Research in context
Evidence before this study
We searched PubMed on June 15, 2018, with the term “PD-1 OR PD-L1 OR MK-3475 OR pembrolizumab OR Keytruda OR BMS-936558 OR nivolumab OR Opdivo OR MPDL3280A OR atezolizumab OR Tecentriq OR MEDI4736 OR durvalumab OR Imfinzi OR MSB0010718C OR avelumab OR Bavencio AND metastatic AND first line OR previously untreated AND non-small cell lung cancer OR NSCLC.” We also used this term to search the abstracts from the 2017 and 2018 American Society of Clinical Oncology annual meetings and the 2016 and 2017 European Society for Medical Oncology congresses to identify results of clinical trials not yet published in full. We applied no other search parameters. We identified several randomised, phase 3 studies of patients with metastatic non-small-cell lung cancer treated with antibodies against programmed death protein 1 (PD-1) or its ligand PD-L1. The KEYNOTE-024 study showed significantly longer progression-free and overall survival with pembrolizumab monotherapy than with platinum-doublet chemotherapy in patients with a PD-L1 tumour proportion score (TPS) of 50% or greater. The CheckMate 026 study did not show improved overall survival with nivolumab monotherapy versus platinum-doublet chemotherapy in the primary population of patients with a PD-L1 expression level of 5% or greater. The KEYNOTE-189 study showed that first-line treatment with pembrolizumab plus platinum-doublet chemotherapy significantly prolonged overall survival and progression-free survival compared with chemotherapy alone, irrespective of PD-L1 TPS, in patients with non-squamous non-small-cell lung cancer. The KEYNOTE-407 study demonstrated similar findings in patients with squamous non-small-cell lung cancer. The IMpower131 study of atezolizumab plus platinum-doublet chemotherapy showed significantly prolonged progression-free survival versus platinum-doublet chemotherapy alone in patients with squamous non-small-cell lung cancer, irrespective of PD-L1 expression. The IMpower150 study showed that the combination of atezolizumab, bevacizumab, and platinum-doublet chemotherapy significantly prolonged progression-free and overall survival in patients with non-squamous non-small-cell lung cancer, irrespective of PD-L1 expression or EGFR or ALK genetic alteration status. The CheckMate 227 study showed that nivolumab plus ipilimumab significantly prolonged progression-free survival versus platinum-doublet chemotherapy in patients with a high tumour mutational burden, irrespective of PD-L1 expression.
Added value of this study
The randomised phase 3 KEYNOTE-042 trial of pembrolizumab monotherapy versus chemotherapy as first-line treatment enrolled patients with locally advanced or metastatic non-small-cell lung cancer and a PD-L1 TPS of 1% or greater, expanding the population of patients compared with that assessed in the KEYNOTE-024 study. Overall survival was assessed as the primary endpoint, and we found a significant survival benefit in patients with PD-L1-positive tumours. The effect was greatest in patients with a TPS of 50% or greater, but remained significant in patients with a TPS of 1% or greater. Despite longer exposure to pembrolizumab treatment than to chemotherapy, the frequency of treatment-related adverse events, including those of grade 3 or worse, was lower in the pembrolizumab group.
Implications of all the available evidence
With our findings of a survival benefit and manageable safety profile for pembrolizumab monotherapy as first-line treatment in patients with PD-L1-positive, locally advanced or metastatic non-small-cell lung cancer, we suggest that use of this drug can be extended to previously untreated patients with a TPS as low as 1%. In the absence of direct prospective comparisons of pembrolizumab given alone and in combination with chemotherapy, patients with PD-L1-positive non-small-cell lung cancer should discuss the benefits and risks of each regimen with their physicians when choosing first-line therapy.