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

BMJ 2018; 362 (Published 10 September 2018) Cite this as: BMJ 2018;362:k3529
1. Xian Shen, clinician1,
2. Bin Zhao, professor1
1. 1Center for Precision Medicine, 109 Xueyuan West Road, the Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, 325027, China
1. Correspondence to: B Zhao doctorbinzhao{at}126.com
• Accepted 25 July 2018

## 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.

## Introduction

The immune suppression and evasion of malignant cancer cells is known as one of the hallmarks of cancer.1 A series of co-inhibitory and co-stimulatory receptors and their ligands, known as immune checkpoints, control this process. Among them, programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) axis stands out as a valuable therapeutic target because it not only plays a key role in physiological immune homoeostasis, but also appears to be a means through which cancer cells evade the immune system.2 The development and application of antibodies targeting PD-1 (nivolumab and pembrolizumab) and PD-L1 (atezolizumab, avelumab, and durvalumab) have advanced the treatment of cancer.3 Currently, PD-1 or PD-L1 inhibitors are being investigated in more than 1000 clinical trials and are licensed to treat a variety of cancers.23

### Weaknesses of this study

This study also has some limitations. Firstly, an optimal treatment strategy needed to maximise the benefit as well as minimise the risk of toxicities. Toxicity profile is another important factor in choosing therapy options. However, it was impossible to conduct such an analysis to deal with this issue here because all the information regarding adverse events from the included patients that were PD-L1 negative were unavailable. Secondly, although all the eligible studies conducted the randomisation process adequately, randomisations were stratified by PD-L1 expression in some trials,131516 an imbalance of patient characteristics between two treatment groups can still exist. However, it should be noted that there is no significant difference in terms of overall survival between studies in which patients are randomised according to PD-L1 expression and trials in which patients are not (see fig 3 and fig 4). Thirdly, we carried out the present study at the trial level, no clinicopathological characteristics at individual level were examined. This might reduce our ability to test for associations between variables in specific subgroups. Fourthly, it should be noted that some subgroup analysis conducted in this study included only a few trials. It cannot be excluded that insufficient statistical power might account for the results obtained from these subgroup analyses. Accordingly, these results should be interpreted with caution. Fifthly, we examined subgroups of patients (ie, patients that were PD-L1 positive and PD-L1 negative) in the eligible eight randomised controlled trials. Although most studies provided a balance between intervention arms, subgroup analysis, by its nature, might introduce bias to our analysis.

Despite these limitations, this study is the largest meta-analysis that incorporates results from eight randomised controlled trials with over 4000 patients with cancer.

### Conclusions

PD-1 or PD-L1 inhibitors, compared with conventional agents, prolonged overall survival in both patients with advanced solid tumour that were PD-L1 positive and PD-L1 negative as second and later lines of treatment. We cannot recommend PD-L1 expression status as prognostic biomarker in patients’ selection in PD-1 or PD-L1 blockade therapy. The finding of this meta-analysis could also assist in biomarker and drug development, economic analyses, and future clinical trial designs.

#### What is already known on this topic

• Programmed cell death 1 (PD-1) and programmed death-ligand 1 (PD-L1) inhibitors are effective at treating several cancers

• Direct evaluation of the PD-L1 expression is treated as biologically plausible and the best available biomarker in predicting the tumour response and survival prognosis

• The literature shows that patients that are PD-L1 negative benefit from PD-1 or PD-L1 blockade therapy

#### What this study adds

• PD-1 or PD-L1 blockade therapy is preferable to conventional therapy for treating patients with advanced solid tumours that are PD-L1 positive and PD-L1 negative

• PD-L1 expression status alone is insufficient in determining which patients should be offered PD-1or PD-L1 blockade therapy

## Footnotes

• Contributors: XS and BZ conceived the study, acquired the data, analysed the data, and wrote the manuscript. BZ is the guarantor.

• Funding: None.

• Competing interests: All authors have completed the ICMJE form disclosure form at www.icmje.org/coi_disclosure.pdf and declare: no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work.

• Ethical approval: Not required.

• Data sharing: No additional data are available.

• Transparency: The manuscripts guarantor (BZ) affirms that the manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned have been explained.

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