Xaluritamig (AMG 509) Latest Clinical Results
Xaluritamig demonstrated a 49% PSA50 response rate and 24% objective response rate across all dose cohorts in heavily pretreated metastatic castration-resistant prostate cancer (mCRPC) patients, with even more impressive results at target doses ≥0.75 mg (59% PSA50; 41% ORR), establishing it as a promising first-in-class STEAP1-targeted T-cell engager for prostate cancer. 1
Mechanism and Target
- Xaluritamig is a novel XmAb 2+1 T-cell engager with two STEAP1 binding sites and one CD3 binding site, designed to redirect T cells to kill STEAP1-expressing prostate cancer cells 2, 3
- STEAP1 expression is present in most prostate tumors and increases in metastatic castration-resistant disease, making it an ideal therapeutic target 2
- The bivalent design enables avidity-dependent selectivity for tumor cells with high STEAP1 expression while sparing normal cells with lower expression 2
Efficacy Results from First-in-Human Study
Response Rates
- Overall cohorts: 49% achieved PSA50 response (≥50% PSA decline); 24% achieved RECIST objective responses 1
- Target doses ≥0.75 mg: 59% achieved PSA50 response; 41% achieved RECIST objective responses 1
- These response rates compare favorably to historical established treatments for late-line mCRPC patients 1
Patient Population
- 97 patients with mCRPC received treatment, primarily taxane-pretreated (heavily pretreated population) 1
- Patients received intravenous doses ranging from 0.001 to 2.0 mg weekly or every 2 weeks 1
Dosing and Pharmacokinetics
Recommended Dosing
- MTD identified: 1.5 mg IV weekly via 3-step dose escalation 1
- Target doses for expansion: 0.75 mg QW, 1.5 mg QW, and 1.5 mg Q2W 3
- Administration is via intravenous infusion 1, 3
Pharmacokinetic Profile
- Dose-proportional increase in exposures across explored dose levels 3
- Terminal half-life approximately 9 days in patients without anti-drug antibodies 3
- Maximum concentration (Cmax) occurs at end of infusion (median ≈1 hour) 3
Safety Profile
Most Common Treatment-Related Adverse Events
- Cytokine release syndrome (CRS): 72% of patients 1
- Fatigue: 45% of patients 1
- Myalgia: 34% of patients 1
Safety Management Strategy
- 3-step dose escalation approach mitigates CRS risk 1
- Premedication protocols reduce CRS severity 1
- The safety profile supports continued clinical development 1
Clinical Development Status
- Xaluritamig is the first STEAP1 T-cell engager to advance to clinical testing 2
- Currently in late-phase clinical development for mCRPC 3
- Represents proof of concept for T-cell engagers as treatment for prostate cancer 1
Mechanism of Action Insights
Tumor Cell Killing
- Facilitates potent T cell-dependent cytotoxicity of prostate cancer cell lines in vitro 2
- Promotes tumor regression in xenograft and syngeneic mouse models 2
- Creates a pro-inflammatory tumor microenvironment in preclinical models 2
Unique Antigen Spreading Effect
- EGFRvIII-containing membrane vesicles can be shed from tumor cells and taken up by antigen-negative cells, allowing AMG 596 (a related BiTE molecule) to engage these cells 4
- This mechanism may extend therapeutic activity beyond cells directly expressing the target antigen 4
Clinical Significance
Xaluritamig addresses a critical unmet need in prostate cancer, where immunotherapy has historically shown limited success due to the immunosuppressive microenvironment and lack of tumor-specific targets. 2 The encouraging response rates in heavily pretreated patients, combined with a manageable safety profile dominated by early-cycle CRS that can be mitigated with step dosing, position xaluritamig as a potentially transformative therapy for mCRPC patients who have exhausted standard treatment options 1, 2.