Phase II study of BGJ398 in patients with FGFR-Altered advanced cholangiocarcinoma

Milind Javle, Maeve Lowery, Rachna T. Shroff, Karl Heinz Weiss, Christoph Springfeld, Mitesh J Borad, Ramesk K Ramanathan, Lipika Goyal, Saeed Sadeghi, Teresa Macarulla, Anthony El-Khoueiry, Robin Kate Kelley, Ivan Borbath, Su Pin Choo, Do Youn Oh, Philip A. Philip, Li Tzong Chen, Thanyanan Reungwetwattana, Eric Van Cutsem, Kun Huei YehKristen Ciombor, Richard S. Finn, Anuradha Patel, Suman Sen, Dale Porter, Randi Isaacs, Andrew X. Zhu, Ghassan K. Abou-Alfa, Tanios Bekaii-Saab

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)276-282
Number of pages7
JournalJournal of Clinical Oncology
Volume36
Issue number3
DOIs
StatePublished - Jan 20 2018

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Receptor, Fibroblast Growth Factor, Type 2
Cholangiocarcinoma
Hyperphosphatemia
Stomatitis
gemcitabine
Phosphotransferases
Therapeutics
Alopecia
3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-(6-(4-(4-ethylpiperazin-1-yl)-phenylamino)pyrimidin-4-yl)-1-methylurea
Disease-Free Survival
Fatigue
Neoplasms
Research Personnel
Drug Therapy
Mutation

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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Phase II study of BGJ398 in patients with FGFR-Altered advanced cholangiocarcinoma. / Javle, Milind; Lowery, Maeve; Shroff, Rachna T.; Weiss, Karl Heinz; Springfeld, Christoph; Borad, Mitesh J; Ramanathan, Ramesk K; Goyal, Lipika; Sadeghi, Saeed; Macarulla, Teresa; El-Khoueiry, Anthony; Kelley, Robin Kate; Borbath, Ivan; Choo, Su Pin; Oh, Do Youn; Philip, Philip A.; Chen, Li Tzong; Reungwetwattana, Thanyanan; Van Cutsem, Eric; Yeh, Kun Huei; Ciombor, Kristen; Finn, Richard S.; Patel, Anuradha; Sen, Suman; Porter, Dale; Isaacs, Randi; Zhu, Andrew X.; Abou-Alfa, Ghassan K.; Bekaii-Saab, Tanios.

In: Journal of Clinical Oncology, Vol. 36, No. 3, 20.01.2018, p. 276-282.

Research output: Contribution to journalArticle

Javle, M, Lowery, M, Shroff, RT, Weiss, KH, Springfeld, C, Borad, MJ, Ramanathan, RK, Goyal, L, Sadeghi, S, Macarulla, T, El-Khoueiry, A, Kelley, RK, Borbath, I, Choo, SP, Oh, DY, Philip, PA, Chen, LT, Reungwetwattana, T, Van Cutsem, E, Yeh, KH, Ciombor, K, Finn, RS, Patel, A, Sen, S, Porter, D, Isaacs, R, Zhu, AX, Abou-Alfa, GK & Bekaii-Saab, T 2018, 'Phase II study of BGJ398 in patients with FGFR-Altered advanced cholangiocarcinoma', Journal of Clinical Oncology, vol. 36, no. 3, pp. 276-282. https://doi.org/10.1200/JCO.2017.75.5009
Javle, Milind ; Lowery, Maeve ; Shroff, Rachna T. ; Weiss, Karl Heinz ; Springfeld, Christoph ; Borad, Mitesh J ; Ramanathan, Ramesk K ; Goyal, Lipika ; Sadeghi, Saeed ; Macarulla, Teresa ; El-Khoueiry, Anthony ; Kelley, Robin Kate ; Borbath, Ivan ; Choo, Su Pin ; Oh, Do Youn ; Philip, Philip A. ; Chen, Li Tzong ; Reungwetwattana, Thanyanan ; Van Cutsem, Eric ; Yeh, Kun Huei ; Ciombor, Kristen ; Finn, Richard S. ; Patel, Anuradha ; Sen, Suman ; Porter, Dale ; Isaacs, Randi ; Zhu, Andrew X. ; Abou-Alfa, Ghassan K. ; Bekaii-Saab, Tanios. / Phase II study of BGJ398 in patients with FGFR-Altered advanced cholangiocarcinoma. In: Journal of Clinical Oncology. 2018 ; Vol. 36, No. 3. pp. 276-282.
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abstract = "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.",
author = "Milind Javle and Maeve Lowery and Shroff, {Rachna T.} and Weiss, {Karl Heinz} and Christoph Springfeld and Borad, {Mitesh J} and Ramanathan, {Ramesk K} and Lipika Goyal and Saeed Sadeghi and Teresa Macarulla and Anthony El-Khoueiry and Kelley, {Robin Kate} and Ivan Borbath and Choo, {Su Pin} and Oh, {Do Youn} and Philip, {Philip A.} and Chen, {Li Tzong} and Thanyanan Reungwetwattana and {Van Cutsem}, Eric and Yeh, {Kun Huei} and Kristen Ciombor and Finn, {Richard S.} and Anuradha Patel and Suman Sen and Dale Porter and Randi Isaacs and Zhu, {Andrew X.} and Abou-Alfa, {Ghassan K.} and Tanios Bekaii-Saab",
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TY - JOUR

T1 - Phase II study of BGJ398 in patients with FGFR-Altered advanced cholangiocarcinoma

AU - Javle, Milind

AU - Lowery, Maeve

AU - Shroff, Rachna T.

AU - Weiss, Karl Heinz

AU - Springfeld, Christoph

AU - Borad, Mitesh J

AU - Ramanathan, Ramesk K

AU - Goyal, Lipika

AU - Sadeghi, Saeed

AU - Macarulla, Teresa

AU - El-Khoueiry, Anthony

AU - Kelley, Robin Kate

AU - Borbath, Ivan

AU - Choo, Su Pin

AU - Oh, Do Youn

AU - Philip, Philip A.

AU - Chen, Li Tzong

AU - Reungwetwattana, Thanyanan

AU - Van Cutsem, Eric

AU - Yeh, Kun Huei

AU - Ciombor, Kristen

AU - Finn, Richard S.

AU - Patel, Anuradha

AU - Sen, Suman

AU - Porter, Dale

AU - Isaacs, Randi

AU - Zhu, Andrew X.

AU - Abou-Alfa, Ghassan K.

AU - Bekaii-Saab, Tanios

PY - 2018/1/20

Y1 - 2018/1/20

N2 - 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.

AB - 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.

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U2 - 10.1200/JCO.2017.75.5009

DO - 10.1200/JCO.2017.75.5009

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JO - Journal of Clinical Oncology

JF - Journal of Clinical Oncology

SN - 0732-183X

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