Xaluritamig, a STEAP1 x CD3 XmAb 2+1 immune therapy, in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC): Initial results from dose expansion cohorts in a phase I study

BackgroundXaluritamig is a novel bispecific XmAb®2+1 T-cell engager targeting STEAP1-expressing cells such as in prostate cancer. In a dose exploration study, xaluritamig monotherapy showed encouraging efficacy and manageable safety in pts with mCRPC. Here, we report the initial safety and efficacy of 3 doses and schedules to select final dose for future development.MethodsEligible pts had mCRPC refractory to ≤2 prior novel hormonal therapies and 1–2 taxane regimens (≤6 lines), ECOG PS 0–1, and adequate organ function. Pts were randomized to receive xaluritamig intravenously to reach target doses of 0.75 mg once weekly (QW), 1.5 mg QW, or 1.5 mg twice weekly (Q2W), using a 2- or 3-step dosing approach in cycle 1. Primary endpoint was safety. Secondary endpoints included efficacy, pharmacokinetics (PK), and pharmacodynamics.ResultsAs of Feb 2, 2024, of the 104 pts enrolled, 99 received xaluritamig (median follow-up: 3.9 months; range: 0.1–9.1). Median age was 67 (37–86) years; 44 pts (44.4%) had received >3 prior lines of therapy, including prior taxane (85.9%). All pts experienced treatment-related adverse events (TRAEs). Cytokine release syndrome (CRS) was the most common TRAE (77.8%), of which 76.8% events occurred in cycle 1, which resolved with standard of care management; no grade 4/5 CRS events. Common musculoskeletal inflammatory TRAEs were myalgia (60.6%; ≥ grade 3: 30.3%) and arthralgia (22.2%; ≥ grade 3: 3.0%). Efficacy results are shown in the table. Primary PK showed dose proportional increase to exposure. Table: 1598P Comparison of efficacy outcomes among the 0.75 mg QW, 1.5 mg QW, and 1.5 mg Q2W groups 0.75 mg QW 1.5 mg QW 1.5 mg Q2W Prostate-specific antigen (PSA) evaluable N = 31 N = 29 N = 29 PSA 50 response confirmed, n (%) 9 (29.0) 18 (62.1) 13 (44.8) PSA 90 response confirmed, n (%) 5 (16.1) 9 (31.0) 9 (31.0) RECIST evaluable N = 25 N = 20 N = 19 Confirmed complete response, n (%) 0 (0.0) 0 (0.0) 1 (5.3) Confirmed partial response, n (%) 2 (8.0) 3 (15.0) 4 (21.1) Stable disease, n (%) 10 (40.0) 13 (65.0) 9 (47.4) Progressive disease, n (%) 12 (48.0) 0 (0.0) 3 (15.8) Not evaluable, n (%) 1 (4.0) 4 (20.0) 2 (10.5) ConclusionsThis randomized, dose-expansion phase confirmed the safety and efficacy findings from the dose-exploration phase in pts with heavily pretreated mCRPC. A target dose of 1.5 vs 0.75 mg improved the efficacy. Grade 3 AEs were mostly transient, manageable, and allowed treatment continuation in most pts. These data support continued development of this novel immunotherapy.Clinical trial identificationNCT04221542.Editorial acknowledgementMedical writing support was provided by Manoj Kumar Goyal, PhD, of Cactus Life Sciences (part of Cactus Communications) and funded by Amgen Inc.Legal entity responsible for the studyAmgen Inc. Thousands Oaks, CA, USA.FundingAmgen Inc. Thousands Oaks, CA, USA.DisclosureW.K. Kelly: Other, Personal and Institutional, Other: Amgen, Janssen, Bayer, Exelixis, Seagen, Astellas, BioClin, Roche, Regeneron; Financial Interests, Personal, Speaker, Consultant, Advisor: Janssen, Bayer. L.J. Appleman: Financial Interests, Institutional, Local PI, Site P.I.: Amgen; Financial Interests, Institutional, Local PI, Local PI: BMS, Merck, Exelixis, Arvina, Surface Oncology, Novartis, Ipsen/Epizyme, Johnson & Johnson, BioNTech, Seagen, Peloton; Financial Interests, Institutional, Local PI, local PI: Pfizer, Genentech/Roche, Astellas; Financial Interests, Personal, Steering Committee Member, Pulmonary Hypertension Data Safety Monitoring Committee Chair: AAdi. C. Lin: Financial Interests, Personal, Other, Travel support: BeiGene, Daiichi Sankyo; Financial Interests, Personal, Advisory Board: Blueprint Medicines, Bristol Myers Squibb, Daiichi Sankyo, Novartis, AbbVie, PharmaEngine, Merck KGaA, Boehringer Ingelheim, Anbogen, IMPACT Therapeutics; Financial Interests, Personal, Invited Speaker: Eli Lilly, Novartis, Roche; Financial Interests, Personal, Other, Travel Support: IMPACT Therapeutics; Financial Interests, Institutional, Other, Local principal investigator: Nuvalent. A.J. Armstrong: Financial Interests, Personal, Other, Consultant: Astellas; Financial Interests, Personal, Advisory Board: Pfizer, AstraZeneca, Merck, Bayer, Janssen, Myovant, Telix, Z Alpha; Financial Interests, Institutional, Coordinating PI: Pfizer, Janssen, BMS, Bayer, Astellas, Pathos; Financial Interests, Institutional, Local PI: Merck, Amgen; Financial Interests, Institutional, Steering Committee Member: AstraZeneca. S.C. Fischer: Financial Interests, Institutional, Invited Speaker: Janssen; Financial Interests, Institutional, Advisory Board: Ipsen; Financial Interests, Institutional, Coordinating PI: MSD, Astellas; Other, Travel support: Bayer. D.W. Pook: Financial Interests, Personal, Invited Speaker: Bayer; Financial Interests, Personal, Advisory Board: BMS, MSD, Ipsen, Pfizer, Eisai, Astellas; Financial Interests, Institutional, Local PI: BMS, Astellas, Roche, MSD, Amgen; Financial Interests, Institutional, Coordinating PI: Pfizer, Ipsen. J.L. Perez Gracia: Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Personal, Advisory Board: MSD, Astellas; Financial Interests, Institutional, Coordinating PI, Research grant: Roche; Financial Interests, Institutional, Local PI: BMS, Amgen, Astellas, Novartis; Financial Interests, Institutional, Coordinating PI: Seattle Genetics; Financial Interests, Personal, Funding: Roche. J.L. Lee: Financial Interests, Personal, Advisory Board: Astellas Korea, AstraZeneca, Bristol Myers Squibb Korea, MSD, Merck; Financial Interests, Personal, Stocks/Shares: Merck, Johnson and Johnson, Amgen, Black Diamond Therapeutics, Zymeworks, Karyopharm Therapeutics; Financial Interests, Institutional, Local PI: Pfizer, Janssen, Novartis, Bristol Myers Squibb, Genentech, Roche, AstraZeneca, MSD, Merck, Bayer Shering Pharma, Seagen, GI Innovation, Amgen, Oscotec. D.R. Berthold: Financial Interests, Institutional, Invited Speaker: Astellas, Janssen; Financial Interests, Institutional, Advisory Board: MSD, Ipsen, Bayer, BMS, Roche. P.J. Ward: Financial Interests, Personal, Advisory Board: Amgen, Fresenius Kabi. D.E. Castellano Gauna: Financial Interests, Personal, Advisory Board: Pfizer, Roche, BMS, Janssen, Astellas, MSD, Ipsen, AstraZeneca, Novartis, GSK; Financial Interests, Institutional, Local PI: Pfizer, Roche, MSD, BMS, AstraZeneca, Janssen, Astellas, Ipsen, Exelisis, Eisai, Lilly, Bayer, GSK, Clovis, QED Therapeutics; Non-Financial Interests, Other, any: Associate Professor of Medical Oncology/Internal Medicine department; Non-Financial Interests, Personal, Other, Executive member: SOGUG (Spanish Oncology Genito-Urinary Group) Foundation; Non-Financial Interests, Personal, Training, Head of GU Alliance for Research and Development Consortium: GUARD Consortium; Other, any: Member of the Internal/local Pharmacy Commission at the Hospital Universitario 12 de Octubre. L.G. Horvath: Financial Interests, Personal, Advisory Board, Honorarium donated back to Chris O'Brien Lifehouse (My hospital): Imagion Biosystems; Financial Interests, Institutional, Invited Speaker: Astellas, Janssen, Amgen; Financial Interests, Institutional, Advisory Board: Astellas, Bayer; Financial Interests, Institutional, Invited Speaker, Bayer paid for travel to Lisbon APEX meeting and accommodation. I gave 3 talks and honorarium paid to be institution: Bayer; Financial Interests, Personal, Member of Board of Directors, No payment: ANZUP (Australia and New Zealand Urogenital and Prostate) Clinical Trials Group; Financial Interests, Personal, Full or part-time Employment, I am a medical oncologist, Director of Research and Chief Clinical Officer of this cancer centre: Chris O'Brien Lifehouse; Financial Interests, Personal, Full or part-time Employment, I am a member of the Garvan Faculty and Laboratory Head: Garvan Institute of Medical Research; Financial Interests, Personal, Stocks/Shares, Stock options: Imagion Biosystems; Financial Interests, Personal, Stocks/Shares: My Emergency Doctor; Financial Interests, Institutional, Other, I am inventor of a patent lead by my institution above: International (PCT) Patent Application No. PCT/AU2023/050849Prognostic Markers (plasma lipid prognostic signature in metastatic prostate cancer).Inventors: Horvath L, Meikle P, Scheinberg S, Lin HM, Sullivan D: Chris O'Brien Lifehouse; Financial Interests, Institutional, Research Grant: Astellas; Financial Interests, Institutional, Local PI, MK7684-001MK3475-991: MSD; Financial Interests, Institutional, Local PI, AMG160 Phase 1AMG509 Phase 1AMG757 Phase 1: Amgen; Financial Interests, Institutional, Local PI, 9785-CL-0335 (ARCHES): Astellas; Financial Interests, Institutional, Local PI, SHR3680-002: Jiangsu Hengrui Medicines; Financial Interests, Institutional, Local PI, TALAPRO2, TALAPRO3: Pfizer; Financial Interests, Institutional, Local PI, CYCLONE-2, CYCLONE-3: Eli Lilly; Financial Interests, Institutional, Steering Committee Member, ENZAMET, ENZARAD, DASL-HiCAP, GUIDE, ANZAdapt: ANZUP; Financial Interests, Institutional, Local PI, GALAHADACISPrevalence: Janssen-Cilag; Financial Interests, Institutional, Local PI, GSK204697: GSK; Financial Interests, Institutional, Local PI, XL184-021: Exelexis; Financial Interests, Institutional, Local PI, BGB-A317BGB-283BGB-A317-290: BeiGene; Financial Interests, Institutional, Local PI, FPT155-001: Five Prime; Financial Interests, Institutional, Local PI, AB928CSP0003: ARCUS; Financial Interests, Institutional, Local PI, ATG-017 and ATG-019: Antagene; Financial Interests, Institutional, Local PI, JANUX007: Janux; Financial Interests, Institutional, Local PI, Petranha: AstraZeneca; Financial Interests, Institutional, Local PI, ENZAMET, ENZA-P, Upfront PSMA, ANZAdapt, GUIDE: ANZUP; Financial Interests, Institutional, Local PI, HP-518-CS-001: Hinova; Financial Interests, Institutional, Local PI, JANX007: Janux Therapeutics; Non-Financial Interests, Leadership Role, Professor of Medical Oncology (Genitourinary cancer): University of Sydney; Non-Financial Interests, Leadership Role, Adjunct Professor: University of New South Wales. M. Kim: Financial Interests, Personal, Speaker, Consultant, Advisor: Merck Sharp & Dohme, Bristol Myers Squibb/Ono Pharmaceutical, Ipsen, Roche, Janssen, Astellas, Eisai, Bayer, Pfizer; Financial Interests, Advisory Board: Merck, Boryung Corporation, Yuhan Corporation. N. Matsubara: Financial Interests, Personal, Invited Speaker: Sanofi; Financial Interests, Institutional, Coordinating PI: Janssen, Roche, MSD, Taiho, Pfizer, Chugai; Financial Interests, Institutional, Local PI: AstraZeneca, Bayer, Astellas, Amgen, Eisai, Eli Lilly, AbbVie. M. Shabooti: Financial Interests, Institutional, Full or part-time Employment: Amgen; Financial Interests, Personal, Stocks/Shares: Amgen. Z. Yang, J. Connarn: Financial Interests, Personal, Full or part-time Employment: Amgen; Financial Interests, Personal, Stocks/Shares: Amgen. J. Stieglmaier: Financial Interests, Personal, Full or part-time Employment: Amgen Research (Munich) GmbH; Financial Interests, Personal and Institutional, Other support: Amgen. D.C. Danila: Financial Interests, Institutional, Research Funding: U.S. Department of Defense; Financial Interests, Personal and Institutional, Research Funding: ASCO, The Prostate Cancer Foundation, Stand Up To Cancer, Amgen Inc., Janssen Research & Development, Astellas, Medivation, Agensys, Genentech, CreaTV; Financial Interests, Personal, Speaker, Consultant, Advisor: Angle LLT, Janssen Research & Development, AstraZeneca, BioView Ltd., Clovis, Astellas, Medivation, Pfizer, Agensys, Merck. All other authors have declared no conflicts of interest.