Dr McGregor on the Rationale for the DAD Trial in Metastatic Urothelial Cancer

Bradley McGregor, MD, senior physician, clinical director, Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, and instructor of medicine, Harvard Medical School, discusses the rationale for conducting the phase 1 Double Antibody-Drug Conjugate (DAD) trial (NCT04724018) investigating sacituzumab govitecan-hziy (Trodelvy) in combination with enfortumab vedotin-ejfv (Padcev) for patients with treatment-resistant metastatic urothelial cancer (mUC).

The initial rationale for the DAD trial stemmed from the significant role that antibody-drug conjugates (ADCs) play in the management of urothelial carcinoma, McGregor begins. Enfortumab vedotin and sacituzumab govitecan have both demonstrated efficacy and received approval in the United States for specific settings within urothelial carcinoma treatment. Enfortumab vedotin was FDA approved in combination with pembrolizumab (Keytruda) in December of 2023, based on the phase 3 EV-301 trial (NCT03474107), which showed superiority over chemotherapy in the post-platinum and post-immuno-oncology setting, he explains. On April 13, 2021, sacituzumab govitecan received accelerated approval by the FDA for patients with locally advanced or metastatic urothelial cancer who had previously received a platinum-containing chemotherapy and either a PD-1 or PD-L1 inhibitor, based on the activity observed in the phase 2 TROPHY-U-01 trial (NCT03547973), McGregor reports.

These 2 ADCs have unique toxicities, different payloads, and target different antigens, suggesting a potential for complementary therapeutic effects, he expands. In oncology, combining different chemotherapy regimens is a common practice, aiming to enhance efficacy and overcome resistance. However, no prior clinical trial had investigated the simultaneous combination of two different ADCs in any type of cancer, McGregor states. The distinct mechanisms of action and non-overlapping toxicity profiles of enfortumab vedotin and sacituzumab govitecan provided a compelling rationale for their combination, he adds.

Results from the DAD trial were presented at the 2023 ESMO Congress, and showed that the combination therapy exhibited a tolerable toxicity profile, with no new or unexpected toxicities observed compared with monotherapy following treatment with either drug. The maximum tolerated dose (MTD) was achieved with 10 mg/kg dose of sacituzumab govitecan and 1.25 mg/kg dose of enfortumab vedotin with G-CSF support. However, the recommended phase 2 dose was determined to be enfortumab vedotin to 1.25 mg/kg plus 8 mg/kg of sacituzumab govitecan.

By leveraging the unique properties of each ADC and their non-overlapping toxicities, the DAD trial aimed to determine the feasibility, safety, and preliminary efficacy of this combination strategy, thereby paving the way for new therapeutic avenues in the treatment of mUC.