Enhanced antitumor effect of binimetinib in combination with capecitabine for biliary tract cancer patients with mutations in the RAS/RAF/MEK/ERK pathway

phase Ib study

Jin Won Kim, Kyung Hun Lee, Ji Won Kim, Koung Jin Suh, Ah Rong Nam, Ju Hee Bang, Yung Jue Bang, Do-Youn Oh

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Background: A phase Ib study of binimetinib and capecitabine for gemcitabine-pretreated biliary tract cancer (BTC) patients was conducted. Methods: Binimetinib and capecitabine were dosed twice daily on days 1–14, in 3-week cycles. In the dose-escalation (DE) part, three dose levels (DL) were tested (DL1: binimetinib/capecitabine, 15 mg/1000 mg/m2; DL2: 30 mg/1000 mg/m2; DL3: 30 mg/1250 mg/m2). Results: In the DE part, nine patients were recruited and no dose-limiting toxicity was noted. Therefore, the recommended phase 2 dose was determined as DL3. In the expansion part, 25 patients were enrolled. In total, 34 patients, 25 (73.5%) and 9 patients (26.5%) were second-line and third-line settings, respectively. The 3-month progression-free survival (PFS) rate was 64.0%, and the median PFS and overall survival (OS) were 4.1 and 7.8 months. The objective response rate and disease control rate were 20.6% and 76.5%. In total, 68.4% of stable diseases were durable (> 12 weeks). Furthermore, patients with RAS/RAF/MEK/ERK pathway mutations (38.5%) showed significantly better tumour response (p = 0.028), PFS (5.4 vs. 3.5 months, p = 0.010) and OS (10.8 vs. 5.9 months, p = 0.160) than wild type. Most of the adverse events were grade 1/2 and manageable. Conclusions: A combination of binimetinib and capecitabine shows acceptable tolerability and promising antitumor efficacy for gemcitabine-pretreated BTC, especially in patients with RAS/RAF/MEK/ERK pathway mutations. Clinical trial registration: ClinicalTrials.gov (Identifier: NCT02773459).

Original languageEnglish
Pages (from-to)332-339
Number of pages8
JournalBritish Journal of Cancer
Volume121
Issue number4
DOIs
StatePublished - 13 Aug 2019

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Biliary Tract Neoplasms
MAP Kinase Signaling System
Mutation
gemcitabine
Disease-Free Survival
Survival
Capecitabine
MEK162
Survival Rate
Clinical Trials

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@article{fe26bd0bc9ab4044affcfef246410322,
title = "Enhanced antitumor effect of binimetinib in combination with capecitabine for biliary tract cancer patients with mutations in the RAS/RAF/MEK/ERK pathway: phase Ib study",
abstract = "Background: A phase Ib study of binimetinib and capecitabine for gemcitabine-pretreated biliary tract cancer (BTC) patients was conducted. Methods: Binimetinib and capecitabine were dosed twice daily on days 1–14, in 3-week cycles. In the dose-escalation (DE) part, three dose levels (DL) were tested (DL1: binimetinib/capecitabine, 15 mg/1000 mg/m2; DL2: 30 mg/1000 mg/m2; DL3: 30 mg/1250 mg/m2). Results: In the DE part, nine patients were recruited and no dose-limiting toxicity was noted. Therefore, the recommended phase 2 dose was determined as DL3. In the expansion part, 25 patients were enrolled. In total, 34 patients, 25 (73.5{\%}) and 9 patients (26.5{\%}) were second-line and third-line settings, respectively. The 3-month progression-free survival (PFS) rate was 64.0{\%}, and the median PFS and overall survival (OS) were 4.1 and 7.8 months. The objective response rate and disease control rate were 20.6{\%} and 76.5{\%}. In total, 68.4{\%} of stable diseases were durable (> 12 weeks). Furthermore, patients with RAS/RAF/MEK/ERK pathway mutations (38.5{\%}) showed significantly better tumour response (p = 0.028), PFS (5.4 vs. 3.5 months, p = 0.010) and OS (10.8 vs. 5.9 months, p = 0.160) than wild type. Most of the adverse events were grade 1/2 and manageable. Conclusions: A combination of binimetinib and capecitabine shows acceptable tolerability and promising antitumor efficacy for gemcitabine-pretreated BTC, especially in patients with RAS/RAF/MEK/ERK pathway mutations. Clinical trial registration: ClinicalTrials.gov (Identifier: NCT02773459).",
author = "Kim, {Jin Won} and Lee, {Kyung Hun} and Kim, {Ji Won} and Suh, {Koung Jin} and Nam, {Ah Rong} and Bang, {Ju Hee} and Bang, {Yung Jue} and Do-Youn Oh",
year = "2019",
month = "8",
day = "13",
doi = "10.1038/s41416-019-0523-5",
language = "English",
volume = "121",
pages = "332--339",
journal = "British Journal of Cancer",
issn = "0007-0920",
publisher = "Nature Publishing Group",
number = "4",

}

Enhanced antitumor effect of binimetinib in combination with capecitabine for biliary tract cancer patients with mutations in the RAS/RAF/MEK/ERK pathway : phase Ib study. / Kim, Jin Won; Lee, Kyung Hun; Kim, Ji Won; Suh, Koung Jin; Nam, Ah Rong; Bang, Ju Hee; Bang, Yung Jue; Oh, Do-Youn.

In: British Journal of Cancer, Vol. 121, No. 4, 13.08.2019, p. 332-339.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Enhanced antitumor effect of binimetinib in combination with capecitabine for biliary tract cancer patients with mutations in the RAS/RAF/MEK/ERK pathway

T2 - phase Ib study

AU - Kim, Jin Won

AU - Lee, Kyung Hun

AU - Kim, Ji Won

AU - Suh, Koung Jin

AU - Nam, Ah Rong

AU - Bang, Ju Hee

AU - Bang, Yung Jue

AU - Oh, Do-Youn

PY - 2019/8/13

Y1 - 2019/8/13

N2 - Background: A phase Ib study of binimetinib and capecitabine for gemcitabine-pretreated biliary tract cancer (BTC) patients was conducted. Methods: Binimetinib and capecitabine were dosed twice daily on days 1–14, in 3-week cycles. In the dose-escalation (DE) part, three dose levels (DL) were tested (DL1: binimetinib/capecitabine, 15 mg/1000 mg/m2; DL2: 30 mg/1000 mg/m2; DL3: 30 mg/1250 mg/m2). Results: In the DE part, nine patients were recruited and no dose-limiting toxicity was noted. Therefore, the recommended phase 2 dose was determined as DL3. In the expansion part, 25 patients were enrolled. In total, 34 patients, 25 (73.5%) and 9 patients (26.5%) were second-line and third-line settings, respectively. The 3-month progression-free survival (PFS) rate was 64.0%, and the median PFS and overall survival (OS) were 4.1 and 7.8 months. The objective response rate and disease control rate were 20.6% and 76.5%. In total, 68.4% of stable diseases were durable (> 12 weeks). Furthermore, patients with RAS/RAF/MEK/ERK pathway mutations (38.5%) showed significantly better tumour response (p = 0.028), PFS (5.4 vs. 3.5 months, p = 0.010) and OS (10.8 vs. 5.9 months, p = 0.160) than wild type. Most of the adverse events were grade 1/2 and manageable. Conclusions: A combination of binimetinib and capecitabine shows acceptable tolerability and promising antitumor efficacy for gemcitabine-pretreated BTC, especially in patients with RAS/RAF/MEK/ERK pathway mutations. Clinical trial registration: ClinicalTrials.gov (Identifier: NCT02773459).

AB - Background: A phase Ib study of binimetinib and capecitabine for gemcitabine-pretreated biliary tract cancer (BTC) patients was conducted. Methods: Binimetinib and capecitabine were dosed twice daily on days 1–14, in 3-week cycles. In the dose-escalation (DE) part, three dose levels (DL) were tested (DL1: binimetinib/capecitabine, 15 mg/1000 mg/m2; DL2: 30 mg/1000 mg/m2; DL3: 30 mg/1250 mg/m2). Results: In the DE part, nine patients were recruited and no dose-limiting toxicity was noted. Therefore, the recommended phase 2 dose was determined as DL3. In the expansion part, 25 patients were enrolled. In total, 34 patients, 25 (73.5%) and 9 patients (26.5%) were second-line and third-line settings, respectively. The 3-month progression-free survival (PFS) rate was 64.0%, and the median PFS and overall survival (OS) were 4.1 and 7.8 months. The objective response rate and disease control rate were 20.6% and 76.5%. In total, 68.4% of stable diseases were durable (> 12 weeks). Furthermore, patients with RAS/RAF/MEK/ERK pathway mutations (38.5%) showed significantly better tumour response (p = 0.028), PFS (5.4 vs. 3.5 months, p = 0.010) and OS (10.8 vs. 5.9 months, p = 0.160) than wild type. Most of the adverse events were grade 1/2 and manageable. Conclusions: A combination of binimetinib and capecitabine shows acceptable tolerability and promising antitumor efficacy for gemcitabine-pretreated BTC, especially in patients with RAS/RAF/MEK/ERK pathway mutations. Clinical trial registration: ClinicalTrials.gov (Identifier: NCT02773459).

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U2 - 10.1038/s41416-019-0523-5

DO - 10.1038/s41416-019-0523-5

M3 - Article

VL - 121

SP - 332

EP - 339

JO - British Journal of Cancer

JF - British Journal of Cancer

SN - 0007-0920

IS - 4

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