Elsevier

The Lancet

Volume 387, Issue 10030, 30 April–6 May 2016, Pages 1837-1846
The Lancet

Articles
Atezolizumab versus docetaxel for patients with previously treated non-small-cell lung cancer (POPLAR): a multicentre, open-label, phase 2 randomised controlled trial

https://doi.org/10.1016/S0140-6736(16)00587-0Get rights and content

Summary

Background

Outcomes are poor for patients with previously treated, advanced or metastatic non-small-cell lung cancer (NSCLC). The anti-programmed death ligand 1 (PD-L1) antibody atezolizumab is clinically active against cancer, including NSCLC, especially cancers expressing PD-L1 on tumour cells, tumour-infiltrating immune cells, or both. We assessed efficacy and safety of atezolizumab versus docetaxel in previously treated NSCLC, analysed by PD-L1 expression levels on tumour cells and tumour-infiltrating immune cells and in the intention-to-treat population.

Methods

In this open-label, phase 2 randomised controlled trial, patients with NSCLC who progressed on post-platinum chemotherapy were recruited in 61 academic medical centres and community oncology practices across 13 countries in Europe and North America. Key inclusion criteria were Eastern Cooperative Oncology Group performance status 0 or 1, measurable disease by Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST v1.1), and adequate haematological and end-organ function. Patients were stratified by PD-L1 tumour-infiltrating immune cell status, histology, and previous lines of therapy, and randomly assigned (1:1) by permuted block randomisation (with a block size of four) using an interactive voice or web system to receive intravenous atezolizumab 1200 mg or docetaxel 75 mg/m2 once every 3 weeks. Baseline PD-L1 expression was scored by immunohistochemistry in tumour cells (as percentage of PD-L1-expressing tumour cells TC3≥50%, TC2≥5% and <50%, TC1≥1% and <5%, and TC0<1%) and tumour-infiltrating immune cells (as percentage of tumour area: IC3≥10%, IC2≥5% and <10%, IC1≥1% and <5%, and IC0<1%). The primary endpoint was overall survival in the intention-to-treat population and PD-L1 subgroups at 173 deaths. Biomarkers were assessed in an exploratory analysis. We assessed safety in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT01903993.

Findings

Patients were enrolled between Aug 5, 2013, and March 31, 2014. 144 patients were randomly allocated to the atezolizumab group, and 143 to the docetaxel group. 142 patients received at least one dose of atezolizumab and 135 received docetaxel. Overall survival in the intention-to-treat population was 12·6 months (95% CI 9·7–16·4) for atezolizumab versus 9·7 months (8·6–12·0) for docetaxel (hazard ratio [HR] 0·73 [95% CI 0·53–0·99]; p=0·04). Increasing improvement in overall survival was associated with increasing PD-L1 expression (TC3 or IC3 HR 0·49 [0·22–1·07; p=0·068], TC2/3 or IC2/3 HR 0·54 [0·33–0·89; p=0·014], TC1/2/3 or IC1/2/3 HR 0·59 [0·40–0·85; p=0·005], TC0 and IC0 HR 1·04 [0·62–1·75; p=0·871]). In our exploratory analysis, patients with pre-existing immunity, defined by high T-effector–interferon-γ-associated gene expression, had improved overall survival with atezolizumab. 11 (8%) patients in the atezolizumab group discontinued because of adverse events versus 30 (22%) patients in the docetaxel group. 16 (11%) patients in the atezolizumab group versus 52 (39%) patients in the docetaxel group had treatment-related grade 3–4 adverse events, and one (<1%) patient in the atezolizumab group versus three (2%) patients in the docetaxel group died from a treatment-related adverse event.

Interpretation

Atezolizumab significantly improved survival compared with docetaxel in patients with previously treated NSCLC. Improvement correlated with PD-L1 immunohistochemistry expression on tumour cells and tumour-infiltrating immune cells, suggesting that PD-L1 expression is predictive for atezolizumab benefit. Atezolizumab was well tolerated, with a safety profile distinct from chemotherapy.

Funding

F Hoffmann-La Roche/Genentech Inc.

Introduction

Outcomes are poor for patients with previously treated, advanced or metastatic non-small-cell lung cancer (NSCLC); systemic chemotherapy (eg, docetaxel) provides only modest benefits.1 Programmed death ligand 1 (PD-L1) is an immune-checkpoint protein expressed on tumour cells and tumour-infiltrating immune cells that downregulates antitumoural T-cell function through binding to programmed death 1 (PD-1) and B7.1 (also known as CD80) receptors.2, 3 The engineered, humanised IgG1 monoclonal anti-PD-L1 antibody atezolizumab (MPDL3280A; F Hoffmann-La Roche/Genentech) blocks PD-L1–PD-1 and PD-L1–B7.1 interactions, resulting in restoration of antitumour T-cell activity and enhanced T-cell priming.4, 5, 6 Clinical studies of anti-PD-1 antibodies (eg, nivolumab or pembrolizumab) have established the therapeutic value of targeting the PD-L1–PD-1 pathway.7, 8, 9, 10 Blocking PD-L1–B7.1 binding on T cells and antigen-presenting cells might additionally inhibit downregulation of immune responses, thus preventing inhibition of T-cell activation and cytokine production.11, 12 Direct targeting of PD-L1 leaves the PD-L2–PD-1 interaction intact, potentially avoiding effects on immune homoeostasis.6, 13, 14, 15, 16 Atezolizumab is engineered to eliminate binding to Fc receptors and prevent Fc-effector function. This modification eliminates antibody-dependent cell-mediated cytotoxicity and thus avoids potential loss of PD-L1-expressing T-effector cells and reduced anticancer immunity. Early-phase clinical trials of atezolizumab monotherapy have shown durable antitumour responses in NSCLC,4, 17, 18 associated with tumour cell and tumour-infiltrating immune cell PD-L1 expression when assessed with immunohistochemistry.17, 18 These studies suggest that the benefit of atezolizumab is pronounced in tumours with pre-existing immunity.4 However, these biomarker hypotheses have not been tested in a randomised clinical trial.

Research in context

Evidence before this study

Outcomes are poor for patients with previously treated, advanced or metastatic non-small-cell lung cancer (NSCLC); systemic chemotherapy provides only modest benefit. Cancer immunotherapy is an exciting new treatment option. We searched PubMed from Dec 18, 2010, to Dec 18, 2015, for clinical trials with the terms “non-small cell lung cancer”, “programmed-death ligand 1”, “PD-L1”, “programmed-death 1”, “PD-1”, and “cancer immunotherapy”, selecting relevant English language publications within the past 5 years. We identified seven studies (phases 1–3, all of which were international and open-label) of atezolizumab, pembrolizumab, or nivolumab. Studies indicated the therapeutic value of targeting the programmed death ligand 1 (PD-L1)–programmed death 1 (PD-1) pathway to treat NSCLC, and that atezolizumab shows durable responses as monotherapy for this disease. These responses were associated with tumour cell and tumour-infiltrating immune cell PD-L1 expression, and the benefit was more pronounced in tumours with pre-existing immunity. However, these biomarker hypotheses had not been tested in an atezolizumab randomised clinical trial.

Added value of this study

POPLAR is the first study of a PD-L1 checkpoint inhibitor in a randomised clinical trial of patients with previously treated NSCLC. In our study, atezolizumab showed a significant improvement in overall survival compared with docetaxel in patients with advanced, previously treated NSCLC. We saw increasing improvement in overall survival with increasing PD-L1 expression in the atezolizumab group, whereas patients with the lowest PD-L1 expression assigned to atezolizumab experienced similar overall survival to those assigned to docetaxel. We also showed that PD-L1 expression on both tumour cells and tumour-infiltrating immune cells is independently predictive of survival improvement with atezolizumab.

Implications of all the available evidence

Targeting the PD-L1–PD-1 pathway improves outcomes for patients with NSCLC. Together with reports of the anti-PD1 antibodies pembrolizumab and nivolumab, our results affirm that not only the receptor, but also the ligand components of the PD-L1–PD-1 axis are valid targets for the treatment of lung cancer. The predictive value of PD-L1 expression on tumour cells and tumour-infiltrating immune cells (rather than tumour cells alone) suggests that an immunohistochemistry test for PD-L1 expression on both cell types would identify a broader patient population likely to benefit from atezolizumab treatment than that identified by testing tumour cells alone. Additionally, the predictive value of the T-effector and interferon-γ gene signature for improvement in overall survival might provide insights into the biology of atezolizumab efficacy and aid development of the next generation of diagnostic assays for therapies targeting this pathway.

Accordingly, we designed POPLAR to investigate the efficacy and safety of atezolizumab versus docetaxel in second-line and third-line NSCLC, and to further assess the predictive value of PD-L1 expression levels on tumour cells and tumour-infiltrating immune cells.

Section snippets

Study design

POPLAR is a multicentre, randomised, open-label, all-comer phase 2 trial, done at 61 academic medical centres and community oncology practices across 13 countries in Europe and North America. The study was done in full accordance with the guidelines for Good Clinical Practice and the Declaration of Helsinki. Protocol (and modification) approval was obtained from an independent ethics committee for each site (listed in appendix).

Patients

We enrolled 287 patients. Eligible patients were aged 18 years or

Results

We screened 527 patients for eligibility, enrolling 287 patients into the study between Aug 5, 2013, and March 31, 2014, at 61 academic medical centres and community oncology practices across 13 countries (figure 2). 144 patients were randomly allocated to receive atezolizumab and 143 to receive docetaxel; 142 patients received at least one dose of atezolizumab and 135 patients received at least one dose of docetaxel. The primary analysis data cutoff was May 8, 2015. Median follow-up was 14·8

Discussion

Atezolizumab showed significant improvement in overall survival compared with docetaxel in patients with advanced, previously treated NSCLC, unselected for PD-L1 expression. Improvement in overall survival increased with increasing PD-L1 expression, whereas patients with the lowest PD-L1 expression levels experienced overall survival similar to that in the docetaxel group. Efficacy outcomes of patients in the docetaxel group compared favourably with those in previous clinical trials in the

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