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

Abstract

ObjectiveTo 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.DesignMeta-analysis of randomised controlled trials.Data sourcesPubMed, 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 methodsStudies 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.Results4174 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.ConclusionsPD-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.

The landscape of immune checkpoint inhibitor plus chemotherapy versus immunotherapy for advanced non‐small‐cell lung cancer: A systematic review and meta‐analysis

“…Thus to some extent, for patients with NSCLC with negative PD‐L1 level, high tumor mutational burden increases the chance of tumor response to immunotherapy (Anagnostou et al, ; Rosenberg et al, ). Therefore, in this study, we concluded that PD‐L1 alone was not an ideal predictive biomarker for survival benefits of advanced patients with NSCLC from immunotherapy because of the unclear function and regulation of PD‐1 pathway and technical limitations including: archived or fresh tissue for PD‐L1 testing, optimal antibody (22C3, 28‐8, SP142, or SP263) and when to conduct PD‐L1 testing or whether to retest PD‐L1 expression (Brahmer et al, ; Shen & Zhao, ).…”

MIR155HG is a prognostic biomarker and associated with immune infiltration and immune checkpoint molecules expression in multiple cancers

“…Herbst et al conducted a large sample of clinical randomized controlled trials, pembrolizumab achieves extended OS and has a favorable benefit‐to‐risk profile in patients with PD‐L1 positive advanced non‐small‐cell lung cancer, and a phase II basket study (KEYNOTE‐158) investigated the antitumor activity and safety of pembrolizumab in multiple cancer types, concluded that in previously treated advanced cervical cancer: PD‐L1–positive tumors have a stronger response after pembrolizumab treatment . Although the expression of PD‐L1 at the tumor site can predict the patient's reactivity to PD‐1 blockers, PD‐L1 expression status alone is insufficient in determining which patients should be accepted PD‐1 or PD‐L1 blockade therapy . The dynamic nature of the immune microenvironment, other checkpoint molecules, tumor infiltrating cells, immune biomarkers, mutational load are critical in immunotherapy response .…”

“…38 Although the expression of PD-L1 at the tumor site can predict the patient's reactivity to PD-1 blockers, PD-L1 expression status alone is insufficient in determining which patients should be accepted PD-1 or PD-L1 blockade therapy. 39 The dynamic nature of the immune microenvironment, other checkpoint molecules, tumor infiltrating cells, immune biomarkers, mutational load are critical in immunotherapy response. 40 Therefore, comprehensive and precision pre-biomarkers are important for clinically personalized immunotherapy.…”

Rational application of the first‐line chemotherapy and immune checkpoint inhibitors in advanced nonsmall cell lung cancer: A meta‐analysis

“…Previous studies have shown that the use of PD‐L1 expression status alone is insufficient to determine which patients should be offered PD‐1 or PD‐L1 blockade therapy and TMB might serve as a complementary diagnostic tool . High TMB is related with increased tumor‐infiltrating lymphocytes, expression of proinflammatory cytokines and immune‐related genes, but the impact on clinical outcome has yet to be clarified .…”