Open AccessEfficacy and safety of trametinib in Japanese patients with advanced biliary tract cancers refractory to gemcitabine
Author(s) -
Ikeda Masafumi,
Ioka Tatsuya,
Fukutomi Akira,
Morizane Chigusa,
Kasuga Akiyoshi,
Takahashi Hideaki,
Todaka Akiko,
Okusaka Takuji,
Creasy Caretha L.,
Gorman Shelby,
Felitsky Daniel J.,
Kobayashi Mikiro,
Zhang Fanghong,
Furuse Junji
Publication year - 2018
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/cas.13438
Subject(s) - trametinib , medicine , gemcitabine , oncology , gastroenterology , clinical endpoint , ampulla of vater , mek inhibitor , biliary tract , adverse effect , surgery , urology , carcinoma , chemotherapy , clinical trial , mapk/erk pathway , biology , kinase , microbiology and biotechnology
Gemcitabine‐based therapy remains the mainstay of treatment for patients with biliary tract cancers ( BTC s) with no second‐line treatment(s) established yet. Aberrant activation of the MAPK pathway in patients with BTC indicates its importance in BTC . Trametinib is a potent, highly selective, allosteric non‐competitive inhibitor of MEK 1/ MEK 2. In this phase II a open‐label, single‐arm study, we investigated the efficacy and safety of trametinib in Japanese patients with advanced BTC refractory to gemcitabine‐based therapy. All patients received oral trametinib 2 mg once daily until progressive disease ( PD ), death, or unacceptable toxicity. The primary objective was to determine the 12‐week non‐ PD rate. Secondary assessments included safety, progression‐free survival ( PFS ), overall survival, and overall response rate. Targeted exome sequencing was used to identify biomarkers for sensitivity or resistance to trametinib monotherapy. Twenty patients (median age, 61.5 years) with carcinoma of gall bladder (40%), intrahepatic (25%) or extrahepatic (30%) bile duct, and ampulla of Vater (5%) were enrolled. The non‐ PD rate at week 12 was 10% (95% confidence interval, 1.2‐31.7); it did not reach the threshold rate of 25%. Median PFS was 10.6 weeks (95% confidence interval, 4.6‐12.1) and 1‐year overall survival was 20.0%. Stable disease and PD were observed in 13 (65%) and seven (35%) patients, respectively. No new safety signals were reported. Although the primary end‐point was not met, prolonged PFS was observed in one patient having six somatic variants including synonymous NF 1 exon 12 splice variant and a loss‐of‐function variant in ARID 1A. Efforts to understand responsive mutations and sensitivity to targeted therapies are warranted. This trial was registered with ClinicalTrials.gov: NCT01943864.