Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial
Herbst RS (1), Baas P (2), Kim DW (3), Felip E (4), Pérez-Gracia JL (5), Han JY (6), Molina J (7), Kim JH (8), Arvis CD (9), Ahn MJ (10), Majem M (11), Fidler MJ (12), de Castro G Jr (13), Garrido M (14), Lubiniecki GM (15), Shentu Y (15), Im E (15), Dolled-Filhart M (15), Garon EB (16).
(1) Yale School of Medicine, Yale Cancer Center, and Smilow Cancer Hospital, New Haven, CT, USA.
(2) The Netherlands Cancer Institute and The Academic Medical Hospital Amsterdam, Amsterdam, Netherlands.
(3) Seoul National University Hospital, Seoul, South Korea.
(4) Vall D'Hebron University Hospital and Vall d'Hebron Institute of Oncology, Barcelona, Spain.
(5) Clinica Universidad de Navarra, Pamplona, Spain.
(6) National Cancer Center, Goyang, South Korea.
(7) Mayo Clinic, Rochester, MN, USA.
(8) CHA Bundang Medical Center, CHA University, Gyeonggi-do, South Korea.
(9) Centre François Baclesse, Caen, France.
(10) Samsung Medical Center Sungkyunkwan University School of Medicine, Seoul, South Korea.
(11) Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
(12) Rush University Medical Center, Chicago, IL, USA.
(13) Instituto do Câncer do Estado de São Paulo, São Paulo, Brazil.
(14) Pontificia Universidad Católica de Chile, Santiago, Chile.
(15) Merck & Co, Kenilworth, NJ, USA.
(16) David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles, CA, USA.
Date: Dec 18, 2015Medical Oncology
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/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.
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.
CITATION Lancet. 2015 Dec 18. pii: S0140-6736(15)01281-7. doi: 10.1016/S0140-6736(15)01281-7.
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