1175 Combining PSMAxCD28 costimulatory T cell engager (TCE) JNJ-87189401 with pasritamig (KLK2xCD3): first-in-human phase 1 results of a dual-antigen targeted TCE regimen in prostate cancer
Year: 2026
Type: conference-abstract
Abstract: Background Prostate cancer is an immunologically ‘cold’ tumor, showing limited clinical benefit with immune checkpoint inhibitors. Optimal T-cell activation requires both T-cell receptor engagement (‘signal 1’) and co-stimulation (‘signal 2’). JNJ87189401 (JNJ-9401) is a novel PSMA x CD28 costimulatory TCE designed to synergize with pasritamig, a first-in-class KLK2 x CD3 TCE, potentiating T-cell activation and anti-tumor activity. In preclinical models, this combination demonstrated increased and sustained T-cell activation, improved function and synergistic antitumor efficacy compared to pasritamig alone ( figure 1). We present results from the first-in-human study of JNJ9401 plus pasritamig, the first dual tumor antigen (KLK2 and PSMA)-targeting TCE regimen in prostate cancer.Methods This openlabel, multicenter Phase 1 study ( NCT06095089) is enrolling adults with metastatic castration-resistant prostate cancer (mCRPC) after ≥1 prior systemic therapy. In Part 1, JNJ9401 was doseescalated in participants receiving fixed-dose pasritamig. Primary objectives were safety and recommended Phase 2 regimen (RP2R) determination. Dose expansion (Part 2) was initiated at RP2R, including a frontline mCRPC cohort.Results As of June 15, 2026, 144 participants were enrolled. In Part 1, participants were heavily pretreated (median 4 prior systemic therapies: 71% taxane; 52% PSMA radioligand therapy); 17% had visceral disease. Among all participants, TRAEs occurred in 64%, mostly low grade (12.5% Grade ≥3). RP2R was determined to be JNJ9401 200 mg SC Q6W plus pasritamig 300 mg IV Q6W (following 2 weekly pasritamig step-up doses).Fifteen participants received ≥1 dose of JNJ-9401 at RP2R in Part 1. At RP2R, there were no dose-limiting toxicities, Grade ≥3 TRAEs, or discontinuations due to AEs. Cytokine release syndrome occurred in 20% of participants (all Grade 1; transient fever only; none required tocilizumab). No immune effector cell-associated neurotoxicity syndrome occurred. PSA50 and PSA90 rates were 73% and 47% (figure 2; 82% and 55% in participants with non-visceral disease; n = 11). At RP2R, 4/15 participants achieved an undetectable PSA (< 0.2 ng/dL). Among participants in Part 1 with a PSA90 response across all doses, 23/30 (7/7 at RP2R) remained on treatment for ≥6 months without disease progression.Conclusions These results provide the first clinical evidence that co-targeting KLK2 and PSMA with concurrent CD3 engagement and CD28-based costimulation with TCEs can augment antitumor activity in prostate cancer. The novel combination of pasritamig (KLK2 x CD3) and JNJ9401 (PSMA x CD28) preserved the favorable safety profile of pasritamig monotherapy and supports Q6W outpatient dosing, while eliciting more frequent, deeper, and durable clinical responses. 1 Pasritamig ± JNJ-9401 is being evaluated in the Phase 3 KLK2-comPAS study (NCT07164443).Acknowledgements We are grateful to the patients, their families/caregivers, and the clinical trial teams for their contribution to this study. Medical writing support was provided by Laura Ganser, PhD, and Grace Orstad, PhD, of Lumanity Communications Inc, under the direction of the authors and in accordance with Good Publication Practice guidelines (Ann Intern Med. 2022;175:1298 1304) and was funded by Johnson & Johnson.Trial Registration ClinicalTrials.gov ID: NCT06095089Reference Stein MN, Vinceneux A, Robbrecht D, et al. Pasritamig, a first-in-class, bispecific T-cell engager targeting human kallikrein 2, in metastatic castration-resistant prostate cancer: a phase I study. J Clin Oncol. 2025;43(22):2515-2526.Ethics Approval Participants provided written informed consent before taking part in the study. Ethics committee (EC) or Institutional Review Board (IRB) approvals: Columbia University Medical Center IRB - IRB-AAAU8797; Salus IRB - START2023.03 & NJEB2025.04; WCG IRB – 20235625; Advarra - Pro00092550: Sabai IRB - RM 1038; Oregon Health & Science University IRB - STUDY00029735; UT MD Anderson Cancer Center IRB - 2025-1971; Advocate Health Wake forest University School of Medicine IRB - IRB0143444; University of Minnesota IRB - STUDY00027319; First Affiliated Hospital of Wenzhou Medical College IRB/EC 2026 128; Ethics Committee of Chongqing Cancer hospital - CZLL2026-225-001; The Cancer Institute Hospital of JFCR IRB - 2025-0122; Peter MacCallum Cancer Centre Ethics Committee and Research Goverance Committee – 127875; Bellberry 2026-03-464 and Ramsay Health Pindara Private Hospital - 2026/RGO/0121; Institut Gustave Roussy, Centre Leon Berard and Institut Bergonie - 2023-50406317-00.Abstract 1175 Figure 1Mechanism of action of JNJ-9401 + pasritamig (KLK2xCD3) TCE doubletAbstract 1175 Figure 2Maximum reduction in PSA from baseline at RP2R in Part 1
Authors: Laura S Graham, Christophe Massard, Drew W Rasco, W Kevin Kelly, Armelle Vinceneux, Diego Teyssonneau, Shahneen Sandhu, Sumit K Subudhi, Mehmet A Bilen, Aaron R Hansen, Alexandra O Sokolova, Earle F Burgess, Jeffrey Russell, Nicholas A Zorko, Song Zhao, Shigehisa Kitano, Wei Chen, Bruno S Fang, Leanne Cartee, Debopriya Ghosh, Daksh Thaper, Jessica E Hawley, Josh Lauring, Fei Shen, Trishala Agrawal, Charles G Drake, Mark N Stein
Institutions: University of Colorado Anschutz, Institut Gustave Roussy, South Texas Accelerated Research Therapeutics, Thomas Jefferson University, Sidney Kimmel Cancer Center, Centre Léon Bérard, Institut Bergonié, Peter MacCallum Cancer Centre, The University of Texas MD Anderson Cancer Center, Winship Cancer Institute, The University of Queensland, Princess Alexandra Hospital, Oregon Health & Science University, Wake Forest Baptist Comprehensive Cancer Center, Tennessee Oncology, Masonic Cancer Center, Swedish Medical Center, The Cancer Institute Hospital, Japanese Foundation For Cancer Research, Johnson & Johnson (United States), Columbia University Irving Medical Center, Herbert Irving Comprehensive Cancer Center
Language: English
Subfield: Cancer Research
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $2,490
OpenAlex ID: W7225410861