Phase II Study of BGJ398 in Patients With FGFR-Altered Advanced Cholangiocarcinoma

被引：564

作者：

Javle, Milind ^{[1
]}

Lowery, Maeve ^{[2
,3
]}

Shroff, Rachna T. ^{[1
]}

Weiss, Karl Heinz ^{[4
]}

Springfeld, Christoph ^{[4
]}

Borad, Mitesh J. ^{[5
]}

Ramanathan, Ramesh K. ^{[5
]}

Goyal, Lipika ^{[6
]}

Sadeghi, Saeed ^{[7
]}

Macarulla, Teresa ^{[10
,11
]}

El-Khoueiry, Anthony ^{[8
]}

Kelley, Robin Kate ^{[9
]}

Borbath, Ivan ^{[12
]}

Choo, Su Pin ^{[15
]}

Oh, Do-Youn ^{[16
]}

Philip, Philip A. ^{[17
]}

Chen, Li-Tzong ^{[18
,19
]}

Reungwetwattana, Thanyanan ^{[22
]}

Van Cutsem, Eric ^{[13
,14
]}

Yeh, Kun-Huei ^{[20
,21
]}

Ciombor, Kristen ^{[23
]}

Finn, Richard S. ^{[7
]}

Patel, Anuradha ^{[24
]}

Sen, Suman ^{[24
]}

Porter, Dale ^{[24
]}

Isaacs, Randi ^{[24
]}

Zhu, Andrew X. ^{[6
]}

Abou-Alfa, Ghassan K. ^{[2
,3
]}

Bekaii-Saab, Tanios ^{[5
]}

机构：

[1] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA

[2] Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA

[3] Weill Cornell Med Coll, New York, NY USA

[4] Univ Klinikum Heidelberg, Heidelberg, Germany

[5] Mayo Clin, Phoenix, AZ USA

[6] Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA

[7] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA

[8] Keck Sch Med, USC Norris Comprehens Canc Ctr, Los Angeles, CA USA

[9] UCSF Helen Diller Family Comprehens Canc Ctr, San Francisco, CA USA

[10] Vall dHebron Univ Hosp, Barcelona, Spain

[11] Vall dHebron Inst Oncol, Barcelona, Spain

[12] Clin Univ St Luc, Brussels, Belgium

[13] Univ Hosp Gasthuisberg, Leuven, Belgium

[14] Katholieke Univ Leuven, Leuven, Belgium

[15] Natl Canc Ctr Singapore, Singapore, Singapore

[16] Seoul Natl Univ, Seoul, South Korea

[17] Karmanos Canc Inst, Detroit, MI USA

[18] Natl Inst Canc Res, Tainan, Taiwan

[19] Natl Cheng Kung Univ Hosp, Tainan, Taiwan

[20] Natl Taiwan Univ Hosp, Ctr Canc, Taipei, Taiwan

[21] Natl Taiwan Univ, Coll Med, Canc Res Ctr, Taipei, Taiwan

[22] Mahidol Univ, Ramathibodi Hosp, Bangkok, Thailand

[23] Ohio State Univ, Wexner Med Ctr, Columbus, OH 43210 USA

[24] Novartis Pharmaceut, E Hanover, NJ USA

来源：

JOURNAL OF CLINICAL ONCOLOGY | 2018年 / 36卷 / 03期

关键词：

INTRAHEPATIC CHOLANGIOCARCINOMAS; GENETIC ALTERATIONS; CANCER; INHIBITOR; CRITERIA;

D O I：

10.1200/JCO.2017.75.5009

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Purpose No standard treatment exists for patients with cholangiocarcinoma for whom first-line gemcitabine-based therapy fails. Fibroblast growth factor receptor 2 (FGFR2) fusions/translocations are present in 13% to 17% of intrahepatic cholangiocarcinomas. BGJ398, an orally bioavailable, selective pan-FGFR kinase inhibitor, has shown preliminary clinical activity against tumors with FGFR alterations. Methods A multicenter, open-label, phase II study (ClinicalTrials.gov identifier: NCT02150967) evaluated BGJ398 antitumor activity in patients age >= 18 years with advanced or metastatic cholangiocarcinoma containing FGFR2 fusions or other FGFR alterations whose disease had progressed while receiving prior therapy. Patients received BGJ398 125 mg once daily for 21 days, then 7 days off (28-day cycles). The primary end point was investigator-assessed overall response rate. Results Sixty-one patients (35 women; median age, 57 years) with FGFR2 fusion (n = 48), mutation (n = 8), or amplification (n = 3) participated. At the prespecified data cutoff (June 30, 2016), 50 patients had discontinued treatment. All responsive tumors contained FGFR2 fusions. The overall response rate was 14.8% (18.8% FGFR2 fusions only), disease control rate was 75.4%(83.3% FGFR2 fusions only), and estimated median progression-free survival was 5.8 months (95% CI, 4.3 to 7.6 months). Adverse events included hyperphosphatemia (72.1% all grade), fatigue (36.1%), stomatitis (29.5%), and alopecia (26.2%). Grade 3 or 4 treatment-related adverse events occurred in 25 patients (41%) and included hyperphosphatemia (16.4%), stomatitis (6.6%), and palmar-plantar erythrodysesthesia (4.9%). Conclusion BGJ398 is a first-in-class FGFR kinase inhibitor with manageable toxicities that shows meaningful clinical activity against chemotherapy-refractory cholangiocarcinoma containing FGFR2 fusions. This promising antitumor activity supports continued development of BGJ398 in this highly selected patient population. (c) 2017 by American Society of Clinical Oncology

引用

页码：276 / +

页数：14

共 21 条

[1]

Alpini G., 2001, LIVER, P421

[2]

American Cancer Society, BIL DUCT CANC CHOL

[3]

[Anonymous], J CLIN ONCOL S4S

[4]

[Anonymous], COMM TERM CRIT ADV E

[5] Cholangiocarcinoma: current knowledge and future perspectives consensus statement from the European Network for the Study of Cholangiocarcinoma (ENS-CCA) [J].

Banales, Jesus M. ;

Cardinale, Vincenzo ;

Carpino, Guido ;

Marzioni, Marco ;

Andersen, JesperB. ;

Invernizzi, Pietro ;

Lind, Guro E. ;

Folseraas, Trine ;

Forbes, Stuart J. ;

Fouassier, Laura ;

Geier, Andreas ;

Calvisi, Diego F. ;

Mertens, Joachim C. ;

Trauner, Michael ;

Benedetti, Antonio ;

Maroni, Luca ;

Vaquero, Javier ;

Macias, Rocio I. R. ;

Raggi, Chiara ;

Perugorria, Maria J. ;

Gaudio, Eugenio ;

Boberg, Kirsten M. ;

Marin, Jose J. G. ;

Alvaro, Domenico .

NATURE REVIEWS GASTROENTEROLOGY & HEPATOLOGY, 2016, 13 (05) :261-280

[6] Genetic heterogeneity in cholangiocarcinoma: a major challenge for targeted therapies [J].

Brandi, Giovanni ;

Farioli, Andrea ;

Astolfi, Annalisa ;

Biasco, Guido ;

Tavolari, Simona .

ONCOTARGET, 2015, 6 (17) :14744-14753

[7] Mutation Profiling in Cholangiocarcinoma: Prognostic and Therapeutic Implications [J].

Churi, Chaitanya R. ;

Shroff, Rachna ;

Wang, Ying ;

Rashid, Asif ;

Kang, HyunSeon C. ;

Weatherly, Jacqueline ;

Zuo, Mingxin ;

Zinner, Ralph ;

Hong, David ;

Meric-Bernstam, Funda ;

Janku, Filip ;

Crane, Christopher H. ;

Mishra, Lopa ;

Vauthey, Jean-Nicholas ;

Wolff, Robert A. ;

Mills, Gordon ;

Javle, Milind .

PLOS ONE, 2014, 9 (12)

[8] New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1) [J].

Eisenhauer, E. A. ;

Therasse, P. ;

Bogaerts, J. ;

Schwartz, L. H. ;

Sargent, D. ;

Ford, R. ;

Dancey, J. ;

Arbuck, S. ;

Gwyther, S. ;

Mooney, M. ;

Rubinstein, L. ;

Shankar, L. ;

Dodd, L. ;

Kaplan, R. ;

Lacombe, D. ;

Verweij, J. .

EUROPEAN JOURNAL OF CANCER, 2009, 45 (02) :228-247

[9] Integrative Genomic Analysis of Cholangiocarcinoma Identifies Distinct IDH-Mutant Molecular Profiles (vol 18, pg 2780, 2017) [J].

Farshidfar, Farshad ;

Zheng, Siyuan ;

Gingras, Marie-Claude ;

Newton, Yulia ;

Shih, Juliann ;

Robertson, A. Gordon ;

Hinoue, Toshinori ;

Hoadley, Katherine A. ;

Gibb, Ewan A. ;

Roszik, Jason ;

Covington, Kyle R. ;

Wu, Chia-Chin ;

Shinbrot, Eve ;

Stransky, Nicolas ;

Hegde, Apurva ;

Yang, Ju Dong ;

Reznik, Ed ;

Sadeghi, Sara ;

Pedamallu, Chandra Sekhar ;

Ojesina, Akinyemi I. ;

Hess, Julian M. ;

Auman, J. Todd ;

Rhie, Suhn K. ;

Bowlby, Reanne ;

Borad, Mitesh J. ;

Zhu, Andrew X. ;

Stuart, Josh M. ;

Sander, Chris ;

Akbani, Rehan ;

Cherniack, Andrew D. ;

Deshpande, Vikram ;

Mounajjed, Taofic ;

Foo, Wai Chin ;

Torbenson, Michael S. ;

Kleiner, David E. ;

Laird, Peter W. ;

Wheeler, David A. ;

McRee, Autumn J. ;

Bathe, Oliver F. ;

Andersen, Jesper B. ;

Bardeesy, Nabeel ;

Roberts, Lewis R. ;

Kwong, Lawrence N. .

CELL REPORTS, 2017, 19 (13) :2878-2880

[10]

Farshidfar F, 2017, CELL REP, V18, P2780, DOI [10.1016/j.celrep.2017.02.033, 10.1016/j.celrep.2017.06.008]

← 1 2 3 →