Online citations, reference lists, and bibliographies.
← Back to Search

Pembrolizumab Versus Docetaxel For Previously Treated, PD-L1-positive, Advanced Non-small-cell Lung Cancer (KEYNOTE-010): A Randomised Controlled Trial

R. Herbst, P. Baas, D. Kim, E. Felip, E. Garon
Published 2016 · Medicine

Save to my Library
Download PDF
Analyze on Scholarcy
Share
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/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. 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.
This paper references
Pembrolizumab 2 mg / kg Q 3 W for previously treated , PD - L 1 - positive advanced NSCLC [ abstract ]
EA Eisenhauer (2015)
10.1158/1078-0432.CCR-13-2702
In Situ Tumor PD-L1 mRNA Expression Is Associated with Increased TILs and Better Outcome in Breast Carcinomas
K. Schalper (2014)
10.1056/NEJMoa1311107
Ceritinib in ALK-rearranged non-small-cell lung cancer.
A. Shaw (2014)
[New response evaluation criteria in solid tumours-revised RECIST guideline (version 1.1)].
H. Watanabe (2009)
10.1056/NEJMoa1411817
AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer.
P. Jänne (2015)
10.1038/nm730
Tumor-associated B7-H1 promotes T-cell apoptosis: A potential mechanism of immune evasion
H. Dong (2002)
Clinical activity and biomarkers of MEDI 4736 , an anti - PD - L 1 antibody , in patients with NSCLC [ abstract ]
V Papadimitrakopoulou (2014)
10.1111/j.1600-065X.2010.00923.x
The PD‐1 pathway in tolerance and autoimmunity
Loise M. Francisco (2010)
Effi cacy , safety and predictive biomarker results from a randomized phase II study comparing MPDL 3280 A vs docetaxel in 2 L / 3 L NSCLC ( POPLAR ) [ abstract ]
AI Spira (2015)
10.1056/NEJMoa1507643
Nivolumab versus Docetaxel in Advanced Nonsquamous Non-Small-Cell Lung Cancer.
H. Borghaei (2015)
10.1001/jamaoncol.2015.3638
Quantitative Assessment of the Heterogeneity of PD-L1 Expression in Non-Small-Cell Lung Cancer.
J. McLaughlin (2016)
10.1200/JCO.2015.33.15_SUPPL.8031
Pembrolizumab (pembro; MK-3475) plus platinum doublet chemotherapy (PDC) as front-line therapy for advanced non-small cell lung cancer (NSCLC): KEYNOTE-021 Cohorts A and C.
V. Papadimitrakopoulou (2015)
Effi cacy , safety and predictive biomarker results from a randomized phase II study comparing MPDL 3280 A vs docetaxel in 2 L / 3 L NSCLC ( POPLAR ) [ abstract ]
LM Francisco (2015)
10.1016/S0887-7963(00)80157-1
B7-H1, a third member of the B7 family, co-stimulates T-cell proliferation and interleukin 10 secretion
S. Dzik (2000)
10.1038/nm1511
Microbial translocation is a cause of systemic immune activation in chronic HIV infection
J. Brenchley (2006)
10.1016/S0140-6736(14)60845-X
Ramucirumab plus docetaxel versus placebo plus docetaxel for second-line treatment of stage IV non-small-cell lung cancer after disease progression on platinum-based therapy (REVEL): a multicentre, double-blind, randomised phase 3 trial
E. Garon (2014)
10.1158/1078-0432.CCR-09-1624
Guidelines for the Evaluation of Immune Therapy Activity in Solid Tumors: Immune-Related Response Criteria
J. Wolchok (2009)
10.1200/JCO.2015.33.15_SUPPL.8011
Phase 1 study of pembrolizumab (pembro; MK-3475) plus ipilimumab (IPI) as second-line therapy for advanced non-small cell lung cancer (NSCLC): KEYNOTE-021 cohort D.
A. Patnaik (2015)
10.1186/1479-5876-11-54
The additional facet of immunoscore: immunoprofiling as a possible predictive tool for cancer treatment
P. Ascierto (2013)
10.1056/NEJMoa1214886
Crizotinib versus chemotherapy in advanced ALK-positive lung cancer.
A. Shaw (2013)
10.1073/pnas.192461099
Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade
Yoshiko Iwai (2002)
10.1038/nrc3239
The blockade of immune checkpoints in cancer immunotherapy
D. Pardoll (2012)
10.1038/nature14011
Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients
R. Herbst (2014)
10.1097/PPO.0000000000000063
B7-H1/PD-1 Blockade Therapy in Non–Small Cell Lung Cancer: Current Status and Future Direction
S. Gettinger (2014)
10.1038/srep00765
12-Chemokine Gene Signature Identifies Lymph Node-like Structures in Melanoma: Potential for Patient Selection for Immunotherapy?
J. Messina (2012)
10.1038/nrclinonc.2014.104
Acquired resistance to TKIs in solid tumours: learning from lung cancer
D. Camidge (2014)
10.1084/JEM.192.7.1027
Engagement of the Pd-1 Immunoinhibitory Receptor by a Novel B7 Family Member Leads to Negative Regulation of Lymphocyte Activation
G. Freeman (2000)
Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma
S. Derijcke (2009)
10.1200/JCO.2014.32.15_SUPPL.8021
Clinical activity and biomarkers of MEDI4736, an anti-PD-L1 antibody, in patients with NSCLC.
J. Brahmer (2014)
10.1002/SIM.4780040211
Comparative analysis of two rates.
O. Miettinen (1985)
10.1200/JCO.2015.33.15_SUPPL.8010
Efficacy, safety and predictive biomarker results from a randomized phase II study comparing MPDL3280A vs docetaxel in 2L/3L NSCLC (POPLAR).
A. Spira (2015)
10.1056/NEJMc1506831
Rociletinib in EGFR-Mutated Non-Small-Cell Lung Cancer.
Y. He (2015)
Pembrolizumab 2 mg / kg Q 3 W for previously treated , PD - L 1 - positive advanced NSCLC [ abstract ]
Ø Fløtten (2015)
10.1056/NEJMoa1504627
Nivolumab versus Docetaxel in Advanced Squamous-Cell Non-Small-Cell Lung Cancer.
J. Brahmer (2015)
10.1517/14712598.2016.1145652
Pembrolizumab for the treatment of non-small cell lung cancer
S. H. Lim (2016)
10.1080/01621459.1977.10480613
The Efficiency of Cox's Likelihood Function for Censored Data
B. Efron (1977)
10.1146/ANNUREV.IMMUNOL.23.021704.115611
The B7 family revisited.
R. Greenwald (2005)
10.1126/science.aaa1348
Mutational landscape determines sensitivity to PD-1 blockade in non–small cell lung cancer
N. Rizvi (2015)



This paper is referenced by
10.1111/ajt.15811
Efficacy and tolerance of immune checkpoint inhibitors in transplant patients with cancer: A systematic review
Thibaut d'Izarny-Gargas (2020)
10.1186/s40164-018-0104-y
Conservative management of nivolumab-induced pericardial effusion: a case report and review of literature
S. Shaheen (2018)
10.3779/j.issn.1009-3419.2020.104.07
[Immune-related Adverse Events Induced by ICIs in Advanced NSCLC: A Meta-analysis and Systematic Review].
Qiaoxi Qin (2020)
10.1186/s12885-016-2451-6
Prognostic implications of PD-L1 expression in patients with soft tissue sarcoma
C. Kim (2016)
10.1055/a-0843-3366
A Systematic Review and Meta-Analysis of Endocrine-Related Adverse Events Associated with Immune Checkpoint Inhibitors.
Jeroen de Filette (2019)
10.1111/cas.13836
Functionally impaired follicular helper T cells induce regulatory B cells and CD14+ human leukocyte antigen‐DR − cell differentiation in non‐small cell lung cancer
Liannv Qiu (2018)
10.1002/ijc.31764
A B7‐CD28 family based signature demonstrates significantly different prognoses and tumor immune landscapes in lung adenocarcinoma
Shanbo Zheng (2018)
10.18632/oncotarget.20281
Which treatment is preferred for advanced non-small-cell lung cancer with wild-type epidermal growth factor receptor in second-line therapy? A meta-analysis comparing immune checkpoint inhibitor, tyrosine kinase inhibitor and chemotherapy
D. Wu (2017)
10.1016/j.critrevonc.2017.06.001
Biomarkers of response to PD-1/PD-L1 inhibition.
Saman Maleki Vareki (2017)
10.3389/fmed.2017.00036
Second-line Treatment of Non-Small Cell Lung Cancer: Focus on the Clinical Development of Dacomitinib
J. Zugazagoitia (2017)
10.1007/978-3-89935-305-1_5
Fälle aus der Praxis
A. Koenig (2017)
10.1007/s11523-017-0514-5
Insulin-Like Growth Factor (IGF) Pathway Targeting in Cancer: Role of the IGF Axis and Opportunities for Future Combination Studies
Aaron Simpson (2017)
10.1016/j.ejca.2017.07.002
Treatment of elderly patients or patients who are performance status 2 (PS2) with advanced Non-Small Cell Lung Cancer without epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) translocations - Still a daily challenge.
C. Su (2017)
10.5301/jo-n.5000019
Renal Toxicity in Patients Treated with Anti-Pd-1 Targeted Agents for Solid Tumors
R. Iacovelli (2017)
10.1016/j.ctrv.2016.12.010
Targeting Epidermal Growth Factor Receptor in triple negative breast cancer: New discoveries and practical insights for drug development.
R. Costa (2017)
10.1080/14740338.2017.1300656
EGFR TKI combination with immunotherapy in non-small cell lung cancer
M. Ahn (2017)
10.1158/1078-0432.CCR-18-2243
Induction of Peripheral Effector CD8 T-cell Proliferation by Combination of Paclitaxel, Carboplatin, and Bevacizumab in Non–small Cell Lung Cancer Patients
P. D. de Goeje (2019)
10.1093/annonc/mdy507
Immune biomarkers of response to immune-checkpoint inhibitors in head and neck squamous cell carcinoma
M. Oliva (2019)
10.1093/ndt/gfy105
Programmed cell death protein 1 inhibitor treatment is associated with acute kidney injury and hypocalcemia: meta-analysis
S. Manohar (2019)
10.3779/j.issn.1009-3419.2019.04.06
[Advances of the Correlation between Driver Gene Status and Immunotherapy 
in Non-small Cell Lung Cancer].
J. Chen (2019)
10.1016/J.LUNGCAN.2019.06.005
Heterogeneity of PD-L1 expression in non-small cell lung cancer: Implications for specimen sampling in predicting treatment response
A. Haragan (2019)
10.1186/s40425-018-0320-3
The impact of PD-L1 on survival and value of the immune check point inhibitors in non-small-cell lung cancer; proposal, policies and perspective
H. M. Guirgis (2018)
10.3747/co.25.3750
Current landscape of immunotherapy for the treatment of metastatic non-small-cell lung cancer.
A. Pabani (2018)
10.1016/j.jtho.2017.12.001
Updated Molecular Testing Guideline for the Selection of Lung Cancer Patients for Treatment With Targeted Tyrosine Kinase Inhibitors: Guideline From the College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology
N. Lindeman (2018)
10.1111/1759-7714.12785
DNA damage response signaling as a predictive biomarker and synergistic therapeutic target for anti‐PD‐1/PD‐L1 immunotherapy in non‐small cell lung cancer
Zhongling Zhu (2018)
10.1158/2326-6066.CIR-17-0026
Soluble CD80 Protein Delays Tumor Growth and Promotes Tumor-Infiltrating Lymphocytes
L. Horn (2017)
10.1111/jebm.12322
Advances in evidence‐based medicine for immunotherapy of non‐small cell lung cancer
J. Dong (2018)
10.1002/cam4.1736
Efficacy of icotinib in advanced lung squamous cell carcinoma
Shuai Liang (2018)
10.1080/14737140.2018.1526084
Pembrolizumab for the treatment of gastric cancer
Suneel D Kamath (2018)
10.1097/PPO.0000000000000300
PD-1/PD-L1 Axis in Lung Cancer
F. Santini (2018)
10.2144/fsoa-2019-0081
Checkpoint inhibitors plus chemotherapy for first-line treatment of advanced non-small cell lung cancer: a systematic review and meta-analysis of randomized controlled trials
A. Tun (2019)
10.1007/s12254-018-0426-9
Cure in metastatic breast cancer
T. Westphal (2018)
See more
Semantic Scholar Logo Some data provided by SemanticScholar