Datopotamab deruxtecan enters phase 3 trial in high-risk muscle-invasive urothelial cancer

The first patient has been dosed in TROPION-Urothelial04, a global phase 3 trial evaluating the TROP2-directed antibody-drug conjugate (ADC) datopotamab deruxtecan (Datroway), alone or in combination with the investigational PD-1/TIGIT bispecific antibody rilvegostomig, as adjuvant treatment for patients with high-risk muscle-invasive urothelial cancer (MIUC) following radical surgical resection with or without prior neoadjuvant therapy.¹

The study will compare both investigational strategies with currently used adjuvant approaches, consisting of nivolumab (Opdivo), durvalumab (Imfinzi), or enfortumab vedotin-ejfv (Padcev) plus pembrolizumab (Keytruda).

The trial is being initiated as treatment options for MIUC continue to expand across the perioperative setting. Adjuvant nivolumab has demonstrated a DFS benefit after radical surgery,² and recent phase 3 data have established additional perioperative immunotherapy-based strategies, including durvalumab with gemcitabine and cisplatin and enfortumab vedotin plus pembrolizumab.^3,4 TROPION-Urothelial04 will test whether adding a TROP2-directed ADC, with or without a dual checkpoint inhibitor, can further reduce recurrence in this setting.

“Patients with muscle invasive urothelial cancer continue to face a significant risk of disease recurrence despite recent new advances,” said Leora Horn, MD, FRCPC, senior vice president, late development oncology, AstraZeneca, in a news release.¹ “TROPION-Urothelial04 will allow us to further evaluate the potential of Datroway in combination with rilvegostomig to help advance treatment approaches and move closer to a cure for these patients with significant unmet need.”

Trial overview

TROPION-Urothelial04 (NCT07720284) is a global, open-label, phase 3 study that is expected to enroll approximately 915 adult patients with high-risk MIUC. Participants will be randomly assigned in a 2:1:2 ratio to datopotamab deruxtecan plus rilvegostomig, datopotamab deruxtecan monotherapy, or investigator-selected standard of care consisting of nivolumab, durvalumab, or enfortumab vedotin plus pembrolizumab.

Eligibility requires an R0 radical resection with negative margins and no evidence of residual or metastatic disease at enrollment.⁵ Patients who did not receive neoadjuvant therapy must have pathologic stage pT3-pT4aN0 disease or any pT stage with node-positive disease. Patients who received neoadjuvant therapy must have ypT2-ypT4a disease or any ypT stage with node-positive disease.

The primary end point is investigator-assessed disease-free survival (DFS) for datopotamab deruxtecan plus rilvegostomig compared with standard of care. Key secondary measures include DFS by blinded independent central review, disease-specific survival, non-urothelial tract recurrence-free survival, distant metastasis-free survival, patient-reported outcomes, overall survival, and safety.

Datopotamab deruxtecan is administered intravenously at 6 mg/kg every 3 weeks. In the combination arm, rilvegostomig is administered at 750 mg every 3 weeks. Datopotamab deruxtecan is planned for at least 9 cycles and may be extended to 17 cycles or 1 year based on tolerability, while rilvegostomig is planned for up to 17 cycles or 1 year, whichever occurs first.

The study’s estimated primary completion date is September 2030.

Datopotamab deruxtecan and rilvegostomig

Datopotamab deruxtecan is a TROP2-directed ADC that links a humanized anti-TROP2 monoclonal antibody to the topoisomerase I inhibitor DXd. The agent is currently approved in the US for certain patients with unresectable or metastatic triple negative breast cancer and for certain patients with = HR-positive/HER2-negative breast cancer. The drug is also indicated for previously treated EGFR-mutated locally advanced or metastatic non–small cell lung cancer.

Rilvegostomig is an investigational bispecific antibody designed to inhibit both PD-1 and TIGIT signaling.

Datopotamab deruxtecan is also being evaluated in combination with platinum-based chemotherapy vs gemcitabine plus platinum-based chemotherapy in patients with metastatic urothelial carcinoma following progression during or after treatment with enfortumab vedotin and pembrolizumab in the phase 2/3 TROPION-Urothelial03 trial.

Neither datopotamab deruxtecan nor rilvegostomig have been approved in the US for MIUC.

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