Xaluritamig (AMG 509), a novel STEAP1-targeted T-cell engager, has shown promising efficacy in patients with advanced metastatic castration-resistant prostate cancer (mCRPC), according to findings presented at ESMO 2024. The drug's unique mechanism facilitates T-cell-mediated killing of STEAP1-expressing cells, offering a potential new treatment option for patients with limited alternatives.
Mechanism and Dosing Optimization
Xaluritamig is designed with two epitopes that bind to STEAP1 and CD3, enhancing its ability to target and eliminate prostate cancer cells. Initial dose escalation studies defined the maximum tolerated dose (MTD) as 1.5 mg. Subsequent dose optimization efforts focused on refining the dosing schedule to improve tolerability and reduce adverse events. The optimized schedule involves step dosing to 1.5 mg, administered every other week, which has shown to mitigate toxicities compared to weekly dosing.
Patient Population and Prior Treatments
The study population consisted of patients with very advanced mCRPC who had progressed on prior novel hormonal therapy and one to two taxane-based therapies. On average, patients had received four or more therapies in the metastatic castration-resistant setting, highlighting the heavily pretreated nature of this cohort. Approximately one-third of the patients had liver metastases, a particularly challenging subgroup to treat.
Safety and Tolerability
Cytokine release syndrome (CRS), a common concern with T-cell engagers, was observed in approximately 75% of patients. However, the CRS was generally mild and primarily occurred during the first dose cycle. Pre-dosing with steroids and monitoring patients for the first 24 hours in the hospital effectively managed the CRS. Tocilizumab was available to reverse CRS if needed. Musculoskeletal inflammatory adverse events were noted in around 76% of patients, typically occurring three to four weeks after dosing. These events improved with drug discontinuation, steroids, or tocilizumab, and were less frequent with every-other-week dosing.
Efficacy Outcomes
Clinical trials have demonstrated deep PSA responses, with PSA 90 responses ranging from 20% to 30% and PSA 50 responses ranging from 36% to 60%. RECIST responses varied from 14% to 28% across different cohorts. Notably, approximately 20% of patients with liver metastases experienced an overall response in the liver. Median radiographic progression-free survival was 7.7 months, with higher doses (0.75 mg and above) showing improved outcomes, including a 40% overall RECIST response and an 8.3-month median radiographic progression-free survival.
Long-Term Survival
Long-term follow-up data from 97 patients in the dose escalation study, with a median follow-up of 27.9 months, revealed a median overall survival of 17.7 months. This compares favorably to the VISION trial, which reported an overall survival of 15.3 months with Lutetium-177 PSMA-617. These results suggest that Xaluritamig can provide durable responses and extend survival in heavily pretreated mCRPC patients.
Phase 3 Trial Plans
A phase 3 trial is planned to evaluate Xaluritamig in a randomized, two-to-one design against either cabazitaxel or an AR switch. The trial will enroll 675 patients who have progressed on an AR inhibitor and one prior chemotherapy regimen, and who may have also received prior radioligand therapy. This trial aims to establish Xaluritamig as a potential new standard of care in the treatment of advanced prostate cancer.
Clinical Implications
William Kevin Kelly, DO, from Thomas Jefferson University, noted that Xaluritamig has the potential to be practice-changing, particularly in breaking the barrier of effective therapies in late-stage prostate cancer. While acknowledging the challenges associated with musculoskeletal toxicities, Dr. Kelly emphasized the encouraging data and the excitement surrounding the drug's advancement. Oliver Sartor, MD, from Mayo Clinic, highlighted the comparable activity to PSMA-lutetium and the potential for utility in multiple settings. Further research is needed to optimize sequencing and combination strategies with other therapies, including Pluvicto, to maximize patient benefits.
