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

Abstract

Background: 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. Data Sources: 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. Results: 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; p = 0.0002, with significant heterogeneity among trials). Notably within the PDL1 low group (1-49) there was a significant heterogeneity (p = 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; P < 0.00007) unlike the atezolizumab backbone trials (HR, 0.92; 95% CI, 0.62-1.37; P < 0.69). However, checkpoint inhibitors plus chemotherapy were associated with prolonged PFS in the ITT (HR, 0.61; 95% CI, 0.56-0.66; P < 0.00001) and across PDL1 subgroups. Conclusion and Relevance: 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.

Keywords: NCSLC; PD1; PDL1; checkpoint inhibition; first line.

Figure 1

Overall survival with chemotherapy plus ICPIs. (A) OS in whole study population. (B) OS by ICPI administered. (C) OS by PD-L1 expression- PD-L1 negative. (D) OS by PD-L1 expression- PD-L1 low. (E) OS by PD-L1 expression- PD-L1 high.

Figure 2

Progression-free survival with chemotherapy plus ICPI. (A) PFS in whole study population. (B) PFS by ICPI administered. (C) PFS by PD-L1 expression- PD-L1 negative. (D) PFS by PD-L1 expression - PD-L1 low. (E) PFS by PD-L1 expression- PD-L1 high.

Figure 3

Overall survival by ICPI drug according to PD-L1 expression. (A) OS in PO-L1 negative population. (B) OS in PO-L1 low population. (C) OS in PO-L1 high population.

Figure 4

Progression-free survival by ICPI drug according to PD-L1 expression. (A) PFS in PO-L1 negative population. (B) PFS in PO-L1 low population. (C) PFS in PO-L1 high population.