pneumonitis. This clinical trial was retrospectively registered in the Japan Registry of Clinical Trials on August 26, 2019, (registry number: jRCTs031190084, https://jrct.niph.go.jp/en-latest-detail/jRCTs031190084).     

免疫检查点抑制剂治疗非小细胞肺癌产生免疫相关不良反应和肺炎的特点及其危险因素分析

目的：探讨免疫检查点抑制剂(ICI)治疗非小细胞肺癌(NSCLC)产生的免疫相关不良反应(irAE)及ICI相关肺炎(ICI-P)的特点及其危险影响因素。方法：回顾性分析2019年1月到2021年12月间在山西白求恩医院胸部肿瘤科接受至少1次ICI治疗的114例NSCLC患者的一般性资料和临床特征的基线特征、治疗细节和发生irAE、ICI-P的数据,分析患者临床特征与irAE及ICI-P的关系,分析ICI-P发生的危险因素。观察ICI-P患者临床特点和治疗效果。结果：114例接受ICI治疗的NSCLC患者中有48例(42.11%)发生68次irAE,整体和严重irAE的发生率分别是59.65%、9.65%;从高到低排列发生率(仅列出前四位)：消化系统>呼吸系统>皮肤>内分泌系统;使用信迪利单抗>度伐利尤单抗>卡瑞利珠单抗=帕博利珠单抗;临床特征中的年龄与irAE发生有关联。15例患者发生ICI-P,整体发生率为13.16%,占irAE患者的31.25%,其中4例为重症,占irAE数的8.33%、ICI-P数的26.66%;发生于联合治疗的多于单药治疗(73...     

A Phase 1/2 Study of Lazertinib 240 mg in Patients With Advanced EGFR T790M-Positive NSCLC After Previous EGFR Tyrosine Kinase Inhibitors

IntroductionThis integrated analysis of a phase 1/2 study (NCT03046992) evaluated the efficacy and safety of lazertinib, a third-generation EGFR tyrosine kinase inhibitor (TKI), in patients with advanced EGFR T790M-positive NSCLC after previous EGFR TKI therapy.MethodsAdults with EGFR mutation-positive NSCLC that progressed after prior EGFR-directed TKIs received once daily oral lazertinib 240 mg continuously until disease progression. Prior TKIs to treat T790M-positive NSCLC were prohibited. Primary endpoints were safety and objective response rate (ORR). Secondary endpoints included progression-free survival, overall survival, and intracranial ORR.ResultsA total of 78 patients received lazertinib 240 mg at 17 centers in South Korea. Among patients with T790M-positive tumors at baseline (N = 76), one (1.3%) had a complete response and 41 (53.9%) had partial responses, giving an ORR of 55.3% (95% confidence interval [CI]: 44.1–66.4). Median progression-free survival was 11.1 months (95% CI: 5.5–16.4). Median overall survival was not reached (median follow-up = 22.0 mo). In patients with measurable intracranial lesions (n = 7), one (14.3%) had a complete intracranial response and five (71.4%) had partial responses, giving an intracranial ORR of 85.7% (95% CI: 59.8%–100.0%). The most common treatment-emergent adverse events were rash (37.2%), pruritus (34.6%), and paresthesia (33.3%); most were mild to moderate in severity. Serious drug-related adverse events occurred in three patients (gastritis, pneumonia, pneumonitis). The major mechanism of resistance was EGFR T790M loss.ConclusionsLazertinib 240 mg/d has a manageable safety profile with durable antitumor efficacy, including brain metastases, in patients with advanced T790M-positive NSCLC after previous EGFR TKI therapy.     

晚期非小细胞肺癌免疫检查点抑制剂治疗全程管理

以免疫检测点抑制剂（ICI）为代表的免疫治疗是晚期非小细胞肺癌（NSCLC）治疗的重要手段之一,它们通过释放免疫检查点介导的免疫抑制,恢复机体免疫平衡,提高了抗肿瘤有效率,使晚期NSCLC 患者的预后得到了显著改善。然而,晚期NSCLC的ICI 治疗过程中仍然存在许多尚未解决的问题。本文将围绕ICI 治疗晚期NSCLC的全程管理展开论述,包括ICI 治疗疗效预测、特殊人群筛查、药物选择、新型药物研发,以及ICI 治疗停止后的重启、耐药及免疫相关不良反应（irAE）的处理等,以期为晚期NSCLC患者的ICI治疗提供指导。     

免疫检查点抑制剂治疗非小细胞肺癌的研究进展

在全世界范围内,肺癌的发病率仍较高,且大部分患者就诊时已失去手术机会,需要化疗、放疗、靶向治疗等联合治疗,但总体治疗效果欠佳,5年生存率仍较低,亟待研究新的治疗方法.免疫治疗作为一种新兴的治疗方式,抑制免疫检查点通路被认为是最具前景的方式之一,本文就免疫检查点抑制剂治疗非小细胞肺癌的最新临床进展作一阐述.     

抗生素对免疫检查点抑制剂治疗非小细胞肺癌疗效影响的Meta分析

目的:通过Meta分析的方法评价抗生素对免疫检查点抑制剂治疗非小细胞肺癌(non-small lung cancer,NSCLC)疗效的影响.方法:检索Pubmed、Cochrane Library、EMbase、EBSCO循证医学数据库、中国生物医学文献数据库(CBM)、中国知网(CNKI)中收录的关于抗生素对免疫检...     

康莱特配合放疗对非小细胞肺癌的疗效及患者免疫功能的影响

目的 观察康莱特配合放疗对非小细胞肺癌的疗效及患者免疫功能的影响.方法 将120例部分晚期非小细胞肺癌患者平均随机分为观察组和对照组.对照组单一采用放疗药物治疗,疗程为2个月.观察组在放疗的基础上配合应用康莱特注射液100 ml静脉注射,1次/天,从化疗前1天开始,1个月为1个疗程,共治疗2个疗程.分析2组患者的有效率,并测定治疗前后患者免疫细胞的变化情况.结果 观察组与对照组相比,总有效率及疾病控制率均明显增高,不良反应发生率明显降低.观察组CD3+、CD4+、CD8+、CD4+/CD8+及NKT细胞活性均显著优于对照组,免疫球蛋白水平也高于对照组,P均<0.05.结论 康莱特配合放射治疗对NSCLC患者存活率、缓解率的提高有重大意义,在改善患者生活质量的同时具有放射增敏作用,有一定临床使用价值.     

安罗替尼三线以上治疗非小细胞肺癌疗效观察

目的:观察安罗替尼在晚期非小细胞肺癌三线以上治疗中的疗效和不良反应.方法:二线或多线治疗后进展的晚期非小细胞肺癌患者75例(其中55例为二线治疗后,15例为三线治疗后,5例为4线治疗后).所有患者均给予安罗替尼12 mg,每天1次口服,连续服用14天,停用1周,每21天重复,直到疾病进展或不能耐受不良反应为止.不能耐受...     

TS和RRM1表达与培美曲塞、吉西他滨联合卡铂治疗晚期非鳞非小细胞肺癌疗效的关系

目的 探讨胸苷酸合成酶(TS)和核苷酸还原酶M1(RRM1)的表达与培美曲塞、吉西他滨联合卡铂治疗晚期非鳞非小细胞肺癌疗效的关系.方法 选取晚期非鳞非小细胞肺癌患者98例,其中接受培美曲塞联合卡铂治疗患者49例(A组),接受吉西他滨联合卡铂治疗患者49例(B组).免疫组化检测所有肿瘤标本中TS和RRM1的表达,并分析其表达与化疗疗效的关系.结果 培美曲塞组TS-患者总有效率为64.3％,显著高于同组TS+患者总有效率42.9％,差异具统计学意义(P＜0.05);培美曲塞组RRM1+和RRM1-患者总有效率分别为52.1％和57.7％,差异无统计学意义(P＞0.05).吉西他滨组RRM1-患者总有效率为57.7％,显著高于同组RRM1+患者总有效率47.8％,差异具统计学意义(P＜0.05);吉西他滨组TS+和TS-患者总有效率分别为50.0％和56.0％,差异无统计学意义(P＞0.05).培美曲塞组TS-患者胃肠道毒副反应和血液毒副反应发生率分别为17.9％和21.4％,显著低于TS+患者(P＜0.05);吉西他滨RRM1-患者胃肠道毒副反应和血液毒副反应发生率分别为23.1％和26.9％,显著低于RRM1+患者(P＜0.05).2组患者不良反应总发生率相比较,培美曲塞组患者相对能较好耐受,差异具统计学意义(P＜0.05).培美曲塞组患者FACT-L评分显著优于吉西他滨组患者,差异具统计学意义(P＜0.05).结论 TS-患者接受培美曲塞治疗有较好临床获益,RRM1-患者接受吉西他滨治疗临床荻益较好,且培美曲塞化疗方案相对吉西他滨有较好临床耐受性,毒副作用相对较低,治疗后患者FACT-L评分较高.