Cost–Utility Analysis of Pembrolizumab Versus Chemotherapy as First-Line Treatment for Metastatic Non-Small Cell Lung Cancer With Different PD-L1 Expression Levels

To evaluate the cost–utility of pembrolizumab versus chemotherapy as the first-line setting for metastatic nonsmall cell lung cancer (NSCLC) from the US health care system perspective, a Markov model was developed to compare the lifetime cost and effectiveness of pembrolizumab versus chemotherapy for untreated metastatic NSCLC, based on the clinical data derived from phase III randomized controlled trial (KEYNOTE- 042; ClinicalTrials.gov; NCT02220894). Weibull distribution was fitted to simulate the parametric survival functions. Drug costs were collected from official websites, and utility values were obtained from published literature. Total costs, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios (ICERs) were computed as primary output indicators. The impact of different PD-L1 expression levels on ICER was also evaluated. One-way and probabilistic sensitivity analyses were performed to assess the model uncertainty. Compared with chemotherapy, patients treated with pembrolizumab provided an additional 1.13, 1.01, and 0.59 QALYs in patients with PD-L1 expression levels of ≥50%, ≥20%, and ≥1%, with corresponding incremental cost of $53,784, $47,479, and $39,827, respectively. The resultant ICERs of pembrolizumab versus chemotherapy were $47,596, $47,184, and $68,061/QALY, in three expression levels of PD-L1, respectively, all of which did not exceed the WTP threshold of 180,000/QALY. Probability sensitivity analysis outcome supported that pembrolizumab exhibited evident advantage over chemotherapy to be cost-effective. One-way sensitivity analysis found that ICERs were most sensitive to utility value of pembrolizumab in progression survival state. All the adjustment of parameters did not qualitatively change the result. For treatment-naive, metastatic NSCLC patients with PD-L1+, pembrolizumab was estimated to be cost-effective compared with chemotherapy for all PD-L1 expression levels at a WTP threshold of $180,000/QALY in the context of the US health care system.     

PD-1/PD-L1抑制剂对比化疗一线治疗晚期非小细胞肺癌的Meta分析

 目的 系统评价PD-1/PD-L1抑制剂对比化疗一线治疗晚期非小细胞肺癌的疗效及安全性。方法 通过Web of science等国内外数据库，ASCO会议摘要及杂志筛选文献，进行Meta分析。结果 纳入7项RCT研究，4 101例患者，荟萃分析显示抑制剂联合化疗对比化疗可显著延长患者的PFS（HR=0.59, 95%CI: 0.50~0.70, P<0.00001）、OS（HR=0.65, 95%CI: 0.46~0.92, P=0.02）及ORR（RR=1.72, 95%CI: 1.13~2.62, P=0.01）。亚组分析显示，抑制剂联合化疗可显著延长PFS及OS，且PD-L1表达程度越高，疗效获益越显著。而单药抑制剂对比化疗在延长晚期NSCLC患者的PFS（HR=0.87, 95%CI: 0.57~1.31, P=0.50）、OS（HR=0.82, 95%CI: 0.65~1.03, P=0.09）及提高ORR（RR=1.12, 95%CI: 0.55~2.28, P=0.76）方面两组差异无统计学意义。与化疗相比，单药抑制剂一线治疗PD-L1高表达的晚期NSCLC患者可显著延长OS，但在延长PFS方面未见明显优势。与化疗组相比，抑制剂联合化疗组3~4级不良反应发生率无明显改善（HR=1.09，95%CI: 0.99~1.20, P=0.09），而单药PD-1/PD-L1抑制剂组3~4级不良反应发生率低（RR=0.43, 95%CI: 0.36~0.52, P<0.00001）。 结论 PD-1/PD-L1抑制剂联合化疗一线治疗晚期NSCLC患者疗效优于化疗方案；PD-L1高表达者单药PD-1/PD-L1抑制剂可作为一线治疗的优先选择，且具有良好的安全性。     

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.     

Steroid Use Independently Predicts for Poor Outcomes in Patients With Advanced NSCLC and High PD-L1 Expression Receiving First-Line Pembrolizumab Monotherapy

BackgroundReal-world data have suggested a detrimental effect of steroid use in patients with advanced non–small-cell lung cancer (NSCLC) receiving immunotherapy. However, previous studies included heterogeneous cohorts of patients receiving different lines of treatment with several immuno-oncology agents and various combinations of chemotherapy and immuno-oncology agents.Patients and MethodsA comprehensive clinicopathologic database of patients with NSCLC and programmed cell death ligand 1 >50% treated with frontline pembrolizumab monotherapy was constructed in 14 centers in Italy, Spain, Greece, and Switzerland. A multivariate analysis adjusting for the established prognostic factors was performed using a Cox regression model.ResultsFor the 265 eligible patients, the median age at diagnosis was 67 years, 66% were male, 90% were current or former smokers, 18% had had an Eastern Cooperative Oncology Group performance status of 2 or 3. Of the NSCLC subtypes, 64% were adenocarcinoma and 25% were squamous cell. Of the patients, 18% had had brain metastases at diagnosis and 24% had received steroids before or during pembrolizumab treatment. The median time to progression was 4.4 months with and 13.7 months without steroid use (hazard ratio [HR], 2.55; 95% confidence interval [CI], 1.69-3.85; log-rank P < .001). The median survival was 22.5 months for the whole cohort, 7.7 months for the steroid group, and not reached for the non-steroid group (HR, 3.64; 95% CI, 2.34-5.68; log-rank P < .001). On multivariate analysis accounting for all established prognostic variables, steroid use was still independently associated with a high risk of progression (HR, 1.864; 95% CI, 1.179-2.949; P = .008) and death (HR, 2.292; 95% CI, 1.441-3.644; P < .001)ConclusionsIn patients with advanced NSCLC and programmed cell death ligand 1 expression > 50% receiving frontline pembrolizumab monotherapy, any use of steroids before or during treatment was associated with an 86% increase in the risk of progression and a 2.3-fold increase in the risk of death, even accounting for palliative indication-related bias, including the presence of central nervous system metastasis. The use of steroids for palliative indications should be restricted to absolutely necessary for patients receiving immuno-oncology monotherapy.     

厄洛替尼一线治疗晚期非小细胞肺癌临床观察

背景与目的 观察厄洛替尼一线治疗晚期非小细胞肺癌的疗效和毒副反应.方法 28例病理确诊的不愿或不能接受传统细胞毒性药物化疗的非小细胞肺癌患者.口服厄洛替尼150mg,每日1次,持续用药直至肿瘤进展或出现不可耐受的毒副反应.结果 厄洛替尼的有效率为28.6%,疾病控制率为60.7%,症状改善率为53.6%,中位无进展生存期为3.2个月(95%CI:0.815-5.585),中位生存期为9.6个月(95%CI:7.179-12.021),1年生存率为32.1%.有皮疹患者的疗效优于无皮疹患者.本组多为Ⅰ、Ⅱ级毒副反应,常见的毒副反应为皮疹(46.4%)、腹泻(32.1%)、皮肤干燥(25.0%)、厌食(17.9%)、疲乏(10.7%)和转氨酶升高(7.1%).结论 对不愿或不能接受传统细胞毒性药物化疗的非小细胞肺癌患者,厄洛替尼为其提供了另一个选择.     

肿瘤干细胞标志物与非小细胞肺癌患者生存的相关性分析

摘 要：［目的］ 探讨肿瘤干细胞（cancer stem cells,CSCs）标志物与非小细胞肺癌（non-small cell lung cancer,NSCLC）患者预后的关系。［方法］ 入组53例2017—2018年在上海市胸科医院进行手术并病理确诊的ⅢA期NSCLC患者,通过单因素和多因素回归方法分析临床因素与NSCLC患者总生存期（overall survival,OS）的相关性。通过免疫组化检测CSCs标志物（OCT4、SOX2、CD44、ALDH1A1）在NSCLC中的表达,并进行免疫组织化学评分。将CSCs标志物高H评分、年龄和微乳头成分6项指标进行累加评分,定义为肿瘤干性指数。利用Kaplan-Meier法分析肿瘤干性评分与NSCLC患者OS的关系。［结果］ 多因素回归分析结果显示年龄(HR=1.948,95%CI：1.092～2.474,P=0.031）、微乳头成分（HR=2.720,95%CI：1.267～5.842,P=0.011）和CEA水平（HR=1.008,95%CI：1.000~1.015,P=0.040）与OS 显著性相关。免疫组化结果显示,OCT4在肺腺癌和肺鳞癌中均有较高的表达。在肺腺癌中,OCT4高表达组预后较差（P=0.004）。SOX2、CD44、ALDH1A1对肺癌预后的影响不明显。肿瘤高干性评分与OS显著性相关(HR=2.212,95%CI：1.245~3.676,P=0.024)。［结论］在肺腺癌患者中,OCT4高表达和肿瘤高干性指数可能与预后差相关。     

Efficacy of First-line Chemotherapy Affects the Second-Line Setting Response in Patients with Advanced Non-Small Cell Lung Cancer

Background: Chemotherapy is the mainstay of treatment for the majority of patients with advanced nonsmall cell lung cancer (NSCLC) without driver mutations and many receive therapies beyond first-line. Secondline chemotherapy has been disappointing both in terms of response rate and survival and we know relatively little about the prognostic factors. Materials and Methods: One thousand and eight patients with advanced NSCLC who received second-line chemotherapy after progression were reviewed in Shanghai PulmonaryHospital, China, from September 2005 to July 2010. We analyzed the effects of potential prognostic factors on the outcomes of second-line chemotherapy (overall response rate, ORR; progression free survival, PFS; overall survival, OS). Results: The response and progression free survival of first-line chemotherapy affects the ORR, PFS and OS of second-line chemotherapy (ORR: CR/PR 15.4%, SD 10.1%, PD2.3%, p<0.001; PFS: CR/PR 3.80 months, SD 2.77 months, PD 2.03 months, p<0.001; OS: CR/PR 11.60 months, SD 10.33 months, PD 6.57 months, p=0.578, p<0.001, p<0.001, respectively). On multivariate analysis, better response to first-line therapy (CR/PR: HR=0.751, p=0.002; SD: HR=0.781, p=0.021) and progression within 3-6 months (HR=0.626, p<0.001), together with adenocarcinoma (HR=0.815, p=0.017), without liver metastasis (HR=0.541, p=0.001), never-smoker(HR=0.772, p=0.001), and ECOG PS 0-1 (HR=0.745, p=0.021) were predictors for good OS following secondline chemotherapy. Conclusions: Patients who responded to first-line chemotherapy had a better outcome after second-line therapy for advanced NSCLC, and the efficacy of first-line chemotherapy, period of progression, histology, liver metastasis, smoking status and ECOG PS were independent prognostic factors for OS.     

Pneumonitis in Non-Small Cell Lung Cancer Patients Receiving Atezolizumab Post Chemo-Radiation

Objective: The use of Durvalumab following chemoradiotherapy in patients with stage III NSCLC, considerably increased PFS (progression free survival) and OS (overall survival). Unfortunately, Durvalumab is currently not reimbursed for this indication in Lebanon so far. We have used Atezolizumab on a series of patients to the similar mechanism of action. We report in this paper the incidence of pneumonitis using this approach. Methods: We selected from our lung cancer registry, a group of patients diagnosed with stage III NSCLC, who received Atezolizumab (Tecentriq) as consolidation therapy following concurrent chemoradiation therapy. We specifically look at the incidence and severity of pneumonitis based on Common Toxicity Criteria and Adverse Events (CTCAE). Finally, we analyzed patient and tumor characteristics looking for predictive markers for pneumonitis. Result: Of the 14 patients who met our selection criteria, 8 developed pneumonitis and 6 did not. Age, gender and smoking status did not affect the probability of having pneumonitis, with p-values of 0.98,1 and 0.86 respectively. The impact of having PDL-1 status on pneumonitis could not be assessed due to our small sample size. The mean onset of pneumonitis after completion of chemoradiotherapy is 3.62 and after starting Atezolizumab is 2.45 months. Conclusion: The administration of Atezolizumab carries a significant risk of developing pneumonitis following chemoradiation therapy for NSCLC. The presence of certain factors and tumor characteristics might affect the chances of having pneumonitis. However due to our small sample size, definitive conclusions could not be drawn.     

NP方案二线化疗对25例晚期非小细胞肺癌的疗效

目的 探索二线化疗方案对晚期非小细胞肺癌(NSCLC)的疗效和不良反应。方法 采用NP方案即进口长春瑞宾(NVB)25mg／m^2，iv，第l，8天；顺铂(DDP)80mg／m^2，iv，第l天；作为二线方案治疗经病理和(或)细胞学诊断的25例晚期NSCLC。22例曾用含铂类方案化疗，经用1个化疗方案治疗后复发或进展。结果 可评价疗效的25例中，无CR(完全缓解)，PR(部分缓解)3例，SD(稳定)14例，PD(进展)8例，有效率12％；中位生存期9个月；1年生存率36％。3例获PR者病理诊断均为腺癌，治疗后生存期分别为7个月、16个月和16个月。化疗的不良反应主要是血液学毒性，但患者可以耐受。结论 NVB联合DDP用于二线化疗方案治疗晚期NSCLC临床有效，患者耐受性尚可，应开展进一步的随机研究。     

阿帕替尼用于一线治疗进展后晚期非鳞非小细胞肺癌的疗效和生存分析

背景与目的 晚期非小细胞肺癌(non-small cell lung cancer,NSCLC)的二线、三线化疗有效率较低,靶向药物的应用为部分患者带来生存获益.阿帕替尼是一种新型小分子抗血管生成药物,在多种恶性肿瘤治疗中展现出令人满意的抗癌活性.本研究旨在评价阿帕替尼用于一线治疗进展后晚期非鳞NSCLC的安全性和疗效.方法 回顾性分析128例晚期非鳞NSCLC不同治疗组患者的疗效和生存情况,用Kaplan-Meier法和Cox模型进行分析.结果 以单纯化疗组为对照,阿帕替尼单药组、单纯化疗组和阿帕替尼联合化疗组的中位无进展生存期(progression free survival,PFS)分别为3.0个月(P=0.381)、3.7个月和6.0个月(P<0.001),中位总生存期(overall survival,OS)分别为6.0个月(P=0.494)、6.5个月和9.0个月(P=0.001).3级-4级不良反应发生率分别为18.5%、15.8%和16.0%(P=0.947).治疗方案(P=0.018)及体能状态(performance status,PS)(P<0.001)是PFS的独立影响因素,吸烟史(P=0.014)、治疗方案(P=0.002)和PS(P<0.001)是OS的独立影响因素.结论 阿帕替尼安全性高,肺癌一线治疗失败后,二线或三线化疗联合阿帕替尼,与单纯化疗相比,患者有PFS和OS获益,阿帕替尼单药与单纯化疗组间PFS和OS无明显差异;无吸烟史、PS 0分-1分和联合治疗的患者预后更好.     

Treatment Patterns and Differences in Survival of Non-Small Cell Lung Cancer Patients Between Academic and Non-Academic Hospitals in the Netherlands

Background

The aims of this study are to analyze differences in survival between academic and non-academic hospitals and to provide insight into treatment patterns for non-small cell lung cancer (NSCLC). Results show the state of NSCLC survival and care in the Netherlands.

力尔凡对晚期非小细胞肺癌化疗的影响

比较全身化疗加或不加力尔凡对晚期非小细胞肺癌(NSCLC)的疗效、不良反应及免疫功能的变化。方法:将60例晚期NSCLC患者以随机方法(开信封)分别分为并用力尔凡组(治疗组)和单用化疗组(对照组),分别接受NP方案(诺维苯、顺铂)加力尔凡或单用NP方案化疗。结果:1)治疗组部分缓解率43.3%,对照组33.3%(P>0.05),中位缓解期分别为4.8个月及3.3个月。2)治疗组疗后和疗前相比CD4及CD4/CD8值显著升高(P<0.05),而对照组则相反,两组差异显著(P<0.05)。3)不良反应:治疗组白细胞下降63.3%,对照组达100%(P<0.05)。结论:力尔凡与化疗同时应用治疗晚期NSCLC,疗效有所提高,可增强细胞的免疫功能,对化疗引起的白细胞下降有保护作用。     

ERCC1 Expression Does Not Predict Survival and Treatment Response in Advanced Stage Non-Small Cell Lung Cancer Cases Treated with Platinum Based Chemotherapy

Background: ERCC1 is considered as a promising molecular marker that may predict platinum basedchemotherapy response in non small cell lung cancer patients. We therefore investigated whether its expression isindeed associated with clinical outcomes in advanced stage NSCLC patients. Materials and Methods: Pretreatmenttumor biopsy samples of 83 stage 3B and 4 non-small cell lung cancer patients treated with platinum basedchemotherapy were retrospectively analyzed for immunohistochemical ERCC1 expression. None of the patientsreceived curative surgery or radiotherapy. Results: By calculating H- scores regarding the extent and intensityof immunohistochemical staining of tumor biopsy samples, ERCC1 expression was found to be positive in 50patients (60.2%). ERCC1 positive and negative groups had no statistically significant differences regardingtreatment response, progression free survival and overall survival (respectively p=0.161; p=0.412; p=0.823).Conclusions: In our study we found no association between ERCC1 expression and survival or treatmentresponse. The study has some limitations, such as small sample size and retrospective analysis method. There isneed of more knowledge for use of ERCC1 guided chemotherapy regimens in advanced stage NSCLC.     

Gemcitabine Plus Paclitaxel as Second-line Chemotherapy in Patients with Advanced Non-Small Cell Lung Cancer

Purpose: The aim of this retrospective study was to determine response rates, progression-free survival(PFS), overall survival (OS) and toxicity of gemcitabine and paclitaxel combinations with advanced or metastaticnon-small cell lung cancer patients (NSCLC) who have progressive disease after platinum-based first-linechemotherapy. Methods: We retrospectively evaluated the file records of patients treated with gemcitabine pluspaclitaxel in advanced or metastatic NSCLC cases in a second-line setting. The chemotherapy schedule was asfollows: gemcitabine 1500 mg/m2 and paclitaxel 150 mg/m2 administered every two weeks. Results: Forty-eightpatients (45 male, 3 female) were evaluated; stage IIIB/IV 6/42; PS0, 8.3%, PS1, 72.9%, PS2, 18.8%; medianage, 56 years old (range 38-76). Six (12.5%) patients showed a partial response (PR), 13 (27.1%) stable disease(SD), and 27 (56.3%) progressive disease (PD). The median OS was 6.63 months (95% CI 4.0-9.2); the medianPFS was 2.7 months (95% CI 1.8-3.6). Grade 3 and 4 hematologic toxicities, including neutropenia (n=4, 8.4%),and anemia (n=3, 6.3%) were encountered, but no grade 3 or 4 thrombocytopenia. One patient developed febrileneutropenia. There were no interruption for reasons of toxicity and no exitus related to therapy. Conclusion:The combination of two-weekly gemcitabine plus paclitaxel was an effective and well-tolerated second-linechemotherapy regimen for advanced or metastatic NSCLC patients previously treated with platinum-containingchemotherapy. Although the most common and dose limiting toxicities were neutropenia and neuropathy, thisregimen was tolerated well by the patients.