The Effect of Dato-DXd Targeting TROP2 in Urothelial Cancer

During the 2025 ASCO Genitourinary Cancer Symposium, CancerNetwork® spoke with Funda Meric-Bernstam, MD, the chair of the Department of Investigational Cancer Therapeutics-the Phase 1 Program, medical director of the Institute for Personalized Cancer Therapy, and the Nellie B. Connally Chair in Breast Cancer at the MD Anderson Cancer Center at the University of Texas about the phase 1 TROPION-PanTumor01 study (NCT03401385).

The TROPION-PanTumor01 study evaluated the efficacy and safety of datopotamab deruxtecan-dlnk (dato-DXd; Datroway) in patients with locally advanced or metastatic urothelial cancer that have been heavily pretreated.

When prompted about targeting TROP2, Meric-Bernstam noted that she was aware that dato-DXd did target the protein and that it has favorably compared with other agents that do as well. Though the trial didn’t specifically select patients with TROP2 expression, she acknowledged that recent research has shown, in other diseases, expression has enhanced results.

Meric-Berstam also stated that dato-DXd has shown enough activity to start considering its usage in earlier lines of treatment.

Transcript:

Of course, we were aware of TROP2 as a target, and more recently there’s been an approval and then a withdrawal of another antibody-drug conjugate [ADC] that targets TROP2. That was, at least in part, because of the challenge of managing cytopenia in a multi-center trial setting—you could see how that would be very relevant to the community setting. From that standpoint, dato-DXd very favorably compares because we don’t see cytopenia as an adverse effect, and that also enhances the possibility of combination [therapies]. From a patient selection standpoint, this trial was an unselected trial, so we did not look for TROP2 expression for enrollment. Of course, we know that TROP2 is frequently expressed, but it’s important to note, in some other diseases, data is emerging that expression may matter and we can even further enhance [that in this] space. In lung cancer, there’s the exploration of quantitative imaging with a continuous scoring strategy, so [we], more easily, have to see if we can better identify patients who would benefit even more from dato-DXd, either from the payload or because of the expression.

It's an active enough agent to start thinking about where we would have to position it. Given the exciting activity so far with enfortumab vedotin-ejfv [Padcev] and pembrolizumab [Keytruda], it’ll be interesting to see whether there’s patients who would benefit from a [TROP2] targeted instead—if we had a selection strategy. Also, we’re thinking about strategies like utilization in the adjuvant setting or potentially in the neoadjuvant setting.

References

Meric-Bernstam F, Alhalabi O, Lisberg A, et al. Datopotamab deruxtecan (Dato-DXd) in locally advanced/metastatic urothelial cancer: updated results from the phase 1 TROPIONPanTumor01 study. J Clin Oncol. 2025;43(suppl 5):663. doi:10.1200/JCO.2025.43.5_suppl.663