XmAb819 Exhibits Acceptable Safety in Advanced Clear Cell RCC

Initial results from an ongoing phase 1 (NCT05433142)¹ dose-escalation study reveal that XmAb819, an ectonucleotide pyrophosphatase/phosphodiesterase 3 (ENPP3) x CD3 T-cell engaging bispecific antibody, demonstrates antitumor activity and exhibits an acceptable safety profile across dose levels in patients with advanced clear cell renal cell carcinoma (RCC).² 

Of the 20 efficacy-evaluable patients (n = 20/69), 25% achieved a partial response (PR) as best response (n = 5, 4 confirmed PRs and 1 unconfirmed PR), with a 70% disease control rate (DCR). Half of the efficacy-evaluable patients (n = 10/20) remain on treatment. One patient showed a first-scan assessment of progressive disease and a subsequent 47% reduction in target lesions.²

Safety Results

The most common treatment-emergent adverse events (AEs) were primarily grade 1 or 2 cytokine release syndrome (CRS), rash, and gastrointestinal-related toxicities. These were predominantly associated with prime-step dosing in the first 4 weeks of treatment. Grade 3 AEs were rash (16%), liver enzyme elevations (7%), and CRS (4%). There was 1 case of dose-limiting toxicity of grade 4 elevated liver enzymes related to treatment.² 

Of the patients, 6% were dose-reduced due to treatment-related AEs, and 4% discontinued treatment. This included 2 patients who experienced elevated liver enzymes, and 1 patient who experienced nonfatal myocardial infarction in the presence of hypotension and CRS.²

As of the September 19, 2025, data cutoff date, patients received XmAb819 across 10 dose arms and 5 subcutaneous dose arms. Patients received a median of 4 prior lines of therapy (range, 1-8). All patients received prior anti–PD1 therapy and VEGF tyrosine kinase inhibitor therapy, with 36% of patients receiving previous treatment with a HIF2α inhibitor.

Serum levels of XmAb819 were higher than expected in 18 patients, which was investigated and linked to priming dose preparation errors that resulted from using certain ports and syringes during drug dilution. Of these 18 patients, 28% (n = 5) experienced grade 3 CRS. In 2026, a low-concentration formulation will be implemented to eliminate dosing errors.

Patient Eligibility Criteria

Patient inclusion criteria included, but were not limited to, having an ECOG performance status of 0 or 1, having an adequate tumor sample available, and having evidence of disease progression on standard-of-care therapies.¹ 

Patient exclusion criteria included, but were not limited to, receiving prior treatment with an investigational anti-ENPP3/CD203c therapy, having a history of serious allergic or anaphylactic/hypersensitivity reaction to monoclonal antibody therapy, and receiving systemic antineoplastic therapy within 5 half-lives on the first dose of study treatment.¹

“We are excited to be developing XmAb819 as a novel first-in-class ENPP3 T-cell engager that could potentially offer a much-needed new therapeutic modality for patients with advanced clear-cell [RCC] and clinicians,” Bassil Dahiyat, PhD, president and CEO of Xencor, said in a news release.² “In our first clinical presentation of dose-escalation data, XmAb819 demonstrated compelling antitumor activity and a well-tolerated safety profile in very heavily pretreated patients. We are on track with our first dose-expansion cohort now selected and are enrolling patients as we continue to dose-escalate. We are confident that we will be able to select a recommended phase 3 dose during 2026 to support the initiation of our first pivotal study in advanced [clear cell] RCC during 2027.”

REFERENCES:

1. Study of XmAb819 in subjects with advanced clear cell renal cell carcinoma. ClinicalTrials.gov. Updated July 31, 2025. Accessed October 30, 2025. https://clinicaltrials.gov/study/NCT05433142 

2. Xencor presents initial data for XmAb819, a first-in-class ENPP3 x CD3 bispecific T-cell engager, in development for clear cell renal cell carcinoma. News release. Xencor. October 24, 2025. Accessed October 30, 2025. https://tinyurl.com/3u2z5nrc