PD-L1 expression in cancer patients receiving anti PD-1/PD-L1 antibodies: A systematic review and meta-analysis

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Abstract

Background

Despite the success of immunotherapy directed at inhibiting of programmed death-1 (PD-1)/PD-ligand (L)1 signaling, it is not established whether PD-L1 expression correlates with the clinical response and outcome in different tumors. The present meta-analysis investigates whether the PD-L1 status, detected by immunohistochemistry, is associated with clinical response and mortality in patients treated with anti-PD-1/PD-L1 therapy.

Methods

A systematic literature search and quantitative analysis were planned, conducted and reported following CONSORT and QUORUM checklists, up to December 2015, to identify clinical trials with information on cancer outcome by PD-L1 immunohistochemical expression in tumor tissues. We used random effects models to estimate Summary Objective Response Rates (SORRs) and Summary Odd Ratio (SOR) for the comparison of PD-L1 positive and negative patients.

Results

We summarized 20 trials carried out in metastatic melanoma (MM), non-small cell lung cancer (NSCLC), and renal cell carcinoma (RCC) patients receiving anti-PD-1/PD-L1 antibodies (4230 MM, 1417 NSCLC and 312 RCC patients). Positive PD-L1 MM patients showed a significant decrease (53%) in the risk of mortality vs. negative cases with no heterogeneity. Furthermore, SORRs were 45% and 27% in PD-L1 positive and negative patients, respectively, and SOR indicates a significant difference in term of responses: 2.14 (95% CI: 1.65, 2.77), with low between-study heterogeneity (I2 = 35%). Furthermore, results from randomized clinical trials on MM showed that PD-L1 expression is significantly associated with greater clinical response rates to anti-PD1 treatments (SOR 1.89; 95%CI: 1.35, 2.64) but not to other treatments (SOR 0.96; 95%CI: 0.5, 1.87).

In non-squamous NSCLC SORRs were 29% and 11% in PD-L1 positive and negative patients, respectively, and SOR indicates a significant difference between responses: 3.78 (1.54, 9.24), with no between-study heterogeneity. Squamous NSCLC and RCC did not show any significant difference in response according to the PD-L1 status.

Conclusion

PD-L1 expression is significantly associated with mortality and clinical response to anti-PD-1/PD-L1 antibodies in MM patients and with clinical response in patients with non-squamous NSCLC.

Introduction

A dynamic relationship exists between host and tumor, and the ability of the tumor to evade immune recognition often determines the clinical course of the disease (Shin and Ribas, 2015). Multiple mechanisms of immune suppression are known to prevent effective antitumor immunity, including increased secretion of immunosuppressive cytokines, i.e., interleukin (IL)-10 and tumor growth factor (TGF)-β, reduced expression of major histocompatibility antigens on cell surface, enhanced differentiation of immune effector cells to a regulatory phenotype, as well as an influx of myeloid-derived suppressor cells and tumor associated macrophages (Pardoll, 2012). Receptors expressed in the plasma membrane of immune cells, by fine tuning cellular activation or inhibition, are key regulators of infections, autoimmunity and cancer. While some of these receptors exert positive activities, others produce detrimental effects. Antibodies, which target regulatory proteins, either inhibiting repressor receptors or stimulating of activating receptors, represent potential strategies to enhance immune responses, and ameliorate cancer outcome (Pardoll, 2012).

The use of immunomodulatory monoclonal antibodies that directly enhance the anti-tumor immune response by T cells, or block immunologic checkpoints that would otherwise restrain effective anti-tumor immunity, have boosted significant enthusiasm in cancer treatment (Postow et al., 2015a). Cancer development is facilitated by dis-regulation of physiological pathways that, under normal circumstances, down-regulate immune activation and maintain tolerance to self. Among these pathways an important contribution is given by the programmed death-1 (PD-1)/PD-ligand (L) 1 axis.

PD-1 is a key immune-checkpoint receptor expressed by activated T cells, which mediates immunosuppression. PD-1 functions primarily in peripheral tissues, where T cells may encounter the immunosuppressive PD-1 ligands, namely PD-L1 (B7-H1) and PD-L2 (B7-DC), which are expressed by tumor cells, stromal cells, or both (Pardoll, 2012). In agreement with the proposed function of the PD-1/PD-L1 axis in the induction and maintenance of peripheral tolerance (Pardoll, 2012), surface expression of PD-L1 in some tumors has been reported to be an independent predictor of adverse clinical outcome (Sznol and Chen, 2013), although the prognostic significance of PD-L1 expression remains controversial (Puzanov et al., 2015, Taube et al., 2012, Konishi et al., 2004, Thompson et al., 2004, Massi et al., 2014). Antibodies blocking the PD-1, or its ligand (PD-L1), were shown in phase I trials to induce a 30% to 50% response in several cancer types (Topalian et al., 2012). Recent phase II and III studies backed the accelerated approval of anti-PD-1 antibodies for metastatic melanoma (MM), non-small cell lung cancer (NSCLC) and renal cell cancer (RCC) (Robert et al., 2015a, Robert et al., 2015b, Gettinger et al., 2015, Garon et al., 2015).

Biomarker-driven selection of immunotherapy responders and non-responders would minimize unnecessary exposure of patients to potentially permanent and life-threatening immune-related toxicities and reduce the financial burden for health systems due to these expensive treatments. Although PD-L1 expression appeared to correlate with response to treatment from exploratory analyses of early reported trials, whether the level of expression of PD-L1 predicts response rate, progression free (PFS) and overall survival (OS) in the context of anti-PD-1/PD-L1 therapy is still object of debate.

At the time of the present manuscript the Food and Drug Administration (FDA) approved anti-PD-1 therapies for three tumor histotypes: MM, NSCLC and RCC. All of them are the focus of the present systematic review and meta-analysis. All current clinical evidence in cutaneous MM, NSCLC and RCC patients receiving anti-PD-1/PD-L1 therapy has been reviewed and quantitatively summarized. We performed a formal systematic literature search and meta-analysis of the controlled clinical trials evaluating anti-PD-1 antibodies with the aim at identifying whether PD-L1 expression is associated with response to treatment and survival benefit. Accordingly, the main endpoint of the study are objective clinical response and mortality. Our study provides the first systematic review of the results of all implemented clinical trials and of the summary estimates of the associations between PD-L1 expression and cancer disease outcomes.

Section snippets

Meta-analysis methods

A systematic literature search and quantitative analysis were planned, conducted and reported following CONSORT and Quality of Reporting of Meta-analyses (QUORUM) checklists regarding meta-analysis of clinical trials (Moher et al., 2001, Clarke, 2000).

Description of literature search and data from included studies

A total of 173 articles, abstracts, or presentations at international conferences were retrieved and checked for relevance in terms of intervention, design and reporting of data both on responses and survival (Fig. 1). We identified 90 articles or abstracts that published information on studies evaluating the effects of anti-PD-1/PD-L1 reporting data on clinical responses or deaths by PD-L1 status. Twenty-five of these articles/abstracts were not included in the meta-analysis for the following

Discussion

The present meta-analysis reports three main findings. The first is that the expression of PD-L1 in tumor tissues correlates with the clinical response to antibodies targeting the PD-1/PD-L1 axis in MM and in non-squamous NSCLC patients. This contention is sup-ported by the difference in the objective response observed in MM (45% vs. 27%) and in non-squamous NSCLC (29% vs. 11%) according to the positive vs. negative expression of PD-L1, respectively. Furthermore, regardless of cut-off for

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