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Br J Cancer. 2019;121(4):332-339.

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.

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제1저자 김진원 · 교신저자 오도연

PMID 31312030 PMC6738070 DOI 10.1038/s41416-019-0523-5 IF 7.8 혈액종양내과
소속 (5)
  1. Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Republic of Korea.
  2. Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea.
  3. Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea.
  4. Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea. ohdoyoun@snu.ac.kr.
  5. Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea. ohdoyoun@snu.ac.kr.

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).

Figures

Fig. 1
Fig. 1 The preclinical efficacy of binimetinib and 5-fluorouracil. a Binimetinib demonstrates antitumour activity in biliary tract cancer cell lines. b Synergistic properties of the combination of binimetinib and 5-FU are identified in SNU245, SNU1196, SNU869 and HuCCT1 (CI < 1 at Fa = 0.5). c TS, a 5-FU resistance marker, is upregulated by 5-FU treatment. TS levels induced by 5-FU are downregulated by the addition of binimetinib. Similarly, 5-FU-induced expression of PD-L1 is abrogated by the addition of binimetinib. Actin was included as a loading control. The data are representative of three independent experiments. CI combination index, Fa fraction affected, 5-FU 5-fluorouracil, TS thymidylate synthase, PD-L1 programmed death-ligand 1
Fig. 2
Fig. 2 The efficacy of the combination of binimetinib and capecitabine. a Waterfall plot of tumour shrinkage, b progression-free survival and overall survival are present. Patients with mutant type on RAS/RAF/MEK/ERK exhibit better results in c waterfall plot, d progression-free survival, e swimmer plot of treatment duration and f overall survival compared with those with wild type. PD progressive disease, SD stable disease, PR partial response, PFS progression-free survival, OS overall survival, CI confidence interval, NR not reached
Fig. 3
Fig. 3 Progression-free survival and overall survival according to IL-6 concentration. a, b The baseline plasma concentrations of IL-6 are significantly associated with survival. c, d Alterations in the IL-6 concentration from baseline to after the second cycle are associated with survival. IL-6 interleukin-6, CI confidence interval, NR not reached

그림 출처: PubMed Central 공개 논문 (PMC6738070)

Conflict of interest statement

The authors declare no competing interests.

그 밖의 정보
출판 형태
Clinical Trial, Phase I, Journal Article, Research Support, Non-U.S. Gov't
저널
British journal of cancer · eISSN 1532-1827
전자 출판
2019-07-17
MeSH
Aged · Antineoplastic Combined Chemotherapy Protocols / therapeutic use · Benzimidazoles / administration & dosage / adverse effects · Biliary Tract Neoplasms / drug therapy / genetics / mortality / psychology · Capecitabine / administration & dosage / adverse effects · Cell Line, Tumor · Extracellular Signal-Regulated MAP Kinases / genetics / physiology · Female · Humans · Male · Middle Aged · Mitogen-Activated Protein Kinase Kinases / genetics / physiology · Mutation* · Quality of Life · Signal Transduction · raf Kinases / genetics / physiology · ras Proteins / genetics / physiology
Substances
Benzimidazoles · binimetinib · Capecitabine · raf Kinases · Extracellular Signal-Regulated MAP Kinases · Mitogen-Activated Protein Kinase Kinases · ras Proteins
데이터
ClinicalTrials.gov: NCT02773459
참고문헌
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