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ENPP3 offers a potentially attractive treatment target in patients with clear cell RCC.
With agents such as XmAb30819 displaying strong preclinical data and moving into examination in a phase 1 study, targeting the ENPP3 pathway could represent a novel treatment approach in patients with renal cell carcinoma (RCC) who have historically had few treatment options after experiencing disease progression on standard targeted therapies, according to Randy F. Sweis, MD, and Karie Runcie, MD.
“ENPP3 is an extracellular protein that has been found to be uniquely expressed in kidney cancer cells, making it an attractive target for kidney cancer, in particular clear cell, but also papillary kidney cancer and some other solid tumors such as colorectal cancer,” Sweis, an assistant professor of medicine at the University of Chicago Medicine in Illinois explained in an interview with OncLive®.
“One of the challenges in finding novel targets for [the treatment of patients with] solid tumors, especially with bispecific T-cell engagers [BiTEs] is finding a target that’s specific to the cancer molecule that’s not expressed widely in normal tissue [so that] you can elicit a strong, targeted response,” Runcie an assistant professor of medicine at Columbia University Medical Center in New York, New York, added in an interview with OncLive. “[ENPP3] has a high expression [rate] in clear cell kidney cancer and but low levels of expression in the gut and other areas.”
One of the ENPP3-directed agents moving through development is the novel BiTE XmAb30819. XmAb30819 is a humanized ENPP3 × CD3 BiTE designed to provide avid tumor targeting and selectivity.1
“XmAb819 is a 2+1 BiTE [that has] 2 sites which bind to ENPP3 and 1 site that binds CD3, bringing them together to create a cytotoxic T-cell response,” Runcie explained. “The point of having 2 binding sites for ENPP3 is to try and home in on that target and have a strong specificity for that molecule.”
Findings from a preclinical study demonstrated that XmAb30819 was well tolerated and showed dose-dependent pharmacodynamics in nonhuman primates.2 Additionally, the agent displayed selective killing of cells with high ENPP3 expression in vitro. In xenograft mice tumor models of clear cell RCC, the agent reduced the median tumor volume over time compared with phosphate-buffered saline and an anti–PD-1 monoclonal antibody. At day 18, increasing doses of XmAb819 led to a significant reduction in tumor volume compared with phosphate-buffered saline or an anti–PD-1 monoclonal antibody (P<.05).3
Given the strong data from preclinical studies, a phase 1 trial (NCT05433142) is underway to evaluate XmAb30819in adult patients with advanced clear cell RCC.4 The first-in-human study is enrolling patients with clear cell disease who experienced disease progression following standard therapies with measurable disease per RECIST 1.1 criteria and an ECOG performance status of 0 or 1.
During the dose escalation phase, subcutaneous and intravenous (IV) XmAb819 will be administered via a priming dose, step-up priming dose(s), and the minimum safe and biologically active dose. The agent will also be evaluated via subcutaneous and IV administration in the dose expansion phase.
The coprimary end points are safety and tolerability, and the incidence of dose-limiting toxicities. Secondary end points include objective response rate (ORR), duration of response (DOR), progression-free survival (PFS), peak plasma concentration, and area under the plasma concentration vs time curve.
“In RCC, we’ve had a tremendous advancement in the life expectancy and PFS with combination immunotherapy approaches over the past 10 years,” Sweis explained. “However, when patients progress after VEGF TKI [tyrosine kinase inhibitor] therapy and prior anti–PD-1 therapy, with or without [anti]-CTLA4, there aren’t great options. We cycle through different TKIs in the refractory space, but drugs with a novel mechanism of action are an unmet need and I believe that [XmAb819] provides that.”
Preliminary data from the phase 1 study revealed that XmAb30819 displayed initial evidence of antitumor activity in patients with clear cell RCC, including responses per RECIST 1.1 criteria.5 Additionally, the treatment duration for several patients in earlier dose cohorts was over 1 year.
In terms of safety, instances of cytokine release syndrome have been manageable, and the maximum tolerated dose has not been reached. The tolerability profile of XmAb30819 continues to support dose escalation. Xencor, the developer of XmAb30819, plans to share full initial data from the phase 1 study at a medical conference during the fourth quarter of 2025.
“We’re looking at different dosing routes, but once we select a dosing route and dose that we believe will be beneficial, we will expand into a larger cohort of [patients with] RCC,” Sweis said. “Ultimately, the goal is to bring this [drug] to other tumor types as well. In kidney cancer, papillary [disease] also has expression of ENPP3, and there are other tumor types such as colorectal cancer and non–small cell lung cancer that we’d be interested in looking at later.”
Another ENPP3 x CD3 BiTE in development is JNJ-87890387.6 The agent employs high-affinity binding to ENPP3 combined with lower-affinity CD3 binding.
Findings from a preclinical study showed that a high prevalence of ENPP3 was detected in clear cell (93%; n=193 of 208) and papillary (78%; n=32 of 41) RCC, as well as lung adenocarcinoma (50%; n=40 of 80), endometroid uterine (53%; n=62 of 118), endometroid ovarian (47%; n=15 of 32), and colorectal carcinoma (51%; n=45 of 88). JNJ-87890387 led to potent ENPP3 specific in vitro T-cell activation, T-cell-mediated cytotoxicity, and proinflammatory cytokine release across multiple ENPP3-expressing tumor cell lines. Robust antitumor efficacy, including complete regressions, was also observed in cell-derived and patient-derived xenograft models.
A phase 1 first-in-human study (NCT06178614) of JNJ-87890387 for treating patients with advanced solid tumors is ongoing.7 The trial is enrolling an estimated 200 patients with clear cell or papillary RCC, endometroid ovarian cancer, endometroid uterine carcinoma, colorectal adenocarcinoma, or lung adenocarcinoma. Patients are required to have an ECOG performance status of 0 or 1.
The study includes dose escalation and expansion phases. The primary outcome in the dose escalation portion of the study is the incidence of DLTs; safety also represents a primary outcome in both parts. Secondary outcomes include ORR, DOR, and pharmacokinetic measures.
“It’s exciting that there are multiple companies exploring this pathway, and this [will] give our patients more options,” Runcie said.
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