Elsevier

European Journal of Cancer

Volume 106, January 2019, Pages 144-159
European Journal of Cancer

Review
Predictive biomarkers of response for immune checkpoint inhibitors in non–small-cell lung cancer

https://doi.org/10.1016/j.ejca.2018.11.002Get rights and content

Highlights

  • At present, tumour PD-L1 expression is the only approved biomarker, albeit imperfect, used in clinical practice for PD-(L)1 blockade in NSCLC.

  • Tumour Mutational Burden may enter clinical practice as a biomarker to select patients who are potential candidates for dual immune blockade.

  • Several biomarker strategies specifically related to NSCLC are under investigation.

  • Tumour-related factors such as genetic alterations and tumour microenvironment play a crucial role and are relevant for a prediction role.

  • Factors related to the host immune system (peripheral blood biomarkers etc.) and their combination with other biomarkers will be the next future.

Abstract

Immune checkpoint blockade has been a pivotal development in the management of advanced non–small-cell lung cancer (NSCLC). Although durable antitumour activity and improved survival have been observed in a subset of patients, there is a need for additional predictive biomarkers to improve patient selection and avoid toxicity in potential non-responders. This review will address the use and limitations of tumour programmed death-ligand 1 expression as a predictive biomarker and review emerging biomarker strategies specifically related to NSCLC including genetic alterations (tumour mutation burden, loss and gain activated mutations), tumour-related factors (tumour microenvironment) and factors related to the host immune system. Novel approaches in biomarker detection such as peripheral blood monitoring will also be reviewed.

Introduction

The advent of immune checkpoint inhibitors (CPIs) as both first- and second-line treatment for advanced non–small-cell lung cancer (NSCLC) results in improved survival and antitumour response compared with chemotherapy in selected patients. Unfortunately, up to 60% of patients with advanced NSCLC will not benefit from antiprogrammed death-1 (PD-1) or programmed death-ligand 1 (PD-L1) agents [1], [2], [3], [4]. The need to discover and validate predictive biomarkers, beyond tumour PD-L1 expression, to better select patients who will derive most benefit and spare unnecessary toxicity and cost in non-responders remains an ongoing challenge.

At present, tumour PD-L1 expression is the only approved predictive biomarker for PD-(L)1 blockade in NSCLC. Even though PD-L1 expression is currently used to inform treatment decisions and regulatory approval, its expression may vary over time and by site among multiple tumour lesions [5]. Archival biopsy specimens collected months or years before starting treatment may not reflect the current expression status [6], particularly in pretreated patients whereby exposure to chemotherapy, radiotherapy and antiangiogenic therapy can upregulate PD-L1 expression [7], [8]. Tumour PD-L1 expression is regulated by two main mechanisms: constitutive (intrinsic) expression and induced (extrinsic) by interferon gamma (IFN-γ) secreted by infiltrating lymphocytes [9]. Hence, in some situations, intrinsic elevated PD-L1 expression should correlate with worse differentiation and poorer prognosis; in contrast, expression induced by INF-y seems to be associated with a better prognosis [10]. Other activation mutations may also alter PD-L1 expression. For example, Janus kinase 3 (JAK3)-activating mutations increase the expression of PD-L1 in NSCLC [11], [12].

Immunohistochemistry (IHC) is used to evaluate tumour PD-L1 expression. Table 1 summarises the five diagnostic PD-L1 assays developed for each anti–PD-1/PD-L1 agent (anti–PD-1: nivolumab and pembrolizumab and anti–PD-L1: atezolizumab, durvalumab and avelumab). These assays differ in their threshold of ‘PD-L1 positivity’ and approval as a companion or complementary assay. Blueprint 2, a phase IIA prospective study, evaluated the analytical comparability of these five assays concluding that three (28-8, 22C3 and SP263) of the five assays were comparable. The SP142 clone (which is used to score both tumour and immune cells) detects consistently less, whereas 73-10 is more sensitive, in PD-L1 positive detection [13], [14]. Possibly because of dynamic expression and differences in diagnostic assays, the use of tumour PD-L1 expression is ultimately limited by its suboptimal negative predictive value. Response rates of 11–20% have been reported in patients with negative PD-L1 expression [3], [15], [16]. Therapeutic strategies under investigation to increase response rates in PD-L1–negative patients include combination cytotoxic T-lymphocyte–associated antigen 4 (CTLA4)/PD-1 or PD-L1 blockade [17], [18] and combination of CPI with chemotherapy in unselected patients [1], [2], [3], [4], [19].

Section snippets

Tumour mutation burden

Clinical outcomes correlate with tumour mutation burden (TMB) in multiple cancers treated with CPI, including NSCLC [20], [21], [22], [23]. TMB is the total number of non-synonymous somatic mutations of the genomic coding area. Germline mutations are excluded from the TMB as the host immune system recognises these as normal alterations [24]. Non-synonymous somatic mutations alter the amino acid sequence of proteins encoded by affected gene, forming neoantigens [20], [22]. It is hypothesised

Discussion and conclusions

Immune CPIs, particularly anti–PD-(L)1 drugs are now firmly embedded in the treatment algorithm for treatment-naive and pretreated advanced NSCLC patients. Furthermore, very recently, the anti–PD-L1 durvalumab has been FDA approved as a consolidation strategy for unselected (by the PD-L1 status) NSCLC patients treated with definitive concurrent chemoradiotherapy.

PD-L1 expression is the only biomarker, albeit imperfect, currently used in clinical practice to select patients most likely to

Conflicts of interest statement

Raffaele Califano received honoraria from BMS, AZ, Roche and MSD; Benjamin Besse received institutional grants for clinical and translational research AstraZeneca, BMS, Boehringer Ingelheim, Lilly, Pfizer, Roche-Genentech, Sanofi-Aventis, Servier, Onxeo, OncoMed, Inivata, OSE Pharma and Loxo. The other authors declare no conflicts interest.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

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