What is AMG 509 (Xaluritamig)?
AMG 509, also known by its generic name xaluritamig, is an investigational drug being developed by Amgen for the treatment of metastatic castration-resistant prostate cancer (mCRPC) [1.2.1, 1.2.2]. It belongs to a class of drugs called bispecific T-cell engagers (BiTEs). These are a type of immunotherapy designed to harness the power of a patient's own immune system to fight cancer [1.3.6]. Specifically, xaluritamig is the first T-cell engager targeting STEAP1 to be tested in clinical trials [1.2.2, 1.4.9]. The research focuses on patients with advanced prostate cancer who have already been treated with other therapies, such as novel hormone therapy and taxane-based chemotherapy [1.2.1].
The Science Behind AMG 509: Mechanism of Action
Xaluritamig works by acting as a bridge between two different cells: a cancer cell and a T-cell [1.3.6]. It is a "bispecific" antibody, meaning it has two different ends. One end binds to a protein called CD3, which is found on the surface of T-cells (a type of immune cell that kills harmful invaders) [1.3.8]. The other end binds to a protein called Six-Transmembrane Epithelial Antigen of the Prostate 1 (STEAP1), which is highly expressed on the surface of most prostate cancer cells [1.3.5, 1.4.7].
By simultaneously grabbing onto both the T-cell and the cancer cell, AMG 509 brings them into close proximity. This engagement activates the T-cell, directing it to recognize the cancer cell as a threat and destroy it through a process called T-cell–mediated lysis [1.2.1, 1.3.2]. This innovative mechanism provides a targeted way to turn the body's immune response directly against the tumor [1.2.2]. The molecule, an XmAb 2+1 antibody, has two binding sites for STEAP1, which increases its binding strength (avidity) and helps it preferentially target tumor cells with high STEAP1 expression over normal tissues that may have low levels of the protein [1.2.2, 1.6.6].
What is the Target? Understanding STEAP1
STEAP1 is a protein found on the cell surface that is highly overexpressed in prostate cancer, especially in metastatic, castration-resistant forms of the disease [1.4.7, 1.3.8]. While it's also found at low levels in some normal tissues, its high prevalence on cancer cells makes it an attractive target for cancer therapies [1.3.8]. By targeting STEAP1, AMG 509 can selectively seek out and promote the destruction of prostate cancer cells while largely sparing healthy cells [1.2.2]. The development of AMG 509 helps validate STEAP1 as a viable therapeutic target in the fight against advanced prostate cancer [1.2.3].
Clinical Development and Efficacy
AMG 509 (xaluritamig) is being evaluated in a first-in-human Phase 1 clinical trial (NCT04221542) for patients with heavily pretreated mCRPC [1.2.1, 1.3.8]. The primary goals of this study are to determine the drug's safety, tolerability, and the recommended Phase 2 dose (RP2D) [1.4.7]. The trial involves administering the drug intravenously (IV) and has also explored subcutaneous (SC) delivery [1.4.4].
Early results have been encouraging. In a study of 97 patients, xaluritamig demonstrated significant anti-tumor activity [1.2.3]. Key findings include:
- PSA Response: 49% of patients had a prostate-specific antigen (PSA) decline of 50% or more (PSA50) [1.2.3]. This rate increased to 59% in patients receiving target doses of 0.75 mg or higher [1.2.3].
- Objective Response Rate (ORR): Across all cohorts, the ORR was 24% based on RECIST criteria (a standard way to measure tumor shrinkage) [1.2.3]. This improved to 41% in the higher-dose groups [1.2.3].
- Duration of Response: The median duration of response was reported as 9.2 months, indicating a durable effect for responders [1.4.9].
These results are promising for a patient population with advanced disease that has already progressed on multiple other treatments [1.4.9]. Active clinical trials are ongoing, including a Phase 3 study comparing xaluritamig to other standard therapies [1.2.8].
Safety Profile and Side Effects
Like many immunotherapies that activate T-cells, AMG 509 has a notable side effect profile. The most common treatment-related adverse event is Cytokine Release Syndrome (CRS), which occurred in 72% of patients in the Phase 1 trial [1.2.3, 1.5.1]. CRS is an inflammatory response that can cause symptoms like fever, fatigue, and myalgia (muscle pain). Importantly, most CRS events were low-grade (Grade 1 or 2) and occurred primarily during the first cycle of treatment [1.2.1, 1.4.9]. The side effects have been deemed clinically manageable with premedication and a step-up dosing schedule, where patients receive smaller initial doses before escalating to the target dose [1.4.9, 1.5.4].
Other common treatment-related side effects include:
- Fatigue (45-52.6%) [1.2.3, 1.5.1]
- Myalgia (muscle pain) (34-60.6%) [1.2.3, 1.5.7]
- Pyrexia (fever) (32-40.2%) [1.5.4, 1.5.1]
- Anemia (45.4%) [1.5.1]
AMG 509 vs. Other Prostate Cancer Therapies
Xaluritamig represents a new mechanistic class for treating mCRPC. Here is how it compares to some existing treatments:
| Therapy | Mechanism of Action | Primary Target | Administration | Key Side Effect Profile |
|---|---|---|---|---|
| AMG 509 (Xaluritamig) | Bispecific T-cell Engager (BiTE) | STEAP1 on cancer cells, CD3 on T-cells [1.2.2, 1.3.5] | Intravenous [1.4.6] | Cytokine Release Syndrome, fatigue, myalgia [1.2.3] |
| Androgen Receptor Inhibitors (e.g., Enzalutamide) | Blocks testosterone from binding to its receptor | Androgen Receptor [1.3.2] | Oral | Fatigue, hypertension, falls |
| Taxane Chemotherapy (e.g., Docetaxel) | Interferes with cell division | Microtubules in all rapidly dividing cells | Intravenous | Neutropenia, fatigue, neuropathy, hair loss |
| Radioligand Therapy (e.g., Lutetium-177 vipivotide tetraxetan) | Delivers radiation directly to cancer cells | PSMA on cancer cells | Intravenous | Fatigue, dry mouth, nausea, bone marrow suppression |
Conclusion
AMG 509 (xaluritamig) is a first-in-class, STEAP1-targeting bispecific T-cell engager that has shown encouraging anti-tumor activity in heavily pretreated patients with metastatic castration-resistant prostate cancer [1.2.1, 1.2.2]. Its novel mechanism of redirecting the patient's own immune system to kill cancer cells offers a new strategy in a field where immunotherapies have had limited success [1.2.2]. While side effects like Cytokine Release Syndrome are common, they have been found to be generally low-grade and manageable [1.4.9]. Ongoing clinical trials will further define its efficacy and role in the evolving landscape of prostate cancer treatment [1.2.8].
