Elsevier

The Lancet

Volume 387, Issue 10027, 9–15 April 2016, Pages 1540-1550
The Lancet

Articles
Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial

https://doi.org/10.1016/S0140-6736(15)01281-7Get rights and content

Summary

Background

Despite recent advances in the treatment of advanced non-small-cell lung cancer, there remains a need for effective treatments for progressive disease. We assessed the efficacy of pembrolizumab for patients with previously treated, PD-L1-positive, advanced non-small-cell lung cancer.

Methods

We did this randomised, open-label, phase 2/3 study at 202 academic medical centres in 24 countries. Patients with previously treated non-small-cell lung cancer with PD-L1 expression on at least 1% of tumour cells were randomly assigned (1:1:1) in blocks of six per stratum with an interactive voice-response system to receive pembrolizumab 2 mg/kg, pembrolizumab 10 mg/kg, or docetaxel 75 mg/m2 every 3 weeks. The primary endpoints were overall survival and progression-free survival both in the total population and in patients with PD-L1 expression on at least 50% of tumour cells. We used a threshold for significance of p<0·00825 (one-sided) for the analysis of overall survival and a threshold of p<0·001 for progression-free survival. This trial is registered at ClinicalTrials.gov, number NCT01905657.

Findings

Between Aug 28, 2013, and Feb 27, 2015, we enrolled 1034 patients: 345 allocated to pembrolizumab 2 mg/kg, 346 allocated to pembrolizumab 10 mg/kg, and 343 allocated to docetaxel. By Sept 30, 2015, 521 patients had died. In the total population, median overall survival was 10·4 months with pembrolizumab 2 mg/kg, 12·7 months with pembrolizumab 10 mg/kg, and 8·5 months with docetaxel. Overall survival was significantly longer for pembrolizumab 2 mg/kg versus docetaxel (hazard ratio [HR] 0·71, 95% CI 0·58–0·88; p=0·0008) and for pembrolizumab 10 mg/kg versus docetaxel (0·61, 0·49–0·75; p<0·0001). Median progression-free survival was 3·9 months with pembrolizumab 2 mg/kg, 4·0 months with pembrolizumab 10 mg/kg, and 4·0 months with docetaxel, with no significant difference for pembrolizumab 2 mg/kg versus docetaxel (0·88, 0·74–1·05; p=0·07) or for pembrolizumab 10 mg/kg versus docetaxel (HR 0·79, 95% CI 0·66–0·94; p=0·004). Among patients with at least 50% of tumour cells expressing PD-L1, overall survival was significantly longer with pembrolizumab 2 mg/kg than with docetaxel (median 14·9 months vs 8·2 months; HR 0·54, 95% CI 0·38–0·77; p=0·0002) and with pembrolizumab 10 mg/kg than with docetaxel (17·3 months vs 8·2 months; 0·50, 0·36–0·70; p<0·0001). Likewise, for this patient population, progression-free survival was significantly longer with pembrolizumab 2 mg/kg than with docetaxel (median 5·0 months vs 4·1 months; HR 0·59, 95% CI 0·44–0·78; p=0·0001) and with pembrolizumab 10 mg/kg than with docetaxel (5·2 months vs 4·1 months; 0·59, 0·45–0·78; p<0·0001). Grade 3–5 treatment-related adverse events were less common with pembrolizumab than with docetaxel (43 [13%] of 339 patients given 2 mg/kg, 55 [16%] of 343 given 10 mg/kg, and 109 [35%] of 309 given docetaxel).

Interpretation

Pembrolizumab prolongs overall survival and has a favourable benefit-to-risk profile in patients with previously treated, PD-L1-positive, advanced non-small-cell lung cancer. These data establish pembrolizumab as a new treatment option for this population and validate the use of PD-L1 selection.

Funding

Merck & Co.

Introduction

Although treatment for non-small-cell lung cancer has improved in recent years with the development of targeted drugs for patients with amenable mutations,1, 2, 3, 4, 5 only a small proportion of patients have these mutations, and most tumours become resistant to targeted treatment.6 Immunotherapy is a new paradigm for the treatment of non-small-cell lung cancer, and targeting the PD-1 pathway is a promising therapeutic option.7, 8, 9, 10, 11 The PD-1 receptor is an immune checkpoint inhibitor expressed on activated B and T cells that normally down-modulates excessive immune responses.12, 13 Binding of PD-1 to its ligands (PD-L1 and PD-L2) on tumour cells suppresses T cells through a negative feedback loop, leading to evasion of the immune response.14, 15, 16, 17

Pembrolizumab (MK-3475) is a highly selective, humanised, IgG4 monoclonal antibody against PD-1. Pembrolizumab 2 mg/kg given once every 3 weeks was granted accelerated approval in the USA for the treatment of patients with metastatic non-small-cell lung cancer whose tumours express PD-L1 (as determined by test approved by the US Food and Drug Administration) with disease progression during or after platinum-containing chemotherapy. This approval was based on data from 550 patients with non-small-cell lung cancer enrolled in the large, multicohort, phase 1b KEYNOTE-001 study.9, 18 In KEYNOTE-001, a PD-L1 tumour proportion score of 50% or greater, defined as PD-L1 expression on at least 50% of tumour cells (appendix p 5), was associated with better outcomes.9

Research in context

Evidence before this study

We searched PubMed on Nov 2, 2015, using the following terms: “PD-1 OR PD-L1 OR MK-3475 OR pembrolizumab OR lambrolizumab OR Keytruda OR nivolumab OR BMS-936558 OR Opdivo OR atezolizumab OR MPDL3280A OR BMS-936559 OR durvalumab OR MEDI4736 OR avelumab OR MSB0010718C OR docetaxel” AND “non-small-cell lung cancer OR NSCLC”. The search was not limited by date. We also searched the abstracts for the 2014 and 2015 American Society of Clinical Oncology Annual Meetings, the 2014 European Society for Medical Oncology Congress, and the 2015 European Cancer Congress using the same search terms. We identified three randomised trials of anti-PD-1 or anti-PD-L1 treatment versus docetaxel for non-small-cell lung cancer: the CheckMate 017 study of nivolumab for squamous non-small-cell lung cancer, the CheckMate 057 study of nivolumab for non-squamous non-small-cell lung cancer, and the POPLAR study of atezolizumab for squamous and non-squamous non-small-cell lung cancer. We focused on the CheckMate studies because they are published in peer-reviewed journals.

Added value of this study

Results of KEYNOTE-010 confirm the efficacy and safety of PD-1 inhibition with pembrolizumab in patients with previously treated non-small-cell lung cancer. These data are the first published report of a randomised, controlled clinical trial of non-small-cell lung cancer that prospectively shows the utility of PD-L1 as a biomarker. This study is also the first of a PD-1 inhibitor for non-small-cell lung cancer to include patients who received more than one line of previous treatment. Both pembrolizumab 2 mg/kg and pembrolizumab 10 mg/kg every 3 weeks provided superior overall survival compared with docetaxel, with similar outcomes for each pembrolizumab dose. Pembrolizumab was also associated with fewer high-grade toxic effects than was docetaxel.

Implications of all the available evidence

Our data support pembrolizumab 2 mg/kg given every 3 weeks as a new treatment option for patients with non-small-cell lung cancer with a PD-L1 tumour proportion score of at least 1% that progressed after platinum-based chemotherapy and, in those with an EGFR sensitising mutation or an ALK translocation, an appropriate tyrosine kinase inhibitor. These data also validate the use of PD-L1 on tumour cells as a biomarker to identify patients most likely to obtain a benefit from pembrolizumab.

We present results of KEYNOTE-010, the first randomised comparison of pembrolizumab 2 mg/kg or 10 mg/kg every 3 weeks versus standard-of-care treatment for PD-L1-positive non-small-cell lung cancer that progressed after at least platinum-based chemotherapy. This study is the first active-control trial that enrolled patients on the basis of prospective assessment of tumour PD-L1 expression based on the association between higher PD-L1 expression and greater clinical benefit from pembrolizumab.

Section snippets

Study design and participants

We did this randomised, controlled, phase 2/3 clinical trial at 202 academic medical centres in 24 countries (Argentina, Australia, Belgium, Brazil, Canada, Chile, Czech Republic, Denmark, France, Germany, Greece, Hungary, Italy, Japan, Lithuania, Netherlands, Portugal, Russia, South Africa, South Korea, Spain, Taiwan, UK, and USA). We included patients aged at least 18 years, with progression as per Response Evaluation Criteria in Solid Tumors (RECIST; version 1.1)19 after two or more cycles

Results

Between Aug 28, 2013, and Feb 27, 2015, we screened 2699 patients for enrolment. Of the 2222 patients whose tumour samples were assessable for PD-L1 expression, 1475 (66%) had PD-L1 expression on at least 1% of tumour cells, including 633 (28%) with PD-L1 expression on at least 50% of tumour cells. 1034 (70%) of 1475 patients met the eligbility criteria and were enrolled in the study: 345 allocated to pembrolizumab 2 mg/kg, 346 to pembrolizumab 10 mg/kg, and 343 to docetaxel (figure 1). 991

Discussion

Pembrolizumab 2 mg/kg and 10 mg/kg every 3 weeks met the prespecified criteria for improved overall survival in all patients (ie, PD-L1 tumour proportion score of 1% or greater) and in those with a tumour proportion score of 50% or greater—patients with high PD-L1 expression had an unprecedented benefit for refractory non-small-cell lung cancer. Both pembrolizumab groups had significantly improved progression-free survival in patients with a tumour proportion score of 50% or greater, and

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