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.