Chest
Volume 152, Issue 2, August 2017, Pages 271-281
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Original Research: Lung Cancer
Incidence of Pneumonitis With Use of Programmed Death 1 and Programmed Death-Ligand 1 Inhibitors in Non-Small Cell Lung Cancer: A Systematic Review and Meta-Analysis of Trials

https://doi.org/10.1016/j.chest.2017.04.177Get rights and content

Background

Programmed death 1 (PD-1) programmed death-ligand 1 (PD-L1) inhibitors show significant clinical activity in non-small cell lung carcinoma (NSCLC). However, they are often associated with potentially fatal immune-mediated pneumonitis. Preliminary reports of trials suggest a difference in the rate of pneumonitis with PD-1 and PD-L1 inhibitors. We sought to determine the overall incidence of pneumonitis and differences according to type of inhibitors and prior chemotherapy use.

Methods

MEDLINE, Embase, and Scopus databases were searched up to November 2016. Rates of pneumonitis of any grade and grade ≥ 3 from all clinical trials investigating nivolumab, pembrolizumab, atezolizumab, durvalumab, and avelumab as single agents in NSCLC were collected. The incidence of pneumonitis across trials was calculated using DerSimonian-Laird random effects models. We compared incidences between PD-1 and PD-L1 inhibitors and between treatment naive and previously treated patients.

Results

Nineteen trials (12 with PD-1 inhibitors [n = 3,232] and 7 with PD-L1 inhibitors [n = 1,806]) were identified. PD-1 inhibitors were found to have statistically significant higher incidence of any grade pneumonitis compared with PD-L1 inhibitors (3.6%; 95% CI, 2.4%-4.9% vs 1.3%; 95% CI, 0.8%-1.9%, respectively; P = .001). PD-1 inhibitors were also associated with higher incidence of grade 3 or 4 pneumonitis (1.1%; 95% CI, 0.6%-1.7% vs 0.4%; 95% CI, 0%-0.8%; P = .02). Treatment naive patients had higher incidence of grade 1 through 4 pneumonitis compared with previously treated patients (4.3%; 95% CI, 2.4%-6.3% vs 2.8%; 95% CI, 1.7%- 4%; P = .03).

Conclusions

There was a higher incidence of pneumonitis with use of PD-1 inhibitors compared with PD-L1 inhibitors. Higher rate of pneumonitis was more common in treatment naive patients.

Section snippets

Methods

We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement to report this systematic review and meta-analysis.7

Eligible Studies

Our search retrieved 3,504 publications. After excluding duplicates and screening titles of the studies, 108 articles were selected on the basis of relevance to the study topic. After abstract and full article review, 19 distinct trials were included. All studies were published in the last 5 years. We found 12 trials with PD-1 inhibitors (nivolumab: n = 9, pembrolizumab: n = 3) and 7 trials with PD-L1 inhibitors (atezolizumab: n = 5, durvalumab: n = 1, avelumab: n = 1). The reasons for

Discussion

In the present meta-analysis of all published clinical trials of PD-1 and PD-L1 inhibitor therapy for patients with NSCLC, the overall incidence of all grade pneumonitis in PD-1 inhibitor group was 3.6% and in the PD-L1 inhibitor group was 1.3%, a difference that was significant. Grade ≥ 3 pneumonitis incidence was significantly higher for PD-1 inhibitors as well.

Use of PD-1 and PD-L1 inhibitors in the frontline setting was associated with significantly higher incidence of all grade pneumonitis

Conclusions

This analysis suggests that PD-1 inhibitors are associated with a significantly higher incidence of pneumonitis than PD-L1 inhibitors. This finding may impact clinical selection of these agents given their overlapping indications in NSCLC. Further understanding of the role of PD-1 and its ligands in generating pneumonitis can yield important clues toward development of safer immune checkpoint therapies. In addition, we observed a significantly higher rate of pneumonitis in treatment naive

Acknowledgments

Author contributions: A. V. H., P. M., J. S., N. A. P., and V. V. contributed to conception and design. V. V. accepts official responsibility for the overall integrity of the manuscript and ensures all statements in the manuscript are true to his knowledge. M. K., S. R., and V. P. contributed to provision of study materials or patients. M. K., S. R., and V. P. contributed to collection and assembly of data. V. P. and A. V. H. contributed to data analysis and interpretation. M. K., S. R., V. P.,

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    FUNDING/SUPPORT: The authors have reported to CHEST that no funding was received for this study.

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