AUTHOR=Addeo Alfredo , Banna Giuseppe Luigi , Metro Giulio , Di Maio Massimo 

TITLE=Chemotherapy in Combination With Immune Checkpoint Inhibitors for the First-Line Treatment of Patients With Advanced Non-small Cell Lung Cancer: A Systematic Review and Literature-Based Meta-Analysis

JOURNAL=Frontiers in Oncology

VOLUME=9

YEAR=2019

URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2019.00264

DOI=10.3389/fonc.2019.00264

ISSN=2234-943X

ABSTRACT=<p><bold>Background:</bold> Checkpoint inhibitors plus platinum-based chemotherapy have shown superiority compared to chemotherapy alone as first-line therapy in advanced non–small cell lung carcinoma (NSCLC). To evaluate the relative benefit in term of Overall Survival (OS) and Progression-free Survival (PFS) of checkpoint inhibitors plus chemotherapy vs. chemotherapy alone, overall and in subgroups defined by PDL1 expression we have performed a meta-analysis.</p><p><bold>Data Sources:</bold> This meta-analysis searched PubMed and checked references of the selected English language articles to identify further eligible trials. Data collection for this study took place from October 1 to October 24, 2018.</p><p><bold>Results:</bold> In total, 8 trials involving 4,646 patients with advanced NSCLC, 3.314 (71%) and 1.332 (29%) with a non-squamous and squamous histology, respectively, were included in this meta-analysis. Four trials used atezolizumab, 3 pembrolizumab, and 1 nivolumab, accounting for 2.985 (64%), 1.298 (28%), and 363 (8%) of patients, respectively. The patients were randomized to receive first-line chemotherapy plus a checkpoint inhibitor vs. first-line chemotherapy, 2,978 patients for the OS endpoint and first-line chemotherapy plus a checkpoint inhibitor vs. first-line chemotherapy, 1,740 patients in the PFS endpoint. Checkpoint inhibitors plus chemotherapy were associated with prolonged OS, compared with chemotherapy in the ITT population (HR, 0.74; 95% CI, 0.64–0.87; <italic>p</italic> = 0.0002, with significant heterogeneity among trials). Notably within the PDL1 low group (1–49) there was a significant heterogeneity (<italic>p</italic> = 0.06) between type of drug and efficacy: the combination of chemotherapy plus pembrolizumab showed an OS benefit (HR, 0.56; 95% CI, 0.40–0.78; <italic>P</italic> &lt; 0.00007) unlike the atezolizumab backbone trials (HR, 0.92; 95% CI, 0.62–1.37; <italic>P</italic> &lt; 0.69). However, checkpoint inhibitors plus chemotherapy were associated with prolonged PFS in the ITT (HR, 0.61; 95% CI, 0.56–0.66; <italic>P</italic> &lt; 0.00001) and across PDL1 subgroups.</p><p><bold>Conclusion and Relevance:</bold> Checkpoint inhibitors plus chemotherapy compared with chemotherapy, are associated with significantly prolonged OS and PFS in first-line therapy in NSCLC. In the low PDL1 subgroups the benefit was statistically significant only in the pembrolizumab backbone trials. The findings of this meta-analysis could assist in the design and interpretation of future trials and in economic analyses.</p>