Karie Danielle Keera Runcie, MD, is the assistant professor of medicine at Columbia University Irving Medical Center and a medical oncologist at NewYork-Presbyterian/Columbia. 

Dr Runcie on the Mechanism of Action of XmAb30819 in ccRCC

“[XmAb30819] is a 2 + 1 bispecific T-cell engager with 2 sites that bind ENPP3 and 1 site that binds CD3. It brings [these] cells together to create a cytotoxic T-cell response.”

Karie Runcie, MD, an assistant professor of medicine at Columbia University Medical Center, discussed the mechanism of action of XmAb30819 for the treatment of patients with clear cell renal cell carcinoma (ccRCC).

XmAb30819 is a bispecific T-cell engager (BiTE) that employs a 2 + 1 design, Runcie began. The BiTE has 2 sites that bind to ENPP3 and another than binds to CD3, she continued. The dual ENPP3 binding sites of XmAb30819 enable the agent to have a strong specificity for the protein on cancer cells and a lower binding affinity to normal tissue, she explained. This mechanism of action brings the ENPP3-positive cancer cells together with T cells to create a cytotoxic response, she concluded.

XmAb30819 being examined for the treatment of patients with advanced clear cell RCC in a phase 1 clinical trial (NCT05433142). The first-in-human study is enrolling patients with ccRCC who experienced disease progression following treatment with standard agents; have measurable disease per RECIST 1.1 criteria; and have an ECOG performance status of 0 or 1. The dual primary end points of the study are safety and tolerability and the incidence of dose-limiting toxicities.

Findings from preclinical studies have shown that XmAb30819 had a tolerable safety profile with dose dependent pharmacodynamics. In vitro, the BiTE demonstrated selective killing of cells with high ENPP3 expression. Moreover, in xenograft mice tumor models of ccRCC, the agent reduced the median tumor volume over time compared with phosphate-buffered saline and an anti–PD-1 monoclonal antibody. Xencor, the developer of XmAb819, plans to share full initial data from the phase 1 study at a medical conference during the 4th quarter of 2025.

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Karie Runcie, MD, discusses the mechanism of action of XmAb30819 in clear cell RCC.

Karie Runcie, MD

"The current challenges are that there's no standard regimen [after progression on adjuvant therapy]. We don't know what the most optimal regimen is. Some patients may receive [cabozantinib], some may receive [lenvatinib], and some may receive lenvatinib plus IO.”

Karie Danielle Keera Runcie, MD, an assistant professor of medicine at Columbia University Herbert Irving Comprehensive Cancer Center and medical oncologist at NewYork-Presbyterian/Columbia University Irving Medical Center, discussed current treatment approaches for patients with clear cell renal cell carcinoma (RCC) who experience disease progression during adjuvant therapy, and highlighted the potential role for the novel TKI zanzalintinib (XL092) in the treatment paradigm.

Runcie explained that there is lack of standardized treatment approaches in advanced RCC following progression on adjuvant therapy, noting that current regimens vary widely. Patients may receive cabozantinib (Cabometyx) alone, lenvatinib (Lenvima) alone, or a combination of a TKI and an immuno-oncology agent, she said. Although adjuvant pembrolizumab (Keytruda) demonstrated a disease-free survival benefit in the phase 3 KEYNOTE-564 trial (NCT03142334), recurrence remains a risk for this patient population.

Runcie emphasized that zanzalintinib , a multi-targeted TKI, demonstrates activity against VEGF signaling as well as potential immunomodulatory properties, which may distinguish it from prior agents. Data from the phase 1b STELLAR 002 trial (NCT05176483) presented at the 2025 ASCO Annual Meeting showed that zanzalintinib plus nivolumab (Opdivo) with or without relatlimab (Opdualag) was generated similar safety data compared with the checkpoint inhibitors alone in patients with advanced solid tumors, including RCC.

The ongoing phase 2 EXACT trial (NCT06863311) is further investigating zanzalintinib in combination with immunotherapy for patients with RCC who experience disease progression during adjuvant anti–PD-1/PD-L1 therapy.

Although additional prospective data are needed to validate early findings for zanzalintinib, Runcie noted that the distinct toxicity profile of the agent may offer an advantage in later-line settings where cumulative toxicity from chronic VEGF inhibition is a concern.

Karie Danielle Keera Runcie, MD, discusses treatment challenges after progression on adjuvant therapy and the potential role for zanzalintinib in renal cell carcinoma. 

Karie Danielle Keera Runcie, MD

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Dr Runcie on the Mechanism of Action of XmAb30819 in ccRCC

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