Xencor (NASDAQ:XNCR) reported updated Phase 1 dose-expansion results for its ENPP3-targeting CD3 T-cell engager, XmAb819, in previously treated advanced clear cell renal cell carcinoma at the ESMO 2026 conference. The company said it selected a 400 microgram-per-kilogram intravenous target dose for planned late-stage development and expects to begin a registration-enabling study in 2027.
XmAb819 is an XmAb 2+1 bispecific antibody designed to bind ENPP3 with two tumor-targeting arms and CD3 with one arm to direct T cells toward tumor cells. Xencor said the format is intended to distinguish between tumor cells with high ENPP3 expression and normal cells with lower expression. ENPP3 is strongly and uniformly expressed in clear cell renal cell carcinoma, according to the company, and the program has also opened cohorts in papillary renal cell carcinoma, microsatellite-stable colorectal cancer and non-squamous non-small cell lung cancer for patients whose tumors show strong ENPP3 expression by immunohistochemistry.
Phase 1 activity across dose cohorts
Reported outcomes across the intravenous target-dose cohorts included:
- 100 micrograms per kilogram: 30% objective response rate and 86.7% disease control rate, with median follow-up of 4.1 months.
- 200 micrograms per kilogram: 44% objective response rate and 64% disease control rate, with median follow-up of about 4.5 months.
- 400 micrograms per kilogram: 45.5% objective response rate and 81.8% disease control rate.
Pal said the 400 microgram-per-kilogram group showed tumor shrinkage in nearly all patients and included ongoing responses. Among patients who had previously received a checkpoint inhibitor, a VEGF-TKI and a HIF-2 inhibitor, the reported response rate was approximately 35% and disease control rate was 78%. In a subgroup that had received two or more prior VEGF-TKIs, the response rate was 45.2% and disease control rate was 85.7%.
Xencor’s updated October 1 data cut showed a pooled median time on treatment of 7.9 months across the expanded intravenous dose cohorts. The company said approximately 25% of responses occurred after more than four months on treatment and that responses continued to deepen over time in some patients. At the 400 microgram-per-kilogram dose, Xencor reported that more than 70% of patients remained on treatment with more than six months of median follow-up and cited an 82% six-month progression-free-survival Kaplan-Meier estimate.
Safety and dose selection
Pal characterized cytokine release syndrome, rash and transaminase elevations as adverse events of special interest. He said cytokine release syndrome was predominantly low-grade, occurred mainly during priming doses and diminished substantially at target dosing. Rash was described as an on-target effect associated with ENPP3 expression on basophils and mast cells and was generally managed with antihistamines and oral or topical steroids.
According to Pal, dose delays due to rash occurred in about 4.5% of patients, with no treatment discontinuations attributed to rash. Transaminase elevations were asymptomatic, transient and largely self-limited, with a median time to resolution of seven days; about 15% of patients had dose delays for transaminase elevations, also without treatment discontinuations.
The company said it has added prophylactic cetirizine, dexamethasone and a single dose of tocilizumab before the first priming dose to help manage early cytokine-related effects. Bassil Dahiyat, Xencor’s president and chief executive officer, said the company has begun or is preparing a reduced-monitoring cohort intended to evaluate removal of overnight stays for later priming and target doses.
Jeff Chou, senior vice president and head of clinical development for oncology programs, said Xencor chose the 400 microgram-per-kilogram intravenous dose as its putative recommended Phase 3 dose based on the efficacy trend, disease-control results and a safety profile that appeared largely consistent with lower-dose cohorts. The company said it expects to present additional data once more than 20 patients treated at that dose have further follow-up.
Regulatory and development plans
Xencor plans to hold an end-of-Phase-1 meeting with the U.S. Food and Drug Administration in the first half of 2027. The company intends to discuss both a potential accelerated-approval pathway and a randomized registration-enabling study designed for full approval.
For the proposed confirmatory study, Xencor expects to compare XmAb819 monotherapy with tivozanib in advanced clear cell renal cell carcinoma after prior PD-1 or PD-L1 inhibitor and VEGFR-TKI exposure. Chou said the company plans to power the trial for a progression-free-survival hazard ratio of 0.7. Xencor cited the third-line subgroup from the TIVO-3 study as relevant context, noting reported tivozanib outcomes of a 10.5% objective response rate, 41% six-month progression-free-survival estimate and 5.4-month median progression-free survival.
Dane Leone, Xencor’s chief strategy officer, said an accelerated-approval submission could potentially rely on a single-arm data set in more heavily pretreated subgroups, subject to discussions with regulators. He said the company expects a safety database of roughly 100 patients to be a typical consideration for such a pathway, while the efficacy analysis could require fewer patients depending on response-rate confidence intervals.
Xencor also plans to report subcutaneous XmAb819 data in the first half of 2027. The company said it will determine after reviewing those results whether to use subcutaneous administration in subsequent development, pursue it as a lifecycle option, or continue with intravenous administration alone.
About Xencor (NASDAQ:XNCR)
Xencor, Inc is a clinical-stage biopharmaceutical company headquartered in Monrovia, California. Founded in 1997, the company develops engineered antibodies and other biologic medicines for the treatment of cancer, autoimmune disorders and other serious diseases.
Xencor’s research is centered on its XmAb technology platform, which is designed to modify antibodies to improve their therapeutic properties or create new antibody-based mechanisms. The platform supports the development of bispecific antibodies, immune-cell engagers and antibodies with extended activity in the body.
