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

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).

Conflict of interest statement

The authors declare no competing interests.

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). cTS, 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

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