Phase 1b investigation of the MEK inhibitor binimetinib in patients with advanced or metastatic biliary tract cancer

Abstract

Background The MAPK pathway plays a central role in regulation of several cellular processes, and its dysregulation is a hallmark of biliary tract cancer (BTC). Binimetinib (MEK162), a potent, selective oral MEK1/2 inhibitor, was assessed in patients with advanced BTC. Patients and Methods An expansion cohort study in patients who received ≤1 line of therapy for advanced BTC was conducted after determination of the maximum tolerated dose in this Phase 1 trial. Patients received binimetinib 60 mg twice daily. The primary objectives were to characterize the safety profile and pharmacokinetics of binimetinib in advanced BTC. Secondary objectives included assessment of clinical efficacy, changes in weight and lean body mass, and pharmacodynamic effects. Tumor samples were assessed for mutations in relevant genes. Results Twenty-eight patients received binimetinib. Common adverse events (AEs) were mild, with rash (82%) and nausea (54%) being most common. Two patients experienced grade 4 AEs, one generalized edema and the other pulmonary embolism. The pharmacokinetics in this patient population were consistent with those previously reported (Bendell JC et al., Br J Cancer 2017;116:575-583). Twelve patients (43%) experienced stable disease and two had objective responses (1 complete response, 1 partial response) per Response Evaluation Criteria in Solid Tumors and stable metabolic disease by positron emission tomography/computed tomography. Most patients (18/25; 72%) did not have KRAS, BRAF, NRAS, PI3KCA, or PTEN mutations, nor was there correlation between mutation status and response. The average non-fluid weight gain was 1.3% for lean muscle and 4.7% for adipose tissue. Conclusion Binimetinib was well tolerated and showed promising evidence of activity in patients with BTC. Correlative studies suggested the potential for binimetinib to promote muscle gain in patients with BTC.

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

“…A previous phase Ib study of binimetinib monotherapy in advanced or metastatic BTC patients reported an ORR of 8% and a DCR of 51%, as well as PFS of 2.1 months and OS of 4.8 months, respectively. 21 Similarly, in a phase II study of selumetinib for metastatic BTC, the ORR, DCR, PFS and OS were 12%, 80%, 3.7 months and 9.8 months, respectively. 10 In contrast, the ORR, DCR, PFS and OS were 20.6%, 76.5%, 4.1 months and 7.8 months, in this study.…”

“…In the previous phase I study of binimetinib monotherapy, 60 mg twice daily was identified as the MTD. 13 , 21 However, due to the frequent treatment-related ocular toxicity at this MTD, 45 mg twice daily was used as the RP2D. 13 , 32 In this study, predefined four DLs were tested, and no DLT was observed.…”

Systemic treatment of advanced or recurrent biliary tract cancer

“…Binimetinib monotherapy resulted in an ORR of 8% and a DCR of 56% (55), and a combination of binimetinib and chemotherapy resulted in an ORR of 20.6% and a DCR of 36% (32,56). Using an MSK-IMPACT 410-gene panel, Lowery et al (32) found aberrations in the RAS-RAF-MEK-ERK pathway and mutations in PIK3CA, AKT2, PIK3CG, BRAF, and MAP3K1 in responders.…”

Therapeutic strategies against cancer cachexia

“…67 A phase Ib investigation showed promising results with the MEK inhibitor binimetinib in patients with advanced or metastatic biliary tract cancer. 68 Cancer cachexia and type II diabetes share common metabolic characteristics, including weight loss, insulin resistance and increased hepatic gluconeogenesis. From this point of view, recent interest has developed around anti-diabetic drugs - such as metformin - for the treatment of muscle wasting in cancer.…”