Defactinib with avutometinib in patients with solid tumors: the phase 1 FRAME trial

Area of Science:

• Oncology
• Pharmacology
• Clinical Trials

Background:

• Cancer treatment resistance arises from intracellular signaling plasticity, necessitating combination therapies.
• Signal transduction inhibitors, like avutometinib and defactinib, offer targeted approaches.
• Combining these inhibitors may overcome resistance and improve treatment efficacy.

Purpose of the Study:

• To evaluate the safety, tolerability, and efficacy of a combination therapy using avutometinib and defactinib in patients with solid tumors.
• To determine the recommended Phase 2 dose and schedule for this combination therapy.
• To explore the anti-tumor activity of this combination, especially in chemotherapy-resistant cancers like low-grade serous ovarian cancer.

Main Methods:

• A first-in-human Phase 1 clinical trial (NCT03875820) involving patients with solid tumors.
• Oral administration of avutometinib (RAF-MEK clamp) and defactinib (focal adhesion kinase inhibitor).
• Intermittent dosing schedule: 3 weeks on, 1 week off, with specific daily and weekly frequencies for each drug.

Main Results:

• The trial met its primary endpoint, establishing a recommended Phase 2 dose and schedule.
• Objective response rate of 42.3% and median progression-free survival of 20.1 months in patients with low-grade serous ovarian cancer.
• Pharmacokinetics and pharmacodynamics were consistent with single-agent studies; combination demonstrated anti-tumor activity and improved tolerability via intermittent dosing.

Conclusions:

• The combination of avutometinib and defactinib is a promising therapeutic strategy for solid tumors, particularly low-grade serous ovarian cancer.
• Intermittent dosing schedules are crucial for enhancing tolerability and efficacy in combined pathway targeting.
• This study provides proof of concept for targeting MAPK and FAK pathways simultaneously to combat resistant cancers.