Efficacy of BGJ398, a Fibroblast Growth Factor Receptor 1-3 Inhibitor, in Patients with Previously Treated Advanced Urothelial Carcinoma with FGFR3 Alterations

被引：207

作者：

Pal, Sumanta K. ^{[1
]}

Rosenberg, Jonathan E. ^{[2
]}

Hoffman-Censits, Jean H. ^{[3
]}

Berger, Raanan ^{[4
]}

Quinn, David I. ^{[5
]}

Galsky, Matthew D. ^{[6
]}

Wolf, Juergen ^{[7
]}

Dittrich, Christian ^{[8
]}

Keam, Bhumsuk ^{[9
]}

Delord, Jean-Pierre ^{[10
]}

Schellens, Jan H. M. ^{[11
]}

Gravis, Gwenaelle ^{[12
]}

Medioni, Jacques ^{[13
]}

Maroto, Pablo ^{[14
]}

Sriuranpong, Virote ^{[15
,16
]}

Charoentum, Chaiyut ^{[17
]}

Burris, Howard A. ^{[18
]}

Grunwald, Viktor ^{[19
]}

Petrylak, Daniel ^{[20
]}

Vaishampayan, Ulka ^{[21
]}

Gez, Eliahu ^{[22
]}

De Giorgi, Ugo ^{[23
]}

Lee, Jae-Lyun ^{[24
]}

Voortman, Jens ^{[25
]}

Gupta, Sumati ^{[26
]}

Sharma, Sunil ^{[26
]}

Mortazavi, Amir ^{[27
]}

Vaughn, David J. ^{[28
]}

Isaacs, Randi ^{[29
]}

Parker, Katie ^{[29
]}

Chen, Xueying ^{[29
]}

Yu, Kun ^{[30
]}

Porter, Dale ^{[30
]}

Porta, Diana Graus ^{[31
]}

Bajorin, Dean F. ^{[2
]}

机构：

[1] City Hope Natl Med Ctr, Duarte, CA USA

[2] Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10065 USA

[3] Thomas Jefferson Univ, Sidney Kimmel Canc Ctr, Philadelphia, PA 19107 USA

[4] Chaim Sheba Med Ctr, Ramat Gan, Israel

[5] USC Norris Canc Ctr, Los Angeles, CA USA

[6] Mt Sinai Hosp, New York, NY 10029 USA

[7] Univ Hosp Cologne, Ctr Integrated Oncol, Cologne, Germany

[8] Kaiser Franz Josef Spital, ACR ITR VIEnna, Appl Canc Res Inst Translat Res Vienna, Vienna, Austria

[9] Seoul Natl Univ Hosp, Seoul, South Korea

[10] IUCT Oncopole, Toulouse, France

[11] Netherlands Canc Inst, Amsterdam, Netherlands

[12] Inst Paoli Calmettes, Marseilles, France

[13] Hop Europeen Georges Pompidou, Paris, France

[14] Hosp Santa Creu & Sant Pau, Barcelona, Spain

[15] Chulalongkorn Univ, Fac Med, Bangkok, Thailand

[16] King Chulalongkorn Mem Hosp, Bangkok, Thailand

[17] Maharaj Nakorn Chiangmai Hosp, Chiang Mai, Thailand

[18] Sarah Cannon Res Inst, Nashville, TN USA

[19] Clin Hematol Hemostasis Oncol & Stem Cell Transp, Med Sch Hannover, Hannover, Germany

[20] Yale Sch Med, New Haven, CT USA

[21] Wayne State Univ, Karmanos Canc Inst, Detroit, MI USA

[22] Tel Aviv Sourasky Med Ctr Ichilov, Tel Aviv, Israel

[23] Inst Sci Romagnolo Studio & Cura Tumori IRST IRC, Meldola, Italy

[24] Univ Ulsan, Asan Med Ctr, Coll Med, Seoul, South Korea

[25] Vrije Univ Amsterdam Med Ctr, Canc Ctr Amsterdam, Amsterdam, Netherlands

[26] Univ Utah, Huntsman Canc Inst, Salt Lake City, UT USA

[27] Ohio State Univ, Ctr Comprehens Canc, Columbus, OH 43210 USA

[28] Univ Penn, Abramson Canc Ctr, Philadelphia, PA 19104 USA

[29] Novartis Pharmaceut, E Hanover, NJ USA

[30] Novartis Inst BioMed Res, Cambridge, MA USA

[31] Novartis Pharma AG, Basel, Switzerland

来源：

CANCER DISCOVERY | 2018年 / 8卷 / 07期

关键词：

CISPLATIN-INELIGIBLE PATIENTS; ACQUIRED-RESISTANCE; GENETIC ALTERATIONS; BLADDER-CANCER; SINGLE-ARM; MULTICENTER; PEMBROLIZUMAB; NVP-BGJ398; MUTATIONS;

D O I：

10.1158/2159-8290.CD-18-0229

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

BGJ398, a potent and selective pan-FGFR antagonist, was prospectively evaluated in patients with metastatic urothelial carcinoma bearing a diverse array of FGFR3 alterations. Patients (N = 67) who were unable to receive platinum chemotherapy were enrolled. The majority (70.1%) had received two or more prior antineoplastic therapies. BGJ398 was administered orally at 125 mg/day on a 3 weeks on, 1 week off schedule until unacceptable toxicity or progression. The primary endpoint was the response rate. Among 87 patients treated, an overall response rate of 25.4% was observed and an additional 38.8% of patients had disease stabilization, translating to a disease control rate of 64.2%. The most common treatment-emergent toxicities were hyperphosphatemia, elevated creatinine, fatigue, constipation, and decreased appetite. Further examination of BGJ398 in this disease setting is warranted. SIGNIFICANCE: BJG398 is active in patients with alterations in FGFR3, resulting in both reductions in tumor volume and stabilization of disease. (C) 2018 AACR.

引用

页码：812 / 821

页数：10

共 32 条

[1] Avelumab, an Anti-Programmed Death-Ligand 1 Antibody, In Patients With Refractory Metastatic Urothelial Carcinoma: Results From a Multicenter, Phase Ib Study [J].

Apolo, Andrea B. ;

Infante, Jeffrey R. ;

Balmanoukian, Ani ;

Patel, Manish R. ;

Wang, Ding ;

Kelly, Karen ;

Mega, Anthony E. ;

Britten, Carolyn D. ;

Ravaud, Alain ;

Mita, Alain C. ;

Safran, Howard ;

Stinchcombe, Thomas E. ;

Srdanov, Marko ;

Gelb, Arnold B. ;

Schlichting, Michael ;

Chin, Kevin ;

Gulley, James L. .

JOURNAL OF CLINICAL ONCOLOGY, 2017, 35 (19) :2117-+

[2] First-line pembrolizumab in cisplatin-ineligible patients with locally advanced and unresectable or metastatic urothelial cancer (KEYNOTE-052): a multicentre, single-arm, phase 2 study [J].

Balar, Arjun V. ;

Castellano, Daniel ;

O'Donnell, Peter H. ;

Grivas, Petros ;

Vuky, Jacqueline ;

Powles, Thomas ;

Plimack, Elizabeth R. ;

Hahn, Noah M. ;

de Wit, Ronald ;

Pang, Lei ;

Savage, Mary J. ;

Perini, Rodolfo F. ;

Keefe, Stephen M. ;

Bajorin, Dean ;

Bellmunt, Joaquim .

LANCET ONCOLOGY, 2017, 18 (11) :1483-1492

[3] Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: a single-arm, multicentre, phase 2 trial [J].

Balar, Arjun V. ;

Galsky, Matthew D. ;

Rosenberg, Jonathan E. ;

Powles, Thomas ;

Petrylak, Daniel P. ;

Bellmunt, Joaquim ;

Loriot, Yohann ;

Necchi, Andrea ;

Hoffman-Censits, Jean ;

Perez-Gracia, Jose Luis ;

Dawson, Nancy A. ;

van der Heijden, Michiel S. ;

Dreicer, Robert ;

Srinivas, Sandy ;

Retz, Margitta M. ;

Joseph, Richard W. ;

Drakaki, Alexandra ;

Vaishampayan, Ulka N. ;

Sridhar, Srikala S. ;

Quinn, David I. ;

Duran, Ignacio ;

Shaffer, David R. ;

Eigl, Bernhard J. ;

Grivas, Petros D. ;

Yu, Evan Y. ;

Li, Shi ;

Kadel, Edward E., III ;

Boyd, Zachary ;

Bourgon, Richard ;

Hegde, Priti S. ;

Mariathasan, Sanjeev ;

Thastrom, AnnChristine ;

Abidoye, Oyewale O. ;

Fine, Gregg D. ;

Bajorin, Dean F. .

LANCET, 2017, 389 (10064) :67-76

[4] Pembrolizumab as Second-Line Therapy for Advanced Urothelial Carcinoma [J].

Bellmunt, J. ;

de Wit, R. ;

Vaughn, D. J. ;

Fradet, Y. ;

Lee, J. -L. ;

Fong, L. ;

Vogelzang, N. J. ;

Climent, M. A. ;

Petrylak, D. P. ;

Choueiri, T. K. ;

Necchi, A. ;

Gerritsen, W. ;

Gurney, H. ;

Quinn, D. I. ;

Culine, S. ;

Sternberg, C. N. ;

Mai, Y. ;

Poehlein, C. H. ;

Perini, R. F. ;

Bajorin, D. F. .

NEW ENGLAND JOURNAL OF MEDICINE, 2017, 376 (11) :1015-1026

[5] Absolute quantification of somatic DNA alterations in human cancer [J].

Carter, Scott L. ;

Cibulskis, Kristian ;

Helman, Elena ;

McKenna, Aaron ;

Shen, Hui ;

Zack, Travis ;

Laird, Peter W. ;

Onofrio, Robert C. ;

Winckler, Wendy ;

Weir, Barbara A. ;

Beroukhim, Rameen ;

Pellman, David ;

Levine, Douglas A. ;

Lander, Eric S. ;

Meyerson, Matthew ;

Getz, Gad .

NATURE BIOTECHNOLOGY, 2012, 30 (05) :413-+

[6] Mechanisms of acquired resistance to tyrosine kinase inhibitors [J].

Chen, Yi-fan ;

Fu, Li-wu .

ACTA PHARMACEUTICA SINICA B, 2011, 1 (04) :197-207

[7] Sensitive detection of somatic point mutations in impure and heterogeneous cancer samples [J].

Cibulskis, Kristian ;

Lawrence, Michael S. ;

Carter, Scott L. ;

Sivachenko, Andrey ;

Jaffe, David ;

Sougnez, Carrie ;

Gabriel, Stacey ;

Meyerson, Matthew ;

Lander, Eric S. ;

Getz, Gad .

NATURE BIOTECHNOLOGY, 2013, 31 (03) :213-219

[8] Intrinsic subtypes of high-grade bladder cancer reflect the hallmarks of breast cancer biology [J].

Damrauer, Jeffrey S. ;

Hoadley, Katherine A. ;

Chism, David D. ;

Fan, Cheng ;

Tiganelli, Christopher J. ;

Wobker, Sara E. ;

Yeh, Jen Jen ;

Milowsky, Matthew I. ;

Iyer, Gopa ;

Parker, Joel S. ;

Kim, William Y. .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2014, 111 (08) :3110-3115

[9] Akt Activation Mediates Acquired Resistance to Fibroblast Growth Factor Receptor Inhibitor BGJ398 [J].

Datta, Jharna ;

Damodaran, Senthilkumar ;

Parks, Hannah ;

Ocrainiciuc, Cristina ;

Miya, Jharna ;

Yu, Lianbo ;

Gardner, Elijah P. ;

Samorodnitsky, Eric ;

Wing, Michele R. ;

Bhatt, Darshna ;

Hays, John ;

Reeser, Julie W. ;

Roychowdhury, Sameek .

MOLECULAR CANCER THERAPEUTICS, 2017, 16 (04) :614-624

[10] COSMIC: exploring the world's knowledge of somatic mutations in human cancer [J].

Forbes, Simon A. ;

Beare, David ;

Gunasekaran, Prasad ;

Leung, Kenric ;

Bindal, Nidhi ;

Boutselakis, Harry ;

Ding, Minjie ;

Bamford, Sally ;

Cole, Charlotte ;

Ward, Sari ;

Kok, Chai Yin ;

Jia, Mingming ;

De, Tisham ;

Teague, Jon W. ;

Stratton, Michael R. ;

McDermott, Ultan ;

Campbell, Peter J. .

NUCLEIC ACIDS RESEARCH, 2015, 43 (D1) :D805-D811

← 1 2 3 4 →