Toxicity Profile of Combining PD-1/PD-L1 Inhibitors and Thoracic Radiotherapy in Non-Small Cell Lung Cancer: A Systematic Review

Abstract

BackgroundThe combination of immune checkpoint inhibitors (ICIs) and thoracic radiotherapy (TRT) has shown significant clinical activity in patients with non-small cell lung cancer (NSCLC). However, the currently available data on adverse events (AEs) were derived from a small subset of patients included in prospective clinical trials or retrospective studies. Thus, we conducted this systematic review to determine the AEs associated with this combination treatment.MethodsAn electronic literature search was performed in databases and conference proceedings of prospective clinical trials assessing the combination of ICIs and TRT for patients with NSCLC. The systematic analysis was conducted to determine the profile and incidence of AEs of combination treatment. We further performed the comparison of AEs between programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) inhibitors, and sequential and concurrent administration of ICIs and TRT to help identify high risk patients. The systematic analyses were conducted with the Review Manager (version 5.3; The Cochrane Collaboration, Oxford, United Kingdom) and Stata version 12.0 (StataCorp, College Station, TX, USA) software.ResultsEleven clinical trials involving 1,113 patients with NSCLC were eligible for analysis. The incidence of all-grade AEs was 95.5%; that of high-grade AEs (grade ≥3) was 30.2%. The most frequent all-grade AE was fatigue (49.7%), while pneumonitis was the most common high-grade AE (3.8%) and grade 5 AE (0.6%). Notably, the toxicity profiles of PD-1 and PD-L1 inhibitors were similar. Concurrent treatment was associated with a higher incidence of higher-grade AEs (41.6% vs 24.8%, P=0.17) and pneumonitis (7.1% vs 3.9%, P=0.14) compared to sequential treatment, but no significant difference was observed.ConclusionMost AEs of this combination treatment are tolerable; as the most common high-grade AE, pneumonitis deserves the utmost attention of physicians. The toxicity profiles of patients receiving PD-1 or PD-L1 were similar, and no significant difference was observed between concurrent and sequential treatment.

Comprehensive Pneumonitis Profile of Thoracic Radiotherapy Followed by Immune Checkpoint Inhibitor and Risk Factors for Radiation Recall Pneumonitis in Lung Cancer

“…In the era of immune therapy, ICI combined with TRT achieved striking survival benefits for both NSCLC and SCLC ( 5 – 7 ). As the most common high-grade and grade 5 adverse event ( 17 ), treatment-related pneumonitis deserves the uttermost attention in additive therapy of ICI and TRT. The incidences of any grade pneumonitis and G3+ pneumonitis in clinical trials of ICI after conventional TRT were 13-33% and 1-9%, respectively ( 6 – 9 ), whereas higher rates (56-62% and 2-14%, respectively) were observed in real-world data ( 11 , 18 – 21 ).…”

Efficacy and safety of radiotherapy/chemoradiotherapy combined with immune checkpoint inhibitors for locally advanced stages of esophageal cancer: A systematic review and meta-analysis

“…Li et al. ( 58 ) thought that RT rather than ICIs might be the leading reason for the similar incidence of PD-1 and PD-L1 inhibitors when combined with RT. Thus, the selection of candidate ICIs is recommended, primarily depending on their efficacy rather than the toxicity.…”

Real‐World Efficacy and Safety of Sintilimab‐Based Regimens against Advanced Esophageal Cancer: A Single‐Center Retrospective Observational Study

“…The incidence of grades 1-2 and grades 3-4 pneumonia in this study were 34% and 10%, respectively, higher than the incidence of <1% and 3% in ORIENT-15. Li et al [ 36 ] conducted a meta-analysis of 11 prospective clinical trials (1113 cases) of thoracic radiotherapy combined with immunotherapy for NSCLC and found that the incidence of pneumonia of all grades was 23%, and that in grades 3-5 was 3.8%, which validated the safety of radioimmunotherapy. However, it should be noted that the incidence of radiation-immune-associated pneumonia in real-world studies is higher than in clinical studies.…”