Association of Survival and Immune-Related Biomarkers With Immunotherapy in Patients With Non–Small Cell Lung Cancer
Authors: Yunfang Yu, Dongqiang Zeng, Qiyun Ou, Shengbo Liu, Anlin Li, Yongjian Chen, Dagui Lin, Quanlong Gao, Haiyu Zhou, Wangjun Liao, Herui Yao
Journal: JAMA Network Open (2019)

<h3>Importance</h3> The beneficial role of immunotherapy and the clinical relevance of current biomarkers in non–small cell lung cancer (NSCLC) remain inconclusive; thus, appropriate strategies and reliable predictors need further definition. <h3>Objectives</h3> To evaluate the association of clinical outcomes with immune checkpoint inhibitors, tumor vaccines, and cellular immunotherapy in patients with advanced NSCLC and to explore appropriate strategies, candidates, and predictors. <h3>Data Sources</h3> The PubMed, EMBASE, and Cochrane Central Register of Controlled Trials databases were searched from inception to June 2018, using relevant search keywords and Medical Subject Headings (MeSH) terms, including<i>tumor vaccine</i>,<i>cellular immunotherapy</i>,<i>immune checkpoint inhibitor</i>,<i>cytotoxic T-lymphocyte-associated protein 4</i>,<i>programmed death-ligand 1</i>,<i>programmed death receptor 1</i>, and<i>non-small cell lung carcinoma</i>. Systematic reviews, meta-analyses, references, and conference proceedings were manually searched. <h3>Study Selection</h3> English-language randomized clinical trials with available data that measured overall survival (OS), progression-free survival (PFS), or objective response rate comparing immune checkpoint inhibitors, tumor vaccines, or cellular immunotherapy with conventional therapy for patients with advanced or metastatic NSCLC were included. Thirty-one immunotherapy randomized clinical trials were included, and multicohort data included next-generation sequencing data from patients with advanced NCSLC. <h3>Data Extraction and Synthesis</h3> Hazard ratios and 95% CIs were pooled to estimate the survival increases in OS and PFS. Dichotomous data, such as object response rate data, were analyzed using the risk ratio. Mantel-Haenszel random-effects model was used.<i>I</i><sup>2</sup>was used to assess the heterogeneity between trials; an<i>I</i><sup>2</sup>value exceeding 50% indicated the existence of substantial heterogeneity. Analyses took place from February 1, 2018, to August 31, 2018. <h3>Main Outcomes and Measures</h3> Primary outcomes were OS and PFS. <h3>Results</h3> In total, 14 395 patients (9500 [66.0%] men) were included in the meta-analysis, and 1833 patients (mean [SD], 65.2 [9.9] years; 1063 [58.0%] men) were included in the individual patient–level study. Compared with conventional therapy, immunotherapy was associated with significantly longer OS (hazard ratio, 0.76; 95% CI, 0.71-0.82;<i>P</i> &lt; .001) and PFS (hazard ratio, 0.76; 95% CI, 0.70-0.83;<i>P</i> &lt; .001). The best checkpoint blockade strategy was first-line pembrolizumab with platinum-based chemotherapy. The combined predictive utility of programmed cell death ligand 1 (PD-L1) expression and tumor mutation burden (TMB) was associated with predictive prognosis (whole-exome sequencing: 1-year PFS area under the receiver operating characteristic curve [AUC], 0.829; 3-year PFS AUC, 0.839; targeted next-generation sequencing: 1-year PFS AUC, 0.826; 3-year PFS AUC, 0.948). Moreover, the addition of CD8<sup>+</sup>T-cell tumor-infiltrating lymphocytes was associated with improved prognosis predictions for OS (3-year OS AUC, 0.659; 5-year OS AUC, 0.665).<i>RYR1</i>or<i>MGAM</i>mutations were significantly associated with concomitantly increased durable clinical benefits (<i>RYR1</i>: durable clinical benefit [DCB], 12 of 51 patients [24%]; no durable benefit [NDB], 2 of 55 patients [4%];<i>P</i> &lt; .001;<i>MGAM</i>: DCB, 12 of 51 patients [24%]; NDB, 0 patients;<i>P</i> &lt; .001), a higher TMB (<i>RYRI</i>: high TMB, 12 of 53 patients [23%]; low TMB, 2 of 53 patients [38%];<i>P</i> &lt; .001;<i>MGAM</i>: high TMB, 9 of 53 patients [17%]; low TMB, 0 patients;<i>P</i> &lt; .001), and higher PD-L1 expression (<i>RYRI</i>: high PD-L1 expression, 8 of 30 patients [27%]; low PD-L1 expression, 6 of 85 [7.1%];<i>P</i> &lt; .001;<i>MGAM</i>: high PD-L1 expression, 6 of 30 patients [20%]; low PD-L1 expression, 5 of 85 patients [6%];<i>P</i> &lt; .001). <h3>Conclusions and Relevance</h3> Immunotherapies showed promising clinical outcomes for patients with NSCLC. Pembrolizumab with platinum-based chemotherapy was found to be the most appropriate first-line immune checkpoint inhibitor regimen for advanced NSCLC, and the combined use of PD-L1 expression and TMB was found to be a promising biomarker to evaluate patients’ survival and response to precision immunotherapy. The further combination of CD8<sup>+</sup>T-cell tumor-infiltrating lymphocytes, PD-L1 expression, and TMB was associated with reliable prognosis. The predictive value of that combination needs to be prospectively validated in large-scale studies.