Abstract B006: Preliminary Phase 1 safety and antitumor activity of XmAb819, a first-in-class ENPP3 x CD3 bispecific antibody, in patients with advanced clear cell renal cell carcinoma (ccRCC)

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Abstract Background: XmAb819 is a T-cell engaging bispecific antibody in development for patients with ccRCC. Despite advances in the treatment of metastatic ccRCC, few patients are cured, and therapies exploiting novel targets are needed. Antigen screening identified ectonucleotide pyrophosphatase/phosphodiesterase family member 3 (ENPP3) as having consistent high expression in ccRCC and low expression in normal tissue. XmAb819 utilizes a multivalent 2+1 format with high-avidity bivalent binding to ENPP3 and low-affinity monovalent binding to CD3, a component of the T-cell receptor (TCR) complex. XmAb819 is engineered for preferential engagement of high ENPP3-expressing cancer cells to induce T-cell-mediated cytolysis. Methods: XmAb819-01 is a Phase 1, multicenter, dose-escalation and expansion study for patients with advanced ccRCC. Patients with previously treated relapsed or refractory ccRCC were enrolled at escalating doses of XmAb819 administered intravenously (IV). XmAb819 was administered QW until disease progression or unacceptable toxicity. Adverse events were graded using CTCAE v5.0 and cytokine release syndrome (CRS) using ASTCT Consensus Grading. Efficacy was assessed by investigator using RECIST v1.1. Results: As of June 30, 2025, 48 patients with ccRCC were enrolled in 9 cohorts; median age was 60 years, with a median of 4 prior lines of therapy (range, 1-8). The most common treatment-related adverse events (TRAEs) (≥15% any grade) were rash (90%), CRS (90%), fatigue (46%), diarrhea (35%), vomiting (31%), nausea (27%), increased aminotransferase levels (21%), pruritus (19%), chills (17%), decreased lymphocytes (17%), and pyrexia (17%). The most common (≥10%) Grade ≥3 TRAEs were decreased lymphocytes (17%), CRS (15%), and rash (13%). Rash was transient and resulted in no discontinuations. CRS most commonly followed the first dose of treatment. One dose-limiting toxicity of Grade 4 elevated liver enzymes was deemed related to treatment. No cases of treatment-related immune effector cell-associated neurotoxicity syndrome (ICANS) were observed. No treatment-related Grade 5 events were observed. Eight patients (17%) remain on treatment; 40 patients (83%) discontinued treatment, 27 (56%) due to progressive disease (PD), 4 (8%) due to clinical progression, 4 (8%) due to adverse event (increased aminotransferase levels, myocardial infarction, elevated liver enzymes, and hematuria; 1 patient each), 2 (4%) due to the patient withdrawal, and 1 (2%) each due to investigator’s decision, death (due to PD), or intolerance to treatment. Preliminary evidence of antitumor activity has been observed, including confirmed partial responses. Conclusions: XmAb819 is safe and well-tolerated at IV doses that induce antitumor activity in patients with advanced ccRCC. A recommended Phase 2 dose has not yet been determined. IV dose escalation continues. Citation Format: Sumanta Kumar. Pal, Randy F. Sweiss, Ritesh Kotecha, Karie Runcie, Mehmet Bilen, Pavlos Msaouel, David A. Braun, Scott S. Tykodi, Christopher Hoimes, Chet Bohac, Vithika Suri, Jitendra Kanodia, Engie Salama, Jacky Woo, Selam Berhe, Yuanquan Yang, Robert Franklin, Claud Grigg, Joseph Maly, Shuchi Gulati, David J. Vanderweele, Adanma Ayanambakkam, Biren Saraiya, Benjamin Garmezy. Preliminary Phase 1 safety and antitumor activity of XmAb819, a first-in-class ENPP3 x CD3 bispecific antibody, in patients with advanced clear cell renal cell carcinoma (ccRCC) [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr B006.

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