Binimetinib plus gemcitabine and cisplatin phase I/II trial in patients with advanced biliary cancers Journal Article

Authors: Lowery, M. A.; Bradley, M.; Chou, J. F.; Capanu, M.; Gerst, S.; Harding, J. J.; El Dika, I.; Berger, M.; Zehir, A.; Ptashkin, R.; Wong, P.; Rasalan-Ho, T.; Yu, K. H.; Cercek, A.; Morgono, E.; Salehi, E.; Valentino, E.; Hollywood, E.; O'Reilly, E. M.; Abou-Alfa, G. K.
Article Title: Binimetinib plus gemcitabine and cisplatin phase I/II trial in patients with advanced biliary cancers
Abstract: Purpose: Mutations in the RAS/RAF/MEK/ERK signaling pathway are commonly found in biliary tract cancer (BTC). Binimetinib, a selective inhibitor of MEK1/2, has single-agent activity. Preclinical data support binimetinib combination with chemotherapy, when given in an interrupted dosing schedule. Patients and Methods: A phase I/II trial evaluated binimetinib in combination with gemcitabine and cisplatin in patients with untreated advanced BTC. The primary endpoints were to determine the MTD (phase I), and PFS 6 and RR (phase II). Tumor tissue for targeted gene sequencing and blood samples for peripheral blood pERK expression were evaluated. Patients received oral binimetinib twice daily with gemcitabine and cisplatin on day 8 and 15 of a 21-day cycle. Binimetinib was held for 2 days prior to and on day of each chemotherapy treatment. Results: Twelve patients enrolled in the phase I showed the MTD of binimetinib at 45 mg orally twice daily with gemcitabine 800 and cisplatin 20 mg/m 2 . Twenty-nine patients were treated in the phase II. Six patients treated at MTD in phase I were evaluable as part of phase II. PFS 6 months was 54% and RR was 36%. Median overall survival was 13.3 months (95% CI, 9.8-16.5). MSK-IMPACT 410-gene panel showed aberrations in the RAS-RAF-MEK-ERK pathway and mutations in PIK3CA, AKT2, PIK3CG, BRAF, and MAP3K1 in responding patients. Conclusions: Binimetinib with gemcitabine and cisplatin did not show an improvement in PFS 6 and RR. Molecular profiling may help select patients who may benefit from this triplet therapy, which is not planned at this time. © 2018 American Association for Cancer Research.
Journal Title: Clinical Cancer Research
Volume: 25
Issue: 3
ISSN: 1078-0432
Publisher: American Association for Cancer Research  
Date Published: 2019-02-01
Start Page: 937
End Page: 945
Language: English
DOI: 10.1158/1078-0432.Ccr-18-1927
PUBMED: 30563938
PROVIDER: scopus
Notes: Source: Scopus
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MSK Authors
  1. Joanne Fu-Lou Chou
    155 Chou
  2. James Joseph Harding
    66 Harding
  3. Ghassan Abou-Alfa
    225 Abou-Alfa
  4. Phillip Wong
    38 Wong
  5. Marinela Capanu
    209 Capanu
  6. Maeve Aine Lowery
    97 Lowery
  7. Scott R Gerst
    42 Gerst
  8. Kenneth Ho-Ming Yu
    62 Yu
  9. Ahmet Zehir
    153 Zehir
  10. Eileen O'Reilly
    321 O'Reilly
  11. Michael Forman Berger
    386 Berger
  12. Teresa Rasalan
    25 Rasalan
  13. Erica Jeanne Salehi
    2 Salehi
  14. Imane El Dika
    10 El Dika