Randomized phase III KEYNOTE-045 trial of pembrolizumab versus paclitaxel, docetaxel, or vinflunine in recurrent advanced urothelial cancer: results of >2 years of follow-up

被引：346
作者：
Fradet, Y. [1 ]
Bellmunt, J. [2 ,3 ]
Vaughn, D. J. [4 ]
Lee, J. L. [5 ,6 ]
Fong, L. [7 ]
Vogelzang, N. J. [8 ]
Climent, M. A. [9 ]
Petrylak, D. P. [10 ]
Choueiri, T. K. [11 ]
Necchi, A. [12 ]
Gerritsen, W. [13 ]
Gurney, H. [14 ,15 ]
Quinn, D., I [16 ]
Culine, S. [17 ]
Sternberg, C. N. [18 ]
Nam, K. [19 ]
Frenkl, T. L. [19 ]
Perini, R. F. [19 ]
de Wit, R. [20 ]
Bajorin, D. F. [21 ]
机构：
[1] Univ Laval, Dept Surg Urol, CHU Quebec, 10 McMahon St, Quebec City, PQ G1L 3L5, Canada
[2] PSMAR IMIM Res Inst, Dept Med Oncol, Barcelona, Spain
[3] Harvard Med Sch Univ, Boston, MA USA
[4] Perelman Ctr Adv Med, Abramson Canc Ctr, Dept Med Oncol, Philadelphia, PA USA
[5] Asan Med Ctr, Dept Oncol, Seoul, South Korea
[6] Univ Ulsan, Coll Med, Seoul, South Korea
[7] Univ Calif San Francisco, Dept Med & Urol, San Francisco, CA 94143 USA
[8] Comprehens Canc Ctr Nevada, Dept Med Oncol, Las Vegas, NV USA
[9] Fdn Inst Valenciano Oncol, Dept Med Oncol, Valencia, Spain
[10] Yale Univ, Div Med Oncol, Smilow Canc Hosp, New Haven, CT USA
[11] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA
[12] Fdn IRCCS, Ist Nazl Tumori, Dept Med Oncol, Milan, Italy
[13] Radboud Univ Nijmegen, Dept Med Oncol, Med Ctr, Nijmegen, Netherlands
[14] Westmead Hosp, Dept Med Oncol, Sydney, NSW, Australia
[15] Macquarie Univ, Sydney, NSW, Australia
[16] Univ Southern Calif, Dept Med Oncol, Norris Comprehens Canc Ctr, Los Angeles, CA USA
[17] Hop St Louis, Dept Med Oncol, Paris, France
[18] Weill Cornell Med, Englander Inst Precis Med, Dept Med Oncol, New York, NY USA
[19] Merck & Co Inc, Dept Med Oncol, Kenilworth, NJ USA
[20] Erasmus MC, Canc Inst, Dept Med Oncol, Rotterdam, Netherlands
[21] Mem Sloan Kettering Canc Ctr, Dept Med Oncol, 1275 York Ave, New York, NY 10021 USA
来源：
ANNALS OF ONCOLOGY | 2019年 / 30卷 / 06期
关键词：
PD-L1; PD-1; pembrolizumab; urothelial cancer; OPEN-LABEL; MULTICENTER; CARCINOMA; THERAPY; CHEMOTHERAPY; NIVOLUMAB; SAFETY;
D O I：
10.1093/annonc/mdz127
中图分类号：
R73 [肿瘤学];
学科分类号：
100214 ;
摘要：
Background Novel second-line treatments are needed for patients with advanced urothelial cancer (UC). Interim analysis of the phase III KEYNOTE-045 study showed a superior overall survival (OS) benefit of pembrolizumab, a programmed death 1 inhibitor, versus chemotherapy in patients with advanced UC that progressed on platinum-based chemotherapy. Here we report the long-term safety and efficacy outcomes of KEYNOTE-045. Patients and methods Adult patients with histologically/cytologically confirmed UC whose disease progressed after first-line, platinum-containing chemotherapy were enrolled. Patients were randomly assigned 1:1 to receive pembrolizumab [200mg every 3weeks (Q3W)] or investigator's choice of paclitaxel (175mg/m(2) Q3W), docetaxel (75mg/m(2) Q3W), or vinflunine (320mg/m(2) Q3W). Primary end points were OS and progression-free survival (PFS) per Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1) by blinded independent central radiology review (BICR). A key secondary end point was objective response rate per RECIST v1.1 by BICR. Results A total of 542 patients were enrolled (pembrolizumab, n=270; chemotherapy, n=272). Median follow-up as of 26 October 2017 was 27.7months. Median 1- and 2-year OS rates were higher with pembrolizumab (44.2% and 26.9%, respectively) than chemotherapy (29.8% and 14.3%, respectively). PFS rates did not differ between treatment arms; however, 1- and 2-year PFS rates were higher with pembrolizumab. The objective response rate was also higher with pembrolizumab (21.1% versus 11.0%). Median duration of response to pembrolizumab was not reached (range 1.6+ to 30.0+ months) versus chemotherapy (4.4months; range 1.4+ to 29.9+ months). Pembrolizumab had lower rates of any grade (62.0% versus 90.6%) and grade >= 3 (16.5% versus 50.2%) treatment-related adverse events than chemotherapy. Conclusions Long-term results (>2 years' follow-up) were consistent with those of previously reported analyses, demonstrating continued clinical benefit of pembrolizumab over chemotherapy for efficacy and safety for treatment of locally advanced/metastatic, platinum-refractory UC. Trial registration ClinicalTrials.gov: NCT02256436.
引用
收藏
页码：970 / 976
页数：7
相关论文
共 18 条
[11]   Efficacy and Safety of Durvalumab in Locally Advanced or Metastatic Urothelial Carcinoma Updated Results From a Phase 1/2 Open-label Study [J].
Powles, Thomas ;
O'Donnell, Peter H. ;
Massard, Christophe ;
Arkenau, Hendrik-Tobias ;
Friedlander, TerenceW. ;
Hoimes, Christopher J. ;
Lee, Jae Lyun ;
Ong, Michael ;
Sridhar, Srikala S. ;
Vogelzang, Nicholas J. ;
Fishman, Mayer N. ;
Zhang, Jingsong ;
Srinivas, Sandy ;
Parikh, Jigar ;
Antal, Joyce ;
Jin, Xiaoping ;
Gupta, Ashok K. ;
Ben, Yong ;
Hahn, Noah M. .
JAMA ONCOLOGY, 2017, 3 (09)
[12]   PD-1 and PD-L1 inhibitors after platinum-based chemotherapy or in first-line therapy in cisplatin-ineligible patients: Dramatic improvement of prognosis and overall survival after decades of hopelessness in patients with metastatic urothelial cancer [J].
Resch I. ;
Shariat S.F. ;
Gust K.M. .
memo - Magazine of European Medical Oncology, 2018, 11 (1) :43-46
[13]   Cost-effectiveness of Pembrolizumab in Second-line Advanced Bladder Cancer [J].
Sarfaty, Michal ;
Hall, Peter S. ;
Chan, Kelvin K. W. ;
Virik, Kiran ;
Leshno, Moshe ;
Gordon, Noa ;
Moore, Assaf ;
Neiman, Victoria ;
Rosenbaum, Eli ;
Goldstein, Daniel A. .
EUROPEAN UROLOGY, 2018, 74 (01) :57-62
[14]   Safety and clinical activity of pembrolizumab for treatment of recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-012): an open-label, multicentre, phase 1b trial [J].
Seiwert, Tanguy Y. ;
Burtness, Barbara ;
Mehra, Ranee ;
Weiss, Jared ;
Berger, Raanan ;
Eder, Joseph Paul ;
Heath, Karl ;
McClanahan, Terrill ;
Lunceford, Jared ;
Gause, Christine ;
Cheng, Jonathan D. ;
Chow, Laura Q. .
LANCET ONCOLOGY, 2016, 17 (07) :956-965
[15]   Nivolumab in metastatic urothelial carcinoma after platinum therapy (CheckMate 275): a multicentre, single-arm, phase 2 trial [J].
Sharma, Padmanee ;
Retz, Margitta ;
Siefker-Radtke, Arlene ;
Baron, Ari ;
Necchi, Andrea ;
Bedke, Jens ;
Plimack, Elizabeth R. ;
Vaena, Daniel ;
Grimm, Marc-Oliver ;
Bracarda, Sergio ;
Arranz, Jose Angel ;
Pal, Sumanta ;
Ohyama, Chikara ;
Saci, Abdel ;
Qu, Xiaotao ;
Lambert, Alexandre ;
Krishnan, Suba ;
Azrilevich, Alex ;
Galsky, Matthew D. .
LANCET ONCOLOGY, 2017, 18 (03) :312-322
[16]   Nivolumab monotherapy in recurrent metastatic urothelial carcinoma (CheckMate 032): a multicentre, open-label, two-stage, multi-arm, phase 1/2 trial [J].
Sharma, Padmanee ;
Callahan, Margaret K. ;
Bono, Petri ;
Kim, Joseph ;
Spiliopoulou, Pavlina ;
Calvo, Emiliano ;
Pillai, Rathi N. ;
Ott, Patrick A. ;
de Braud, Filippo ;
Morse, Michael ;
Le, Dung T. ;
Jaeger, Dirk ;
Chan, Emily ;
Harbison, Chris ;
Lin, Chen-Sheng ;
Tschaika, Marina ;
Azrilevich, Alex ;
Rosenberg, Jonathan E. .
LANCET ONCOLOGY, 2016, 17 (11) :1590-1598
[17]   Health-Related Quality-of-Life Analysis From KEYNOTE-045: A Phase III Study of Pembrolizumab Versus Chemotherapy for Previously Treated Advanced Urothelial Cancer [J].
Vaughn, David J. ;
Bellmunt, Joaquim ;
Fradet, Yves ;
Lee, Jae Lyun ;
Fong, Lawrence ;
Vogelzang, Nicholas J. ;
Climent, Miguel A. ;
Petrylak, Daniel P. ;
Choueiri, Toni K. ;
Necchi, Andrea ;
Gerritsen, Winald ;
Gurney, Howard ;
Quinn, David I. ;
Culine, Stephane ;
Sternberg, Cora N. ;
Mai, Yabing ;
Li, Haojie ;
Perini, Rodolfo F. ;
Bajorin, Dean F. ;
de Wit, Ronald .
JOURNAL OF CLINICAL ONCOLOGY, 2018, 36 (16) :1579-+
[18]   Updated 2016 EAU Guidelines on Muscle-invasive and Metastatic Bladder Cancer [J].
Witjes, J. Alfred ;
Lebret, Thierry ;
Comperat, Eva M. ;
Cowan, Nigel C. ;
De Santis, Maria ;
Bruins, Harman Maxim ;
Hernandez, Virginia ;
Espinos, Estefania Linares ;
Dunn, James ;
Rouanne, Mathieu ;
Neuzillet, Yann ;
Veskimae, Erik ;
van der Heijden, Antoine G. ;
Gakis, Georgios ;
Ribal, Maria J. .
EUROPEAN UROLOGY, 2017, 71 (03) :462-475
12