Safety and Antitumor Activity Revealed for T-Cell Engager XmAb819 in RCC

The first-in-class T-cell engager XmAb819 demonstrated a well-tolerated safety profile and early antitumor activity in patients with clear cell renal cell carcinoma (ccRCC), according to findings of a phase 1 trial (NCT05433142) presented during the International Kidney Cancer Symposium 2025 in Denver, Colorado.¹

“The toxicity profile was relatively easy to manage, with largely grade 1 or 2 cytokine release syndrome and no immune effector cell-associated neurotoxicity syndrome,” Sumanta Kumar Pal, MD, said during the presentation of data. “Patients treated in the target-dose range demonstrated a 25% objective response rate,” continued Pal, who is codirector of the Kidney Cancer Program, professor in the Department of Medical Oncology & Therapeutics Research, and vice chair of academic affairs at City of Hope, Duarte, California.

The transmembrane protein ENPP3 is highly expressed in renal cell tissue as compared with adjacent normal cells, and XmAb819 offers a specific mode of action against the protein. The agent offers 2 sites of binding, allowing for more selective binding to tumor cells.¹

The study, following a 3+3+3 dose-escalation design, will determine safety, tolerability, recommended dose, pharmacokinetics, and antitumor activity in patients with relapsed/refractory ccRCC. Eligible patients were over 18 years of age, received prior treatment with checkpoint inhibitors and VEGF tyrosine kinase inhibitors (TKIs), and with no prior anti-ENPP3 therapy.

A total of 11 cohorts comprised of 69 patients were randomly assigned, with cohorts 1 to 7 in the below-target dose range (low-dose cohorts) and cohorts 8 to 11 in the target dose range (high-dose cohorts). All patients received intravenous therapy during the priming portion of the study but during cycle 1, patients in cohorts 1 to 6 received the agent subcutaneously.

Pharmacokinetic data revealed a half-life of 8.7 days and a bioavailability in the range between 55% to 70%. “We feel that we achieved steady state drug concentrations in cohorts 9 and 10, which is the target dose range that we were aiming for,” Pal said.

Baseline Characteristics

Patients were a median age of 60 years (range, 34-77), 80% were male, 88% were White, and the time since initial diagnosis was 53.6 months (range, 8-259). Ten percent of patients had sarcomatoid features, and 32% had a favorable IMDC risk score at baseline.

Thirty-eight percent of patients had 5 or greater prior lines of therapy. All patients who received prior therapy were treated with a checkpoint inhibitor and a VEGF TKI, with 61% receiving 2 TKIs, and 36% receiving a HIF-2α inhibitor.

“Eighty-eight percent of patients in the study had very high levels of ENPP3 membrane expression,” Pal said. “That underscores the rationale for us to include all patients, irrespective of baseline ENPP3 expression regarding patient disposition,” he continued.

Pal explained that there was a low rate of discontinuation due to adverse events (AEs), with about 25% of patients remaining on study. Fifty-five percent discontinued treatment based on disease progression and 9% based on clinical progression but only 4% discontinued because of AEs.

Safety Profile

Seventy percent of patients (n = 68) reported grade 3 or greater toxicities, with 51% reporting serious treatment-related AEs (TRAEs). Dose reduction occurred in 6% of patients, and only 4% of patients reported treatment discontinuation.

“One of the unique toxicities associated with this bispecific antibody is rash,” Pal said. “The investigators came together to define what I think is a good working strategy for managing rash that includes administration of antihistamines and corticosteroids,” Pal continued.

He noted that once patients made it through the priming phase and entered the maintenance phase of the study, “it tends to be smooth sailing with limited fatigue, rash, and other toxicities at that point.”

Efficacy Findings

Patients in the low-dose cohorts (n = 38) demonstrated signals of antitumor activity with one patient experiencing a partial response, 14 experiencing progressive disease, and 16 experiencing stable disease, 3 of which were ongoing. Four patients were excluded because they did not have post-baseline scans, and 3 patients had nonevaluable post–baseline measurements.

In the target dose cohorts (n = 20), there were 5 patients with partial response, 9 with stable disease, and 6 with disease progression. “Despite patients being heavily pretreated, patients have achieved very deep responses,” Pal said.

“Looking at efficacy in a different way, among the 20 patients in the target-dose range, we see a 25% response rate with a stable disease rate of 45%,” Pal said. “This amounts to a disease control rate of 70% in this cohort. Although these are early days with patients in the target dose range, I’m hoping we see continuation of these exciting data,” Pal said.

“Overall, I think these data are encouraging. We’re excited about ongoing assessments of XmAb819 in other tumor types, and we look forward to its potential use in combination therapy,” Pal concluded.

REFERENCE

Pal KM, Sweis RF, Kotecha RR, et al. XmAB819-01: preliminary results from a dose-escalation study of ENPP3 targeted, CD3 bispecific antibody XmAb819 in patients with clear cell renal cell carcinoma. Presented at: 2025 International Kidney Cancer Symposium: North America; November 13-15, 2025; Denver, Colorado.