(UroToday.com) The 2024 European Society of Medical Oncology (ESMO) Annual Congress held in Barcelona, Spain between September 13th and 17th was host to the session Poster 1598 presentation. Dr. William K. Kelly presented the initial results from a dose expansion cohorts in a phase 1 study exploring Xaluritamig, a STEAP1 x CD3 XmAb 2+1 ImmuneTherapy, in Patients with Metastatic Castration-Resistant Prostate Cancer (mCRPC).
Six transmembrane epithelial antigen of the prostate 1 (STEAP1) is a cell surface antigen highly expressed in prostate cancer, strongly expressed in >80% of mCRPC with bone or lymph node involvement, and often associated with poor survival.1 Xaluritamig is a novel bispecific XmAb® 2+1 T-cell engager targeting STEAP1 and designed to facilitate T-cell–mediated lysis of STEAP1-expressing cells, such as prostate cancer cells.
At the 2023 ESMO annual meeting, Dr. Kelly and colleagues presented results from the first-in-human, open-label study exploring the dose of xaluritamig monotherapy in patients with mCRPC. The most common adverse events were cytokine release syndrome (CRS) (72.2%), fatigue (52.6%), anemia (45.4%), pyrexia (40.2%), and myalgia (39.2%). The responses across cohorts were promising, with a 49% PSA50 response rate and a 24% objective response rate (ORR), with responses observed more frequently at doses ≥0.75 mg. (2)
At ESMO this year (2024), Dr. Kelly presented the initial results from a randomized dose-expansion study (NCT04221542) comparing three regimens to further evaluate the efficacy and safety of xaluritamig using a data cutoff of April 30, 2024.
Eligible patients had mCRPC that was refractory to prior novel hormonal therapy and 1–2 taxane regimens, with an ECOG PS of 0–1 and adequate organ function. Patients were randomized 1:1:1 to receive IV xaluritamig monotherapy with target dosing regimens of 0.75 mg weekly (QW), 1.5 mg weekly (QW), or 1.5 mg every two weeks, utilizing a 2- or 3-step dosing approach during Cycle 1. Importantly, patients who were ineligible for or declined taxane treatment were allowed to participate without prior taxane exposure. Overall, patients were limited to a maximum of 2 novel hormonal therapies, 2 taxane regimens, and 2 other systemic anti-cancer treatments. The study design and target dosing regimens are illustrated in the graphic below.
As of April 30, 2024, 106 patients had received at least one dose of Xaluritamig. The baseline demographics and clinical characteristics of these patients are shown in the table below. Briefly, most patients were of Caucasian race, the median age was 67 years (range: 37–86), 56.6% had an ECOG-PS of 1, 86% had prior taxane therapy, and 54.7% had visceral metastasis.
The safety profile observed during the dose-expansion phase was consistent with that of the dose exploration study presented last year. There were no fatal treatment-related adverse events (TRAEs). Serious TRAEs occurred in 64 patients (60.4%) and included musculoskeletal events (n = 23), CRS (n = 19), and infections (n = 9). Discontinuation of Xaluritamig due to TRAEs was observed in 16% of patients. Other frequently reported TRAEs included rash (35.8%; 5.7% grade ≥3), anemia (34.0%; 17.0% grade ≥3), and fatigue (32.1%; 9.4% grade ≥3). Grade 3 events were more frequently observed in 72% of the 1.5mg Q2W cohort, 68.6% of the 1.5mg QW cohort, and 57% of the 0.75 mg QW study group.
Cytokine release syndrome (CRS) was the most common TRAE and it was observed in 75.5% of the patients. The CRS was consistent across the dose-expansion cohorts and was most frequent in Cycle 1, with the majority of events occurring on Day 1 of Cycle 1.
The every 2 weeks (Q2W) schedule was associated with lower rates of musculoskeletal events, which were reported overall in 76.4% of patients. Rates of musculoskeletal events were lowest in the 1.5 mg Q2W cohort (69.4%) compared to 74.3% in the 0.75 mg QW cohort and 85.7% in the 1.5 mg QW cohort.
Clinical Outcomes
PSA50 (≥ 50% PSA decline) responses occurred in 47 patients (49.5%) and PSA90 (≥ 90% PSA decline) in 27 patients (28.4%). PSA responses were observed to be more frequent at higher dose levels (1.5mg) than in lower dose levels as shown in the table below. 
The figure below reflects the maximum PSA reduction at a single assessment for the different dose schedules, along with the number of patients who achieved PSA90 and PSA50 responses.
Overall, RECIST-evaluable responses included a complete response in 1 patient (1.4%) and a partial response in 13 patients (18.8%) in the dose expansion cohort. Notably, 49.3% of patients treated with Xaluritamig achieved stable disease.
The duration of response was encouraging; however, the data remains immature. The duration of PSA50 response for ≥3 months was 48.9%, while the duration of objective response for ≥3 months was 71.4%.
Dr. Kelly acknowledged some limitations of the study, including that the dosing regimens evaluated in this dose expansion study were not powered to demonstrate definitive differences in safety and efficacy, and that the durability of response and other time-to-event endpoints are not yet fully mature.
Dr. Kelly concluded his poster presentation with the following take-home points:
- In this randomized dose-optimization study, xaluritamig monotherapy 1.5 mg Q2W demonstrated the most favorable efficacy and safety profile in heavily pretreated patients with mCRPC
- The safety profile of xaluritamig was clinically manageable, with the majority of events being transient and reversible.
- Grade 3 events, such as CRS were similar across all dose regimens and allowed treatment continuation in most patients.
- There was encouraging antitumor activity in heavily pre-treated men with mCRPC.
- STEAP1 stands as a promising target in prostate cancer and xaluritamig 1.5 mg Q2W would be the recommended dose for a phase 3 trial in patients with mCRPC.
Presented by: William K. Kelly DO, Genitourinary Medical Oncology. Jefferson Health, Philadelphia, PA
Written by: Julian Chavarriaga, MD – Urologic Oncologist at Cancer Treatment and Research Center (CTIC) Luis Carlos Sarmiento Angulo Foundation via Society of Urologic Oncology (SUO) Fellow at The University of Toronto. @chavarriagaj on Twitter during the 2024 European Society of Medical Oncology (ESMO) Annual Congress held in Barcelona, Spain between September 13th and 17th
Related content: STEAP1-Targeted T-Cell Engager Demonstrates Efficacy in mCRPC Patients - William Kevin Kelly
- Bhatia, V., Kamat, N.V., Pariva, T.E. et al. Targeting advanced prostate cancer with STEAP1 chimeric antigen receptor T cell and tumor-localized IL-12 immunotherapy. Nat Commun14, 2041 (2023).
- Kelly, William K., et al. "Xaluritamig, a STEAP1× CD3 XmAb 2+ 1 immune therapy for metastatic castration-resistant prostate cancer: results from dose exploration in a first-in-human study." Cancer Discovery 14.1 (2024): 76-89.