Efficacy and safety of trametinib in Japanese patients with advanced biliary tract cancers refractory to gemcitabine.
Masafumi IkedaTatsuya IokaAkira FukutomiChigusa MorizaneAkiyoshi KasugaHideaki TakahashiAkiko TodakaTakuji OkusakaCaretha L CreasyShelby GormanDaniel J FelitskyMikiro KobayashiFanghong ZhangJunji FurusePublished in: Cancer science (2017)
Gemcitabine-based therapy remains the mainstay of treatment for patients with biliary tract cancers (BTCs) 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 MEK1/MEK2. In this phase IIa 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 NF1 exon 12 splice variant and a loss-of-function variant in ARID1A. Efforts to understand responsive mutations and sensitivity to targeted therapies are warranted. This trial was registered with ClinicalTrials.gov: NCT01943864.
Keyphrases
- end stage renal disease
- newly diagnosed
- free survival
- ejection fraction
- open label
- chronic kidney disease
- clinical trial
- prognostic factors
- randomized controlled trial
- radiation therapy
- copy number
- spinal cord injury
- patient reported outcomes
- multiple sclerosis
- physical activity
- dna methylation
- phase iii
- cancer therapy
- case report
- double blind
- quality improvement
- young adults
- phase ii
- rectal cancer
- chemotherapy induced