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Antibody-Drug Conjugate Combination Therapy in Patients with Metastatic Urothelial Cancer - Expert Commentary

The standard treatment for metastatic urothelial carcinoma (mUC) is platinum-based chemotherapy followed by immunotherapy. Recently, two antibody-drug conjugates (ADCs), enfortumab vedotin (EV) and sacituzumab govitecan (SG) have been approved for mUC. Due to a potential synergistic effect between the modes of action of the two drugs and non-overlapping toxicities, McGregor et al. designed a phase I clinical trial (Double Antibody Drug Conjugate, DAD) to test the safety and dosing of EV and SG for treatment-resistant mUC.

The study cohort consisted of 23 patients with a median age of 70 years. Twenty-two patients had received at least two lines of therapy while one patient had received only immunotherapy. Liver metastases were present in 26% of patients. Patients received the combination treatment at different dose levels (DLs), with nine patients in the DL1 group, eight patients in the DL2 group, and six patients in the DL3 group. The median follow-up was 14 months. Eleven patients discontinued treatment due to disease progression and one patient died before assessment in the DL3 group. Four patients elected to discontinue treatment due to neuropathic toxicity and two patients discontinued treatment due to grade 2 neuropathy.

The objective response rate was 70% (95% CI, 47 – 87) and 87% of patients exhibited any degree of tumor shrinkage. The 12-month progression-free survival and overall survival rates were 41% (95% CI, 18 – 62) and 86% (95% CI, 61 – 95), respectively. The number of dose-limiting toxicities was two in DL1, one in DL2, and three in DL3. Across the study cohort, 78% of patients experienced an adverse event (AE) of grade 3 or higher. The most common treatment-related adverse events (TRAEs) of any grade were diarrhea, anemia, neutropenia, fatigue, alopecia, neuropathy, and nausea. The most common TRAEs that were of grade 3 or higher were neutropenia (35%), anemia (35%), urinary tract infection (13%), fatigue (9%), and diarrhea (9%). Dose reduction was required in 48% of patients due to TRAEs.

The potential of combining EV and SG is promising for treating patients with mUC. Future larger clinical trials of this combination are warranted. Studies on the optimal duration and sequence of lines of treatment, and de-escalation studies for patients who develop neuropathy will also be critical.

Written by: Bishoy M. Faltas, MD, Director of Bladder Cancer Research, Englander Institute for Precision Medicine, Weill Cornell Medicine

References:

  1. McGregor BA, Sonpavde GP, Kwak L, et al. The Double Antibody Drug Conjugate (DAD) phase I trial: sacituzumab govitecan plus enfortumab vedotin for metastatic urothelial carcinoma. Ann Oncol. 2024;35(1):91-97. doi:10.1016/j.annonc.2023.09.3114
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