A First-in-Human Phase I Study to Evaluate the ERK1/2 Inhibitor GDC-0994 in Patients with Advanced Solid Tumors

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• Dysregulation of Extracellular signal-Regulated Kinase (ERK1/2) signaling is implicated in cancer development.
• Targeting the mitogen-activated protein kinase (MAPK) pathway is a strategy for cancer therapy.

Purpose of the Study:

• To evaluate the safety, pharmacokinetics, and preliminary efficacy of GDC-0994, an oral ERK1/2 inhibitor.
• To determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of GDC-0994.
• To assess pharmacodynamic effects and antitumor activity in patients with advanced solid tumors.

Main Methods:

• A first-in-human, phase I, dose-escalation study of GDC-0994 administered orally once daily.
• Patients with locally advanced or metastatic solid tumors were enrolled in dose-escalation cohorts.
• Expansion cohorts included patients with pancreatic adenocarcinoma and BRAF-mutant colorectal cancer.

Main Results:

• Forty-seven patients were treated across dose levels from 50-800 mg; a DLT of grade 3 rash occurred at 600 mg.
• Common adverse events included diarrhea, rash, nausea, fatigue, and vomiting.
• Pharmacokinetics demonstrated dose-proportional exposure with a 23-hour half-life, supporting once-daily dosing.
• MAPK pathway inhibition ranged from 19% to 51% in tumor biopsies.
• Partial metabolic responses were observed in 11/20 patients by FDG-PET.
• Best overall response was stable disease in 15/45 patients, with 2 confirmed partial responses in BRAF-mutant colorectal cancer.

Conclusions:

• GDC-0994 demonstrated an acceptable safety profile in patients with advanced solid tumors.
• Pharmacodynamic effects, including MAPK pathway inhibition, were observed.
• Preliminary single-agent activity was noted, particularly in BRAF-mutant colorectal cancer, warranting further clinical evaluation.