RESEARCH AND DEVELOPMENT | ONCOLOGY

Mechanism of Action:

ARV-806 is an investigational novel PROTAC designed to selectively target and degrade mutant Kirsten rat sarcoma (KRAS) G12D in solid tumors. KRAS is one of the most frequently mutated human oncogenes and G12D is the most common mutation of the KRAS protein. KRAS exists in both an “ON” and “OFF” form and most inhibitors target one state or the other. However, the ternary complex formed by PROTAC degraders between the protein of interest and the E3 ligase allows ARV-806 to target both “ON” and “OFF” forms of KRAS G12D. By using the body’s own disposal system to eliminate the KRAS G12D protein, rather than inhibiting its activity, ARV-806 aims to directly block oncogenic signaling and disrupt pathways that drive tumor growth and survival.

ARV-806 has demonstrated potent, selective degradation of KRAS G12D and robust anti-tumor activity in preclinical models with the potential to address high unmet need in solid tumors, such as pancreatic, colorectal, and NSCLC.

Diseases of Interest for Development:

Pancreatic, colorectal, and NSCLC are solid tumor cancers frequently driven by KRAS G12D mutations. No approved therapies exist that specifically target this mutation.

Clinical Status:

ARV-806 is currently being evaluated in a Phase 1/2 clinical trial in patients with advanced solid tumors harboring KRAS G12D mutations (NCT07023731).

Mechanism of Action:

ARV-6723 is an investigational oral PROTAC designed to degrade hematopoietic progenitor kinase 1 (HPK1) in solid malignancies and is Arvinas’ first clinical candidate in the immuno-oncology (IO) space. HPK1 acts as a negative regulator in T-cell receptor signaling, and therefore degrading HPK1 has the potential to unleash an immune response with potent anti-tumor effects and minimal off-target toxicity. Preclinically, ARV-6723 has shown potent, selective HPK1 degradation and anti-tumor immune responses in low- and high-immunogenic tumor models, as a single agent or in combination with IO therapy.

Diseases of Interest for Development:

Solid malignancies such as NSCLC, melanoma, and RCC, where dysfunctional tumor microenvironment contributes to immune suppression and resistance to IO therapy.

Clinical Status:

A Phase 1 trial is planned to begin in 2026.

Mechanism of Action:

Vepdegestrant is an investigational oral PROTAC estrogen receptor (ER) degrader. ER signaling drives ER positive breast cancer leading to cell division and growth.

Vepdegestrant degrades the ER that relies on estrogen signaling.

Diseases of Interest for Development:

Vepdegestrant is being developed as a potential monotherapy for estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) (ER+/HER-) advanced or metastatic breast cancer with estrogen receptor 1 (ESR1) mutations in the second line-plus setting.

Vepdegestrant is being evaluated as part of combination therapy in ER+/HER2- advanced or metastatic breast cancer.

Clinical Status:

In the pivotal Phase 3 VERITAC-2 clinical trial, vepdegestrant demonstrated a statistically significant and clinically meaningful improvement in progression-free survival versus fulvestrant among patients with an ESR1 mutation. The U.S. Food and Drug Administration (FDA) is reviewing and has filed the New Drug Application (NDA) for vepdegestrant for the treatment of patients with ER+/HER2-, ESR1-mutated advanced or metastatic breast cancer who have previously received endocrine-based therapy. The FDA has assigned a Prescription Drug User Fee Act (PDUFA) action date of June 5, 2026.

Vepdegestrant was granted Fast Track designation in February 2024 by the FDA, underscoring the significant unmet need in this patient population and the potential for vepdegestrant to offer a meaningful new treatment option.

In September 2025, Arvinas and Pfizer announced their plan to jointly select a third party for the out-licensing and commercialization of vepdegestrant.