Dataset Information

Clinical and Molecular Characteristics Associated With Survival Among Patients Treated With Checkpoint Inhibitors for Advanced Non-Small Cell Lung Carcinoma: A Systematic Review and Meta-analysis.

ABSTRACT: Importance:Checkpoint inhibitors have replaced docetaxel as the new standard second-line therapy in advanced non-small cell lung carcinoma (NSCLC), but little is known about the potential predictive value of clinical and molecular characteristics. Objective:To estimate the relative efficacy of checkpoint inhibitor vs docetaxel overall and in subgroups defined by clinicopathological characteristics. Data Sources:This systematic review and meta-analysis searched MEDLINE, Embase, PubMed, and the Cochrane Central Register of Controlled Trials for randomized clinical trials published in the English language between January 1, 1996, and January 30, 2017. Study Selection:Randomized clinical trials that compared a checkpoint inhibitor (nivolumab, pembrolizumab, or atezolizumab) with docetaxel. For each trial included in this study, the trial name, year of publication or conference presentation, patients' clinicopathological characteristics, type of chemotherapy, and type of checkpoint inhibitor were extracted. Data collection for this study took place from February 1 to March 31, 2017. Data Extraction and Synthesis:Two reviewers performed study selection, data abstraction, and risk of bias assessment. Hazard ratios (HR) and 95% CIs for the overall population and subgroups were extracted. Pooled treatment estimates were calculated using the inverse-variance-weighted method. Results:In total, 5 trials involving 3025 patients with advanced NSCLC were included in this meta-analysis. These patients were randomized to receive a checkpoint inhibitor (nivolumab, 427 [14.1%]; pembrolizumab, 691 [22.8%]; or atezolizumab, 569 [18.8%]) or docetaxel (1338 [44.2%]). Checkpoint inhibitors were associated with prolonged overall survival, compared with docetaxel (HR, 0.69; 95% CI, 0.63-0.75; P?

SUBMITTER: Lee CK

PROVIDER: S-EPMC5838598 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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Clinical and Molecular Characteristics Associated With Survival Among Patients Treated With Checkpoint Inhibitors for Advanced Non-Small Cell Lung Carcinoma: A Systematic Review and Meta-analysis.

Lee Chee Khoon CK Man Johnathan J Lord Sally S Cooper Wendy W Links Matthew M Gebski Val V Herbst Roy S RS Gralla Richard J RJ Mok Tony T Yang James Chih-Hsin JC

JAMA oncology 20180201 2

<h4>Importance</h4>Checkpoint inhibitors have replaced docetaxel as the new standard second-line therapy in advanced non-small cell lung carcinoma (NSCLC), but little is known about the potential predictive value of clinical and molecular characteristics.<h4>Objective</h4>To estimate the relative efficacy of checkpoint inhibitor vs docetaxel overall and in subgroups defined by clinicopathological characteristics.<h4>Data sources</h4>This systematic review and meta-analysis searched MEDLINE, Emba ...[more]

PMID: 29270615

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Project description:ObjectivesImmune checkpoint inhibitors (ICIs) have changed the landscape of lung cancer therapy. However significant proportions of patients have primary or acquired resistance to ICIs. Molecular characterization is critical for patient selection and overcoming resistance to checkpoint inhibitors. The purpose of this study is to investigate the molecular characteristics associated with ICIs outcomes in advanced non-small cell lung cancer (NSCLC) patients.Materials and methodsAll advanced stage NSCLC patients at City of Hope who received ICIs (pembrolizumab, nivolumab, atezolizumab, and durvalumab) were identified retrospectively. Overall survival (OS, from the start of the ICIs), Pathology and information on genomic alterations (GAs) including next-generation sequencing (NGS) data, tumor mutation burden (TMB), and Programmed death-ligand 1 (PD-L1) levels were collected. Chi-square and Fisher's exact test, Log-rank test were used for comparison of demographics, and survival curves respectively. Univariate and multivariate COX proportional hazards model was used for survival analysis.Results346 NSCLC patients were identified. Univariate and multivariate analysis found the association of OS with PD-L1 level ≥50% (Hazard ratio [HR], 0.19; 95% confidence interval [CI], 0.06-0.59; P < 0.01), EGFR (HR 7.38; 95% CI, 1.15-47.42; P < 0.05), and TET2 (HR 0.15; 95% CI, 0.03-0.90; P < 0.05). The median OS was not reached [NR] for the 12 patients who had genomic alterations (GAs) in TET2 (12/108, 11%) versus (vs) 11.5 months in TET2 negative patients (98/108, 89%). Interestingly, GAs in TET2 and FANCA were mutually exclusive and patients who had GAs in FANCA gene (6%) had shorter OS (5.5 months vs 14.5 months, Log-rank test, P < 0.05).ConclusionsWe described the clinical and molecular features of NSCLC patients treated with ICIs. The association of GAs in TET2 with longer OS and its mutual exclusivity with FANCA GAs were insightful for developing novel therapeutic strategies to improve ICIs outcomes in NSCLC.

Project description:BackgroundImmune checkpoint inhibitors (ICIs) have witnessed the achievements of convincing clinical benefits that feature the significantly prolonged overall survival (OS) of patients suffering from advanced non-small cell lung cancer (NSCLC), according to reports recently. Sensitivity to immunotherapy is related to several biomarkers, such as PD-L1 expression, TMB level, MSI-H and MMR. However, a further investigation into the novel biomarkers of the prognosis on ICIs treatment is required. In addition, there is an urgent demand for the establishment of a systematic hazard model to assess the efficacy of ICIs therapy for advanced NSCLC patients.MethodsIn this study, the gene mutation and clinical data of NSCLC patients was obtained from the TCGA database, followed by the analysis of the detailed clinical information and mutational data relating to two advanced NSCLC cohorts receiving the ICIs treatment from the cBioPortal of Cancer Genomics. The Kaplan-Meier plot method was used to perform survival analyses, while selected variables were adopted to develop a systematic nomogram. The prognostic significance of ERBB4 in pan-cancer was analyzed by another cohort from the cBioPortal of Cancer Genomics.ResultsThe mutation frequencies of TP53 and ERBB4 were 54% and 8% in NSCLC, respectively. The mutual exclusive analysis in cBioPortal has indicated that ERBB4 does show co-occurencing mutations with TP53. Patients with ERBB4 mutations were confirmed to have better prognosis for ICIs treatment, compared to those seeing ERBB4 wild type (PFS: exact p = 0.017; OS: exact p < 0.01) and only TP53 mutations (OS: p = 0.021). The mutation status of ERBB4 and TP53 was tightly linked to DCB of ICIs treatment, PD-L1 expression, TMB value, and TIICs. Finally, a novel nomogram was built to evaluate the efficacy of ICIs therapy.ConclusionERBB4 mutations could serve as a predictive biomarker for the prognosis of ICIs treatment. The systematic nomogram was proven to have the great potential for evaluating the efficacy of ICIs therapy for advanced NSCLC patients.

Dataset Information

Clinical and Molecular Characteristics Associated With Survival Among Patients Treated With Checkpoint Inhibitors for Advanced Non-Small Cell Lung Carcinoma: A Systematic Review and Meta-analysis.

Publications

Clinical and Molecular Characteristics Associated With Survival Among Patients Treated With Checkpoint Inhibitors for Advanced Non-Small Cell Lung Carcinoma: A Systematic Review and Meta-analysis.

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