Lancet. 2016 Apr 9;387(10027):1540-50. doi: 10.1016/S0140-6736(15)01281-7. Epub 2015 Dec 19.
Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial.
Herbst RS1, Baas P2, Kim DW3, Felip E4, Pérez-Gracia JL5, Han JY6, Molina J7, Kim JH8, Arvis CD9, Ahn MJ10, Majem M11, Fidler MJ12, de Castro G Jr13, Garrido M14, Lubiniecki GM15, Shentu Y15, Im E15, Dolled-Filhart M15, Garon EB16.
Yale School of Medicine, Yale Cancer Center, and Smilow Cancer Hospital, New Haven, CT, USA. Electronic address: roy.herbst@yale.edu.
The Netherlands Cancer Institute and The Academic Medical Hospital Amsterdam, Amsterdam, Netherlands.
Seoul National University Hospital, Seoul, South Korea.
Vall D'Hebron University Hospital and Vall d'Hebron Institute of Oncology, Barcelona, Spain.
Clinica Universidad de Navarra, Pamplona, Spain.
National Cancer Center, Goyang, South Korea.
Mayo Clinic, Rochester, MN, USA.
CHA Bundang Medical Center, CHA University, Gyeonggi-do, South Korea.
Centre François Baclesse, Caen, France.
Samsung Medical Center Sungkyunkwan University School of Medicine, Seoul, South Korea.
Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
Rush University Medical Center, Chicago, IL, USA.
Instituto do Câncer do Estado de São Paulo, São Paulo, Brazil.
Pontificia Universidad Católica de Chile, Santiago, Chile.
Merck & Co, Kenilworth, NJ, USA.
David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles, CA, USA.
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.
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/m(2) 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.
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).
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.
Merck & Co.
Are we ready for immune checkpoint inhibitors for advanced non-small-cell lung cancer? [Lancet. 2016]
KEYNOTE-010: flash of a supernova (immune-checkpoint inhibitors) in second-line non-small cell lung cancer. [J Thorac Dis. 2017]
Optimal pembrolizumab dosing for non-small cell lung cancer: further studies still needed. [J Thorac Dis. 2017]
Publication types, MeSH terms, Substances, Secondary source ID
Antibodies, Monoclonal, Humanized/administration & dosage
Antibodies, Monoclonal, Humanized/adverse effects
Antibodies, Monoclonal, Humanized/therapeutic use*
Antineoplastic Agents/administration & dosage
Antineoplastic Agents/adverse effects
Antineoplastic Agents/therapeutic use*
B7-H1 Antigen/analysis*
Carcinoma, Non-Small-Cell Lung/chemistry
Carcinoma, Non-Small-Cell Lung/drug therapy*
Carcinoma, Non-Small-Cell Lung/pathology
Disease-Free Survival
Docetaxel
Gene Expression Regulation, Neoplastic
Kaplan-Meier Estimate
Lung Neoplasms/chemistry
Lung Neoplasms/drug therapy*
Lung Neoplasms/pathology
Molecular Targeted Therapy*
Taxoids/administration & dosage
Taxoids/adverse effects
Taxoids/therapeutic use*
Antibodies, Monoclonal, Humanized
B7-H1 Antigen
CD274 protein, human
Taxoids
pembrolizumab
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