Atezolizumab Versus Docetaxel in Pretreated Patients With NSCLC: Final Results From the Randomized Phase 2 POPLAR and Phase 3 OAK Clinical Trials

IntroductionThe phase 2 POPLAR and phase 3 OAK studies of the anti–programmed death-ligand 1 (PD-L1) immunotherapy atezolizumab in patients with previously treated advanced NSCLC revealed significant improvements in survival versus docetaxel (p = 0.04 and 0.0003, respectively). Longer follow-up permits evaluation of continued benefit of atezolizumab. This study reports the final overall survival (OS) and safety findings from both trials.MethodsPOPLAR randomized 287 patients (atezolizumab, 144; docetaxel, 143) and OAK randomized 1225 patients (atezolizumab, 613; docetaxel, 612). The patients received atezolizumab (1200 mg fixed dose) or docetaxel (75 mg/m²) every 3 weeks. Efficacy and safety outcomes were evaluated.ResultsA longer OS was observed in patients receiving atezolizumab versus docetaxel in POPLAR (median OS = 12.6 mo versus 9.7 mo; hazard ratio = 0.76, 95% confidence interval [CI]: 0.58–1.00) and OAK (median OS = 13.3 versus 9.8 mo; hazard ratio = 0.78, 95% CI: 0.68–0.89). The 4-year OS rates in POPLAR were 14.8% (8.7–20.8) and 8.1% (3.2–13.0) and those in OAK were 15.5% (12.4–18.7) and 8.7% (6.2–11.3) for atezolizumab and docetaxel, respectively. Atezolizumab had improved OS benefit compared with docetaxel across all PD-L1 expression and histology groups. Most 4-year survivors in the docetaxel arms received subsequent immunotherapy (POPLAR, 50%; OAK, 65%). Of the 4-year survivors, most had Eastern Cooperative Oncology Group performance status of 0 and nonsquamous histological classification and approximately half were responders (POPLAR: atezolizumab, seven of 15; docetaxel, three of four; OAK: atezolizumab, 24 of 43; docetaxel, 11 of 26). Treatment-related grade 3/4 adverse events occurred in 27% and 16% of atezolizumab 4-year survivors in POPLAR and OAK, respectively.ConclusionsLong-term follow-up suggests a consistent survival benefit with atezolizumab versus docetaxel in patients with previously treated NSCLC regardless of PD-L1 expression, histology, or subsequent immunotherapy. Atezolizumab had no new safety signals, and the safety profile was similar to that in previous studies.     

泰索帝治疗晚期肺癌的Ⅱ期临床研究

目的 评价泰索帝（ｄｏｃｅｔａｘｅｌ）单药治疗晚期非小细胞肺癌的客观有效率及毒性。方法 使用泰索帝单药治疗晚期非小细胞肺癌患者１５例,其中男性１０例,女性５例。初治１１例,复汉４例。Ⅲ期患者７例,Ⅳ期患者８例。给予泰索帝７５￣１００ｍｇ／ｍ＾２。在给药前１天开始口服地塞米松７．５ｍｇ,每天２次,连续５天。结果 １５例患者均完成２个疗程以上的化疗。３例患者达到部分缓解,６例患者病守稳定,６例病情进展     

Association of PALB2 Messenger RNA Expression with Platinum-Docetaxel Efficacy in Advanced Non–Small Cell Lung Cancer

Introduction

Partner and localizer of BRCA2 (PALB2) is essential for homologous recombination repair. We examined mRNA levels of DNA repair genes, including partner and localizer of BRCA2 gene (PALB2), ring finger protein 8 gene (RNF8), replication timing regulatory factor 1 gene (RIF1), ATM serine/threonine kinase gene (ATM), and tumor protein p53 binding protein 1 gene (53BP1) as predictive biomarkers for cisplatin-docetaxel in the European phase III BRCA1, DNA repair associated (BRCA1)–receptor-associated protein 80 (RAP80) expression customization (BREC) phase III clinical trial (ClinicalTrials.gov identifier NCT00617656).

多西紫杉醇联合顺铂每周给药治疗Ⅲ—Ⅳ期NSCLC 30例

目的：观察多西紫杉醇（DOC）联合顺铂（DDP）以每周给药方案治疗Ⅲ－Ⅳ期非小细胞肺癌（NSCLC）的临床疗效,生存期及毒副反应。方法：治疗Ⅲ-Ⅳ期SNCLC患者30例,DOC 25mg/m2静脉点滴1小时,第1,8,15天;DDP 25mg/m2静脉点滴,第1,8,15天,28天为一疗程,至少治疗二周期。结果：总有效率为43＝．4％（13／30）,均为部分缓解,对原发灶和转移灶均有较好疗效,Karnofsky计分增加或不变者占66．7％,中位缓解期为7月,生存年以上者占40％,主要毒副反应为骨髓抑制,Ⅲ-Ⅳ度白细胞下降占16．7％,III度血小板下降占6．7％,无III－IV度血红蛋白下降,非血液学性轻微,结论：DOC与DDP每周给药方案治疗NSCLC有较好疗效,耐受性。     

Molecular Adequacy of Image-Guided Rebiopsies for Molecular Retesting in Advanced Non–Small Cell Lung Cancer: A Single-Center Experience

Introduction

In the era of biomarker-driven systemic therapy for advanced NSCLC, the role of routine repeated biopsies for decision making outside EGFR-mutant disease remains unproven. We report our center’s experience of safety and adequacy for molecular retesting of tumor material obtained from image-guided lung rebiopsies in NSCLC.

Current and Emergent Therapy Options for Advanced Squamous Cell Lung Cancer

Squamous cell lung cancer (SqCLC) is a distinct histologic subtype of NSCLC that is challenging to treat because of specific clinicopathologic characteristics, which include older age, advanced disease at diagnosis, comorbid diseases, and the central location of tumors. These characteristics have a bearing on treatment outcomes in advanced SqCLC, resulting in a median survival approximately 30% shorter than for patients with other NSCLC subtypes. In the context of the specific features of SqCLC, we review challenges of treating SqCLC and the current guideline-recommended treatments for advanced (metastatic) SqCLC in different patient subpopulations. We also evaluate recently approved treatment options, including necitumumab, afatinib, nivolumab, pembrolizumab, and atezolizumab; discuss the survival benefits associated with each agent in the advanced SqCLC population; and propose a treatment algorithm incorporating these agents for this challenging-to-treat disease. Lastly, we review the preliminary clinical evidence for immunotherapy agents in development for advanced NSCLC.     

Geographic Variation in EGFR Mutation Frequency in Lung Adenocarcinoma May Be Explained by Interethnic Genetic Variation

Our understanding of the etiology of EGFR-mutant lung cancer remains incomplete. One persistent finding in the literature is the geographic variation in the frequency of EGFR mutations in lung adenocarcinoma. We investigated the association between two biomarkers of East Asian ancestry, the genetic polymorphisms ectodysplasin A receptor gene (EDAR) V370A and ATP binding cassette subfamily C member 11 gene (ABCC11) G180A, and the frequency of EGFR mutations in patients with lung adenocarcinoma in a range of countries. The Pearson’s linear correlation between the frequency of EGFR mutations and the EDAR polymorphism was 0.92 (p <2.2 × 10^-10), and for the ABCC11 polymorphism it was 0.72 (p <1.6 × 10^-4). These results suggest that the variation in the measured frequency of EGFR mutations in lung adenocarcinoma can be explained, at least in part, by interethnic genetic variation. To improve our understanding of this disease, studies exploring the genetic polymorphism(s) that cause these interethnic differences, as well as the mechanisms of actions through which they work, are warranted.     

Cost-Effectiveness Analysis of Afatinib versus Gefitinib for First-Line Treatment of Advanced EGFR-Mutated Advanced Non–Small Cell Lung Cancers

IntroductionThe irreversible ErbB family blocker afatinib and the reversible EGFR tyrosine kinase inhibitor gefitinib were compared in the multicenter, international, randomized, head-to-head phase 2b LUX-Lung 7 trial for first-line treatment of advanced EGFR mutation–positive NSCLCs. Afatinib and gefitinib costs and patients’ outcomes in France were assessed.MethodsA partitioned survival model was designed to assess the cost-effectiveness of afatinib versus gefitinib for EGFR mutation–positive NSCLCs. Outcomes and safety were taken primarily from the LUX-Lung 7 trial. Resource use and utilities were derived from that trial, an expert-panel questionnaire, and published literature, limiting expenditures to direct costs. Incremental cost-effectiveness ratios (ICERs) were calculated over a 10-year time horizon for the entire population, and EGFR exon 19 deletion or exon 21 L858R mutation (L858R) subgroups. Deterministic and probabilistic sensitivity analyses were conducted.ResultsFor all EGFR mutation–positive NSCLCs, the afatinib-versus-gefitinib ICER of was €45,211 per quality-adjusted life-year (QALY) (0.170 QALY gain for an incremental cost of €7697). ICERs for EGFR exon 19 deletion and L858R populations were €38,970 and €52,518, respectively. Afatinib had 100% probability to be cost-effective at a willingness-to-pay threshold of €70,000/QALY for patients with common EGFR mutations.ConclusionFirst-line afatinib appears cost-effective compared with gefitinib for patients with EGFR mutation–positive NSCLCs.