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
William K Kelly, Daniel C Danila, Chia-Chi Lin, Jae-Lyun Lee, Nobuaki Matsubara, Patrick J Ward, Andrew J Armstrong, David Pook, Miso Kim, Tanya B Dorff, Stefanie Fischer, Yung-Chang Lin, Lisa G Horvath, Christopher Sumey, Zhao Yang, Gabor Jurida, Kristen M Smith, Jamie N Connarn, Hweixian L Penny, Julia Stieglmaier, Leonard J Appleman, William K Kelly, Daniel C Danila, Chia-Chi Lin, Jae-Lyun Lee, Nobuaki Matsubara, Patrick J Ward, Andrew J Armstrong, David Pook, Miso Kim, Tanya B Dorff, Stefanie Fischer, Yung-Chang Lin, Lisa G Horvath, Christopher Sumey, Zhao Yang, Gabor Jurida, Kristen M Smith, Jamie N Connarn, Hweixian L Penny, Julia Stieglmaier, Leonard J Appleman
Abstract
Xaluritamig (AMG 509) is a six-transmembrane epithelial antigen of the prostate 1 (STEAP1)-targeted T-cell engager designed to facilitate lysis of STEAP1-expressing cancer cells, such as those in advanced prostate cancer. This first-in-human study reports monotherapy dose exploration for patients with metastatic castration-resistant prostate cancer (mCRPC), primarily taxane pretreated. Ninety-seven patients received ≥1 intravenous dose ranging from 0.001 to 2.0 mg weekly or every 2 weeks. MTD was identified as 1.5 mg i.v. weekly via a 3-step dose. The most common treatment-related adverse events were cytokine release syndrome (CRS; 72%), fatigue (45%), and myalgia (34%). CRS occurred primarily during cycle 1 and improved with premedication and step dosing. Prostate-specific antigen (PSA) and RECIST responses across cohorts were encouraging [49% PSA50; 24% objective response rate (ORR)], with greater frequency at target doses ≥0.75 mg (59% PSA50; 41% ORR). Xaluritamig is a novel immunotherapy for prostate cancer that has shown encouraging results supporting further development.
Significance: Xaluritamig demonstrated encouraging responses (PSA and RECIST) compared with historical established treatments for patients with late-line mCRPC. This study provides proof of concept for T-cell engagers as a potential treatment for prostate cancer, validates STEAP1 as a target, and supports further clinical investigation of xaluritamig in prostate cancer. See related commentary by Hage Chehade et al., p. 20. See related article by Nolan-Stevaux et al., p. 90. This article is featured in Selected Articles from This Issue, p. 5.
©2023 The Authors; Published by the American Association for Cancer Research.
Figures
References
- Siegel RL, Miller KD, Wagle NS, Jemal A. Cancer statistics, 2023. CA Cancer J Clin 2023;73:17–48.
- Cancer Fact Sheets, Prostate . Lyon (France), Geneva (Switzerland): International Agency for Research on Cancer, World Health Organization; 2020 [cited 2023 Jul 3]. Available from: .
- Wadosky KM, Koochekpour S. Molecular mechanisms underlying resistance to androgen deprivation therapy in prostate cancer. Oncotarget 2016;7:64447–70.
- Cancer Stat Facts: Prostate Cancer; [about 4 screens]. [cited 2023 Jul 3]. Available from: .
- Turco F, Gillessen S, Cathomas R, Buttigliero C, Vogl UM. Treatment landscape for patients with castration-resistant prostate cancer: patient selection and unmet clinical needs. Res Rep Urol 2022;14:339–50.
- Gillessen S, Bossi A, Davis ID, de Bono J, Fizazi K, James ND, et al. . Management of patients with advanced prostate cancer-metastatic and/or castration-resistant prostate cancer: Report of the Advanced Prostate Cancer Consensus Conference (APCCC) 2022. Eur J Cancer 2023;185:178–215.
- Sorrentino C, Di Carlo E. Molecular targeted therapies in metastatic prostate cancer: recent advances and future challenges. Cancers (Basel) 2023;15:2885.
- Powers E, Karachaliou GS, Kao C, Harrison MR, Hoimes CJ, George DJ, et al. . Novel therapies are changing treatment paradigms in metastatic prostate cancer. J Hematol Oncol 2020;13:144.
- Merck Provides Update on Phase 3 Trials KEYNOTE-641 and KEYNOTE-789. 2023 Feb 28 [cited 2023 Jul 20] . Available from: .
- Powles T, Yuen KC, Gillessen S, Kadel EE, Rathkopf D, Matsubara N, et al. . Atezolizumab with enzalutamide versus enzalutamide alone in metastatic castration-resistant prostate cancer: a randomized phase 3 trial. Nat Med 2022;28:144–53.
- Antonarakis ES, Park SH, Goh JC, Shin SJ, Lee JL, Mehra N, et al. . Pembrolizumab plus olaparib for patients with previously treated and biomarker-unselected metastatic castration-resistant prostate cancer: the randomized, open-label, phase III KEYLYNK-010 trial. J Clin Oncol 2023;41:3839–50.
- Zhou S, Liu M, Ren F, Meng X, Yu J. The landscape of bispecific T cell engager in cancer treatment. Biomark Res 2021;9:38.
- Atallah-Yunes SA, Robertson MJ, Davé UP, Ghione P, Perna F. Novel immune-based treatments for diffuse large B-cell lymphoma: the post-CAR T cell era. Front Immunol 2022;13:901365.
- Kantarjian H, Stein A, Gökbuget N, Fielding AK, Schuh AC, Ribera J-M, et al. . Blinatumomab versus chemotherapy for advanced acute lymphoblastic leukemia. N Engl J Med 2017;376:836–47.
- Nathan P, Hassel JC, Rutkowski P, Baurain J-F, Butler MO, Schlaak M, et al. . Overall survival benefit with tebentafusp in metastatic uveal melanoma. N Engl J Med 2021;385:1196–206.
- Ravi G, Costa LJ. Bispecific T-cell engagers for treatment of multiple myeloma. Am J Hematol 2023;98:S13–21.
- Tucker MD, Zhu J, Marin D, Gupta RT, Gupta S, Berry WR, et al. . Pembrolizumab in men with heavily treated metastatic castrate-resistant prostate cancer. Cancer Med 2019;8:4644–55.
- Lim EA, Schweizer MT, Chi KN, Aggarwal R, Agarwal N, Gulley J, et al. . Phase 1 study of safety and preliminary clinical activity of JNJ-63898081, a PSMA and CD3 bispecific antibody, for metastatic castration-resistant prostate cancer. Clin Genitourin Cancer 2023;21:366–75.
- De Bono JS, Fong L, Beer TM, Gao X, Geynisman DM, Burris HA III, et al. . Results of an ongoing phase 1/2a dose escalation study of HPN424, a tri-specific half-life extended PSMA-targeting T-cell engager, in patients with metastatic castration-resistant prostate cancer (mCRPC). J Clin Oncol 2021;39:5013–13.
- Tran B, Horvath L, Dorff T, Rettig M, Lolkema MP, Machiels JP, et al. . Results from a phase I study of AMG 160, a half-life extended (HLE), PSMA-targeted, bispecific T-cell engager (BiTE®) immune therapy for metastatic castration-resistant prostate cancer (mCRPC). Ann Oncol 2020;31 Suppl 4:S507. Abstract nr 609O.
- Xu M, Evans L, Bizzaro CL, Quaglia F, Verrillo CE, Li L, et al. . STEAP1–4 (six-transmembrane epithelial antigen of the prostate 1–4) and their clinical implications for prostate cancer. Cancers (Basel) 2022;14:4034.
- Nolan-Stevaux O. AMG 509: a novel, humanized, half-life extended, bispecific STEAP1 × CD3 T cell recruiting XmAb® 2+1 antibody [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27–28 and Jun 22–24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr DDT02-03).
- Danila DC, Szmulewitz RZ, Vaishampayan U, Higano CS, Baron AD, Gilbert HN, et al. . Phase I study of DSTP3086S, an antibody-drug conjugate targeting six-transmembrane epithelial antigen of prostate 1, in metastatic castration-resistant prostate cancer. J Clin Oncol 2019;37:3518–27.
- Bhatia V, Kamat NV, Pariva TE, Wu LT, Tsao A, Sasaki K, et al. . Targeting advanced prostate cancer with STEAP1 chimeric antigen receptor T cell and tumor-localized IL-12 immunotherapy. Nat Commun 2023;14:2041.
- Lee Lab, Human Biology and Clinical Research Divisions, Cancer Consortium. Boost and attack approach for metastatic prostate cancer therapy! Fred Hutch Cancer Center . Available from: .
- Nolan-Stevaux O, Li C, Liang L, Zhan J, Estrada J, Osgood T, et al. . AMG 509 (xaluritamig), an anti-STEAP1 XmAb 2+1 T-cell redirecting immune therapy with avidity-dependent activity against prostate cancer. Cancer Discov 2024;14:90–103.
- Ball K, Dovedi SJ, Vajjah P, Phipps A. Strategies for clinical dose optimization of T cell-engaging therapies in oncology. MAbs 2023;15:2181016.
- Project Optimus. Reforming the dose optimization and dose selection paradigm in oncology; [about 4 screens]. [cited 2023 Jul 24]. Available from: .
- The Human Protein Atlas. STEAP1; [about 5 screens]. [cited 2023 Jul 24]. Available from: .
- Dickinson MJ, Carlo-Stella C, Morschhauser F, Bachy E, Corradini P, Iacoboni G, et al. . Glofitamab for relapsed or refractory diffuse large B-cell lymphoma. N Engl J Med 2022;387:2220–31.
- Neuenschwander B, Branson M, Gsponer T. Critical aspects of the Bayesian approach to phase I cancer trials. Stat Med 2008;27:2420–39.
- Scher HI, Morris MJ, Stadler WM, Higano C, Basch E, Fizazi K, et al. . Trial design and objectives for castration-resistant prostate cancer: updated recommendations from the Prostate Cancer Clinical Trials Working Group 3. J Clin Oncol 2016;34:1402–18.
- Lee DW, Gardner R, Porter DL, Louis CU, Ahmed N, Jensen M, et al. . Current concepts in the diagnosis and management of cytokine release syndrome. Blood 2014;124:188–95.
- Coiffier B, Altman A, Pui CH, Younes A, Cairo MS. Guidelines for the management of pediatric and adult tumor lysis syndrome: an evidence-based review. J Clin Oncol 2008;26:2767–78.
- Kuznetsova A, Brockhoff PB, Christensen RHB. lmerTest Package: tests in linear mixed effects models. J Stat Softw 2017;82:1–26.
- Benjamini Y, Hochberg Y. Controlling the false discovery rate: a practical and powerful approach to multiple testing. J R Stat Soc Series B Methodol 1995;57:289–300.
Source: PubMed