Safety and Efficacy of PD-1/PD-L1 inhibitors combined with radiotherapy in patients with non-small-cell lung cancer: a systematic review and meta-analysis

Abstract

Background: A combination of programmed cell death protein-1 (PD-1)/programmed cell death ligand-1 (PD-L1) inhibitors and radiotherapy (RT) is increasingly being used to treat non-small-cell lung cancer (NSCLC). However, the safety and efficacy of this approach remains controversial. We performed a systematic review and meta-analysis to summarize the related research.

Methods: We searched the China Biology Medicine, EMBASE, Cochrane Library, and PubMed databases for all the relevant studies. The Stata software, version 12.0 was used for the meta-analysis.

Results: The study included 20 clinical trials that enrolled 2027 patients with NSCLC. Compared with non-combination therapy, combination therapy using PD-1/PD-L1 inhibitors and RT was associated with prolonged overall survival (OS) (1-year OS: odds ratio [OR] 1.77, 95% confidence interval [CI] 1.35-2.33, p = 0.000; 2-year OS: OR 1.77, 95% CI 1.35-2.33, p = 0.000) and progression-free survival (PFS) (0.5-year PFS: OR 1.83, 95% CI 1.13-2.98, p = 0.014; 1-year PFS: OR 2.09, 95% CI 1.29-3.38, p = 0.003; 2-year PFS: OR 2.47, 95% CI 1.13-5.37, p = 0.023). Combination therapy also improved the objective response rate (OR 2.76, 95% CI 1.06-7.19, p = 0.038) and disease control rate (OR 1.80, 95% CI 1.21-2.68, p = 0.004). This meta-analysis showed that compared with non-combination therapy, combination therapy using PD-1/PD-L1 inhibitors and RT did not increase the serious adverse event rates (≥grade 3); however, this approach increased the rate of grade 1-2 immune-related or radiation pneumonitis. Subgroup analyses revealed that the sequence of PD-1/PD-L1 inhibitors followed RT outperformed in which concurrent PD-1/PD-L1 inhibitor and RT followed PD-1/PD-L1 inhibitor. Combination of stereotactic body RT or stereotactic radiosurgery with PD-1/PD-L1 inhibitors may be more effective than a combination of conventional RT with PD-1/PD-L1 inhibitors in patients with advanced NSCLC.

Conclusion: Combination therapy using PD-1/PD-L1 inhibitors and RT may improve OS, PFS, and tumor response rates without an increase in serious adverse events in patients with advanced NSCLC. However, combination therapy was shown to increase the incidence of mild pneumonitis.

Keywords: combined radio-immunotherapy; meta-analysis; non-small-cell lung cancer; programmed cell death protein-1/programmed cell death ligand-1 inhibitors; radiotherapy; systematic review.

FIGURE 1

Flow diagram of the identification of eligible studies.

FIGURE 2

Subgroup analyses of 1–2 year OS. (A), 1‐year OS, Sequence of RT and ICIs. (B), 1‐year OS, RT techniques. (C), 2‐year OS, Study design. RT, radiotherapy; ICIs, immune checkpoint inhibitors; OS, overall survival; SBRT, stereotactic body radiotherapy; SRS, stereotactic radiosurgery; RCT, randomized controlled trial; NRCT, non‐randomized controlled trial.

FIGURE 3

Subgroup analyses of 0.5–2 year PFS. (A), 0.5‐year PFS, Overall population. (B), 1‐year PFS, Study design. (C), 2‐year PFS, Overall population. PFS, progression‐free survival; RCT, randomized controlled trial; NRCT, non‐randomized controlled trial.

FIGURE 4

Subgroup analyses of ORR and DCR. (A), ORR, Study design. (B), ORR, Different groups. (C), DCR, Study design. (D), DCR, Different groups. RT, radiotherapy; ICIs, immune checkpoint inhibitors; ORR, objective response rate; DCR, disease control rate; RCT, randomized controlled trial; NRCT, non‐randomized controlled trial.

FIGURE 5

Subgroup analyses of AEs and mild pneumonitis. (A), AEs ≥grade 3, Overall population. (B), AEs grade 1–2, Overall population. (C), Pneumonitis grade 1–2, The site of RT. (D), Pneumonitis grade 1–2, PD‐1 vs PDL1. RT, radiotherapy; AEs, adverse events.