Addition of Bevacizumab to Erlotinib as First-Line Treatment of Patients With EGFR-Mutated Advanced Nonsquamous NSCLC: The BEVERLY Multicenter Randomized Phase 3 Trial

IntroductionAdding bevacizumab to erlotinib prolonged progression-free survival (PFS) of patients with EGFR-mutated advanced NSCLC in the Japanese JO25567 trial, but limited data were available in non-Asian patients. BEVERLY is an Italian, multicenter, randomized, phase 3 investigating the addition of bevacizumab to erlotinib as first-line treatment of advanced EGFR-mutated NSCLC.MethodsEligible patients were randomized 1:1 to erlotinib plus bevacizumab or erlotinib alone. Investigator-assessed PFS and blinded independent centrally reviewed PFS were coprimary end points. With 80% power in detecting a 0.60 hazard ratio and two-sided α error of 0.05, 126 events of 160 patients were needed. The trial was registered as NCT02633189 and EudraCT 2015-002235-17.ResultsFrom April 11, 2016, to February 27, 2019, a total of 160 patients were randomized to erlotinib plus bevacizumab (80) or erlotinib alone (80). At a median follow-up of 36.3 months, median investigator-assessed PFS was 15.4 months (95% confidence interval [CI]: 12.2–18.6) with erlotinib plus bevacizumab and 9.6 months (95% CI: 8.2–10.6) with erlotinib alone (hazard ratio = 0.66, 95% CI: 0.47–0.92). Blinded independent centrally reviewed PFS analysis confirmed this result. A statistically significant interaction with treatment effect was found for smoking habit (p = 0.0323), with PFS prolongation being clinically significant only among current or previous smokers. Hypertension (grade ≥3: 24% versus 5%), skin rash (grade ≥ 3: 31% versus 14%), thromboembolic events (any grade: 11% versus 4%), and proteinuria (any grade: 23% versus 6%) were more frequent with the combination.ConclusionsThe addition of bevacizumab to first-line erlotinib prolonged PFS in Italian patients with EGFR-mutated NSCLC; toxicity was increased with the combination but without unexpected safety issues.     

Disease Burden on PET Predicts Outcomes for Advanced NSCLC Patients Treated with First-Line Immunotherapy

BackgroundFirst-line immunotherapy (IMT), with or without cytotoxic chemotherapy, is now recommended for most patients with advanced non-small cell lung cancer (NSCLC) with no targetable mutations. We reviewed outcomes for NSCLC patients treated with first-line IMT at our institution to test the hypothesis that measures of disease burden on staging FDG-PET/CT have prognostic value.Materials and MethodsPatient, disease, and treatment details were collected. A gradient-based segmentation tool was used to delineate each PET-avid extracranial lesion. Numbers of extrathoracic lesions and metabolic tumor volumes were tabulated. Oligometastatic disease (OMD) was defined as having ≤3 extrathoracic lesions, with any number of thoracic lesions. Progression-free survival (PFS) and overall survival (OS) rates following initiation of IMT were evaluated using the Kaplan-Meier method, and predictors of PFS and OS were assessed using Cox proportional hazards models and logrank tests.ResultsOne hundred twenty-four patients met inclusion criteria, and 1143 lesions were contoured. The presence of OMD was associated with favorable PFS (median 13.1 vs. 6.9 months; P = .016) and favorable OS (median 36.5 vs. 15.4 months; P = .002). In multivariable models, OMD was associated with favorable PFS (HR = 0.64; P = .034) and favorable OS (HR = 0.61; P = .063), and metabolic tumor volumes exceeding the cohort median (88 cc) was associated with inferior OS (HR = 1.85; P = .028).ConclusionFor advanced NSCLC patients receiving first-line IMT, the presence of extrathoracic OMD and low volumetric disease burden on PET are favorable prognostic factors that could be useful stratification factors in clinical trials and may influence clinical decisions about local and systemic therapy.     

Nivolumab Plus Erlotinib in Patients With EGFR-Mutant Advanced NSCLC

Introduction

This phase I study evaluated nivolumab combined with erlotinib in patients with advanced EGFR-mutant NSCLC.

厄洛替尼一线治疗老年晚期非小细胞肺癌临床观察

[目的]比较厄洛替尼靶向与紫杉醇单药一线治疗老年晚期非小细胞肺癌(NSCLC)患者的疗效和不良反应。[方法]经病理确诊的老年晚期NSCLC患者62例,厄洛替尼治疗组32例:口服厄洛替尼150mg,1次/d;紫杉醇化疗组30例:紫杉醇75mg/m2,d1、8,静脉滴注,21d为1个周期,2个周期后评价疗效。[结果]厄洛替尼治疗组和紫杉醇化疗组近期有效率(RR)分别为28.1%、36.7%,肿瘤控制率(TGCR)分别为71.9%、66.7%,差异无统计学意义(P>0.05);中位无疾病进展时间(PFS)分别为5.6个月、5.1个月;中位生存期(OS)分别为9.0个月、8.0个月。两组不良反应均可耐受,厄洛替尼治疗组骨髓抑制发生率明显低于紫杉醇化疗组(P<0.05),厄洛替尼治疗组皮疹及腹泻发生率明显较高(P<0.05)。[结论]老年晚期NSCLC患者可从厄洛替尼靶向治疗中获益,不良反应轻微。     

Pembrolizumab in Combination With Erlotinib or Gefitinib as First-Line Therapy for Advanced NSCLC With Sensitizing EGFR Mutation

Introduction

Anti-EGFR agents are standard treatments for patients with EGFR-mutant advanced NSCLC. The feasibility of combining erlotinib or gefitinib with the anti–programmed death 1 immunotherapy pembrolizumab was evaluated in the phase 1/2 KEYNOTE-021 study (NCT02039674).

探讨影响厄洛替尼治疗晚期非小细胞肺癌预后的因素

目的 探讨影响厄洛替尼治疗晚期非小细胞肺癌预后的临床因素。方法 收集55例厄洛替尼治疗晚期非小细胞肺癌患者的临床资料,分析临床特征与PFS、OS的关系。结果 血清LDH升高及0~1度皮疹是不良预后的独立危险因素。结论 血清LDH水平是否正常与皮疹是否严重是影响厄洛替尼治疗晚期NSCLC患者预后的重要因素。     

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.     

Concurrent Genetic Alterations Predict the Progression to Target Therapy in EGFR-Mutated Advanced NSCLC

Introduction

EGFR-mutant NSCLC displays diverse outcomes to tyrosine kinase inhibitor (TKI) treatment. Because co-occurring genomic alterations might describe different biological subsets of patients with this cancer, exploring co-occurring genomic alterations that impact patients’ outcomes using a comprehensive gene panel is potentially important.

A Randomized,Open-Label Phase II Study Evaluating Emibetuzumab Plus Erlotinib and Emibetuzumab Monotherapy in MET Immunohistochemistry Positive NSCLC Patients with Acquired Resistance to Erlotinib

IntroductionThe hepatocyte growth factor receptor MET represents a resistance mechanism to epidermal growth factor receptor (EGFR) inhibition in EGFR mutant (mt) non–small cell lung cancer (NSCLC). This Phase 2 study tested whether acquired resistance to erlotinib in MET protein positive NSCLC patients enriched for EGFRmt can be overcome by emibetuzumab plus erlotinib.Patient and MethodsPatients with Stage IV NSCLC with acquired resistance to erlotinib and MET diagnostic (+) (≥ 10% of cells expressing MET at ≥ 2+ IHC staining intensity at any time) were randomized (3:1) to receive emibetuzumab 750 mg every 2 weeks with or without erlotinib 150 mg once daily. The primary objective was to evaluate the overall response rate (ORR) relative to historic control, with a co-primary objective of ORR in patients with MET expression in ≥ 60% of cells ≥ 2+ (MET ≥ 60%).ResultsOne hundred and eleven MET+ patients received emibetuzumab plus erlotinib (N = 83) or emibetuzumab monotherapy (N = 28). 89 of 111 MET+ samples were post-erlotinib. ORR was 3.0% for emibetuzumab plus erlotinib (95% CI: 0.4, 10.5) and 4.3% for emibetuzumab (95% CI: 0.1, 21.9), in patients with post-erlotinib progression biopsies available (n = 89). Similar results were observed in patients with MET ≥ 60% expression (n = 74). Disease control rate and progression-free survival were higher for emibetuzumab plus erlotinib (50%/3.3 months) than for emibetuzumab (26%/1.6 months). No unexpected safety signals emerged. Partial responses were observed in patients with and without EGFRmt or MET amplification. EGFR sensitizing mutations were identified retrospectively in 84.2% of those with available tissue (85/101).ConclusionAcquired resistance to erlotinib in MET diagnostic (+) patients was not reversed by emibetuzumab plus erlotinib or emibetuzumab monotherapy, although a subset of patients obtained clinical benefit.     

厄洛替尼治疗晚期非小细胞肺癌的临床研究

背景与目的 厄洛替尼在NSCLC患者中已有广泛应用,并能使部分NSCLC患者明显获益.本研究探讨厄洛替尼单药一线或二、三线治疗晚期非小细胞肺癌的临床疗效及毒副反应.方法 研究对象为2007年6月-2008年8月接受过化疗或未化疗过的Ⅲb或Ⅳ期非小细胞肺癌患者,给予厄洛替尼口服150mg/d,直至疾病进展,观察疗效及毒副反应.结果 共有42例患者入组,随访至2009年7月10日,中位随访期为17个月,依从性为100%.42例患者中CR2.4%(1/42)、PR 35.8%(15/42)、SD 47.6%(20/42)、PD 14.396(6/42)、疾病控制率(CR+PR+SD)85.7%;中位疾病进展时间和中位生存时间分别为7个月和12.2个月;1年肿瘤无进展生存率和1年生存率分别为29%和56%.毒副反应为痤疮样皮疹78.6%(33/42)、腹泻35.7%(15/42)、转氨酶升高7.1%(3/42)、急性间质性肺病2.4%(1/42).结论 不管作为一线或者二、三线治疗,厄洛替尼治疗晚期非小细胞肺癌疗效较好.毒副反应轻微,临床获益率高,能明显改善患者的生活质量.     

EGFR Mutation Subtypes Influence Survival Outcomes following First-Line Gefitinib Therapy in Advanced Asian NSCLC Patients

IntroductionActivating mutations in the EGFR gene have been shown to confer sensitivity to EGFR tyrosine kinase inhibitors in patients with advanced NSCLC. However, wide interpatient variability in treatment outcomes in response to EGFR tyrosine kinase inhibitors in these patients remains unaccounted for. This study aimed to evaluate the influence of EGFR mutation types and subtypes on survival outcomes in advanced Asian patients with NSCLC receiving first-line gefitinib therapy.MethodsPatients with stage IIIB or IV NSCLC who were harboring EGFR mutations, receiving first-line gefitinib treatment, and of Asian descent (N = 383) were evaluated. Overall survival (OS) and progression-free survival (PFS) were estimated by Kaplan-Meier analysis. Log-rank tests and Cox proportional hazards models were implemented to evaluate the differences in PFS and OS.ResultsSignificant differences in PFS were observed between patients carrying EGFR mutations in exons 18, 19, 20, and 21, with patients carrying EGFR exon 19 mutations having the longest median PFS (overall p = 8.88 × 10^-15). Comparison of PFS among the five different exon 19 mutation subtypes and among the two exon 19 deletion start codons did not reveal any significant differences. No significant difference was observed in OS among patients carrying EGFR mutations on different exons (overall p = 0.054); however, OS was found to be significantly different among the various subtypes of exon 19 mutations, with the 15–nucleotide deletion “non-ELREA” group having the shortest OS of 11.3 months (overall p = 0.025).ConclusionsEGFR mutation types and subtypes significantly influence survival outcomes in patients with advanced NSCLC who are receiving first-line gefitinib treatment.     

Classification of Tumor Immune Microenvironment According to Programmed Death-Ligand 1 Expression and Immune Infiltration Predicts Response to Immunotherapy Plus Chemotherapy in Advanced Patients With NSCLC

IntroductionAccording to mechanisms of adaptive immune resistance, tumor immune microenvironment (TIME) is classified into four types: (1) programmed death-ligand 1 (PD-L1)–negative and tumor-infiltrating lymphocyte (TIL)–negative (type I); (2) PD-L1–positive and TIL-positive (type II); (3) PD-L1–negative and TIL-positive (type III); and (4) PD-L1–positive and TIL-negative (type IV). However, the relationship between the TIME classification model and immunotherapy efficacy has not been validated by any large-scale randomized controlled clinical trial among patients with advanced NSCLC.MethodsOn the basis of RNA-sequencing and immunohistochemistry data from the ORIENT-11 study, we optimized the TIME classification model and evaluated its predictive value for the efficacy of immunotherapy plus chemotherapy.ResultsPD-L1 mRNA expression and immune score calculated by the ESTIMATE method were the strongest predictors for the efficacy of immunotherapy plus chemotherapy. Therefore, they were determined as the optimized definition of the TIME classification system. When compared between combination therapy and chemotherapy alone, only the type II subpopulation with high immune score and high PD-L1 mRNA expression was significantly associated with improved progression-free survival (PFS) (hazard ratio = 0.12, 95% confidence interval: 0.06–0.25, p < 0.001) and overall survival (hazard ratio = 0.27, 95% confidence interval: 0.13–0.55, p < 0.001). In the combination group, the type II subpopulation had a much longer survival time, not even reaching the median PFS or overall survival, but the other three subpopulations were susceptible to having similar PFS. In the chemotherapy group, there was no marked association between survival outcomes and TIME subtypes.ConclusionsOnly patients with both high PD-L1 expression and high immune infiltration could benefit from chemotherapy plus immunotherapy in first-line treatment of advanced NSCLC. For patients lacking either PD-L1 expression or immune infiltration, chemotherapy alone might be a better treatment option to avoid unnecessary toxicities and financial burdens.