Abstract
To evaluate the safety, pharmacokinetics, and pharmacodynamics of BAY 86-9766, a selective, potent, orally available, small-molecule allosteric inhibitor of mitogen-activated protein kinase 1/2 in patients with advanced solid tumors. BAY 86-9766 was administered orally daily in 28-day courses, with doses escalated to establish the maximum-tolerated dose (MTD). An expanded cohort was evaluated at the MTD. Pharmacokinetic and pharmacodynamic parameters were assessed, with extracellular signal-regulated kinase (ERK) phosphorylation evaluated in paired biopsies from a subset of the expanded MTD cohort. Tumor specimens were evaluated for mutations in select genes. Sixty-nine patients were enrolled, including 20 patients at the MTD. The MTD was 100 mg given once-daily or in two divided doses. BAY 86-9766 was well-tolerated. The most common treatment-related toxicities were acneiform rash and gastrointestinal toxicity. BAY 86-9766 was well-absorbed after oral administration (plasma half-life ~12 hours), and displayed dose proportional pharmacokinetics throughout the tested dose range. Continuous daily dosing resulted in moderate accumulation at most dose levels. BAY 86-9766 suppressed ERK phosphorylation in biopsied tissue and tetradecanoylphorbol acetate-stimulated peripheral blood leukocytes. Of 53 evaluable patients, one patient with colorectal cancer achieved a partial response and 11 patients had stable disease for 4 or more courses. An ocular melanoma specimen harbored a GNAQ-activating mutation and exhibited reduced ERK phosphorylation in response to therapy. This phase I study showed that BAY 86-9766 was well-tolerated, with good oral absorption, dose proportional pharmacokinetics, target inhibition at the MTD, and some evidence of clinical benefit across a range of tumor types.
Highlights
The RAS/RAF/mitogen-activated protein/extracellular signal– regulated kinase (MEK)/extracellular signal– regulated kinase (ERK) pathway transduces signals from cell surface receptors to the intracellular machinery involved in cell proliferation, survival, and migration (1–3).Authors' Affiliations: 1University of Colorado Cancer Center, Aurora, Colorado; 2Translational Genomics Research Institute (TGen); 3Virginia G
BAY 86-9766 was well-absorbed after oral administration, and displayed dose proportional pharmacokinetics throughout the tested dose range
An ocular melanoma specimen harbored a GNAQ-activating mutation and exhibited reduced ERK phosphorylation in response to therapy. This phase I study showed that BAY 86-9766 was well-tolerated, with good oral absorption, dose proportional pharmacokinetics, target inhibition at the maximum-tolerated dose (MTD), and some evidence of clinical benefit across a range of tumor types
Summary
The RAS/RAF/MEK/ERK pathway transduces signals from cell surface receptors to the intracellular machinery involved in cell proliferation, survival, and migration (1–3). Authors' Affiliations: 1University of Colorado Cancer Center, Aurora, Colorado; 2Translational Genomics Research Institute (TGen); 3Virginia G. This pathway is constitutively activated in many tumors, often reflective of dysfunctional receptor tyrosine kinases or activating mutations in RAS or RAF family members (4–11). The mitogen-activated protein/extracellular signal– regulated kinase (MEK) enzyme is a critical component of the pathway that transduces signals to extracellular signal– regulated kinase (ERK), which in turn phosphorylates numerous nuclear and cytoplasmic substrates involved in regulating cellular responses (1, 11–13), and second, the MEK protein structure is amenable to the design of highly selective inhibitors (14, 15). As pathway activation occurs upstream of MEK in many human malignancies (4, 6–8), it is hypothesized that MEK inhibitors may have broad clinical use in cancer therapy
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