Avenzo Therapeutics Initiates CDK4/CDK2 Dual Inhibitor Combination Trial for HR+/HER2- Breast Cancer
Key Insights
Avenzo Therapeutics (search) has initiated a combination cohort in its Phase 1/2 ORION-1 study evaluating AVZO-023 (search) (CDK4 (search) inhibitor) plus AVZO-021 (CDK2 (search) inhibitor) with fulvestrant for advanced HR+/HER2- breast cancer (search).
The dual inhibitor approach targets CDK2 (search) hyperactivation, which has emerged as a key resistance mechanism to current CDK4 (search)/6 inhibitors in breast cancer treatment.
The selective profiles of both agents may provide a tolerability advantage over less selective approaches while optimizing CDK4 (search) target coverage and addressing CDK2 (search)-driven resistance.
Avenzo Therapeutics (search) has announced the initiation of a combination cohort in its ongoing Phase 1/2 ORION-1 clinical study, evaluating the dual CDK inhibitor approach of AVZO-023 (search) and AVZO-021 with fulvestrant in patients with advanced or metastatic hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) breast cancer.
Novel Dual CDK Targeting Strategy
The combination represents a strategic approach to address resistance mechanisms that limit the effectiveness of current CDK4 (search)/6 inhibitors. AVZO-023 (search) is a potential best-in-class cyclin-dependent kinase 4 (CDK4) selective inhibitor, while AVZO-021 targets cyclin-dependent kinase 2 (CDK2 (search)) with high selectivity.
"Hyperactivation of CDK2 (search) has emerged as a key resistance mechanism to CDK4 (search)/6 inhibitors, and we believe addressing both CDK4 and CDK2 with selective inhibitors represents a rational approach to improving outcomes for patients with HR+/HER2- breast cancer (search)," said Antonio Giordano, M.D., Ph.D., Clinical Director, Center for Cancer Therapeutic Innovation, Dana-Farber Cancer Institute.
ORION-1 Study Design and Objectives
The Phase 1/2 first-in-human, open-label ORION-1 clinical study is designed to assess the safety, tolerability, and preliminary clinical activity of AVZO-023 (search) with endocrine therapy as well as the combination of AVZO-023 and AVZO-021 with endocrine therapy. The combination cohort specifically evaluates AVZO-023 and AVZO-021 with fulvestrant in patients with HR+/HER2- metastatic breast cancer (search).
Selective Inhibitor Advantage
According to Giordano, "The combination of AVZO-023 (search) and AVZO-021 is designed to optimize CDK4 (search) target coverage while simultaneously targeting CDK2 (search)-driven resistance, and the selective profiles of both agents may enable a tolerability advantage over less selective approaches."
Clinical Development Progress
AVZO-021 is currently being studied in a separate Phase 1/2 clinical study in HR+/HER2- metastatic breast cancer (search) and other advanced solid tumors (search). The company plans to present updated safety and efficacy results from the Phase 1 portion of the ongoing study at the 2026 American Society of Clinical Oncology (ASCO) Annual Meeting.
"We are encouraged by the early emerging data from AVZO-023 (search) and believe the combination of our potential best-in-class CDK4 (search) and CDK2 (search) selective inhibitors has the potential to meaningfully improve outcomes for patients with HR+/HER2- breast cancer (search)," said Mohammad Hirmand, M.D., Co-founder, and Chief Medical Officer of Avenzo Therapeutics (search). "We look forward to advancing this program and exploring the full potential of this novel combination."
Company Pipeline
Avenzo Therapeutics (search) is a clinical-stage biotechnology company focused on developing next-generation oncology therapies. The company's pipeline includes potential best-in-class small molecules and antibody-drug conjugates (ADCs). Beyond the CDK inhibitors, Avenzo's portfolio includes AVZO-1418, a potential best-in-class EGFR (search)/HER3 (search) bispecific ADC, and AVZO-103 (search), a potential best-in-class Nectin4 (search)/TROP2 (search) bispecific ADC, both in Phase 1/2 studies for advanced solid tumors (search).