Efficacy of PD-1 or PD-L1 inhibitors and PD-L1 expression status in cancer: meta-analysis

Abstract

Objective: To evaluate the relative efficacy of programmed cell death 1 (PD-1) or programmed cell death ligand 1 (PD-L1) inhibitors versus conventional drugs in patients with cancer that were PD-L1 positive and PD-L1 negative.

Design: Meta-analysis of randomised controlled trials.

Data sources: PubMed, Embase, Cochrane database, and conference abstracts presented at the American Society of Clinical Oncology and European Society of Medical Oncology up to March 2018.

Review methods: Studies of PD-1 or PD-L1 inhibitors (avelumab, atezolizumab, durvalumab, nivolumab, and pembrolizumab) that had available hazard ratios for death based on PD-L1 positivity or negativity were included. The threshold for PD-L1 positivity or negativity was that PD-L1 stained cell accounted for 1% of tumour cells, or tumour and immune cells, assayed by immunohistochemistry staining methods.

Results: 4174 patients with advanced or metastatic cancers from eight randomised controlled trials were included in this study. Compared with conventional agents, PD-1 or PD-L1 inhibitors were associated with significantly prolonged overall survival in both patients that were PD-L1 positive (n=2254, hazard ratio 0.66, 95% confidence interval 0.59 to 0.74) and PD-L1 negative (1920, 0.80, 0.71 to 0.90). However, the efficacies of PD-1 or PD-L1 blockade treatment in patients that were PD-L1 positive and PD-L1 negative were significantly different (P=0.02 for interaction). Additionally, in both patients that were PD-L1 positive and PD-L1 negative, the long term clinical benefits from PD-1 or PD-L1 blockade were observed consistently across interventional agent, cancer histotype, method of randomisation stratification, type of immunohistochemical scoring system, drug target, type of control group, and median follow-up time.

Conclusions: PD-1 or PD-L1 blockade therapy is a preferable treatment option over conventional therapy for both patients that are PD-L1 positive and PD-L1 negative. This finding suggests that PD-L1 expression status alone is insufficient in determining which patients should be offered PD-1 or PD-L1 blockade therapy.

Fig 1

Flowchart diagram of selected randomised controlled trials included in this meta-analysis

Fig 2

Hazard ratio of death for patients that are PD-L1 positive and PD-L1 negative assigned to intervention treatment, compared with those in control group. The therapy effects are calculated with fixed effects models. NR=not reported.

Fig 3

Subgroup analyses for overall survival in patients that are PD-L1 positive assigned to intervention treatment, compared with those assigned to control treatment

Fig 4

Subgroup analyses for overall survival in patients that are PD-L1 negative assigned to intervention treatment, compared with those assigned to control treatment