Commentary
Video
Author(s):
Bradley McGregor, MD, discusses the next steps for investigating cabozantinib plus atezolizumab in patients with advanced renal cell carcinoma.
Bradley A. McGregor, MD, senior physician, clinical director, Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute; instructor, medicine, Harvard Medical School, discusses the toxicity, synergy, and clinical activity of sacituzumab govitecan-hziy (Trodelvy) and enfortumab vedotin-ejfv (Padcev) when administered to patients with treatment-resistant metastatic urothelial cancer (mUC).
Given the different toxicity profiles and preclinical evidence of synergy for taxanes and irinotecan, investigators developed the phase 1 Double Antibody-Drug Conjugate (DAD) trial (NCT04724018) to test the safety, tolerability and feasibility of combining these 2 antibody-drug conjugates (ADCs) for patients with mUC.
Twenty-three patients were enrolled onto the study and randomly assigned to 1 of 3 different dose levels of sacituzumab govitecan plus enfortumab vedotin. Dose level 1 comprised 8 mg/kg of sacituzumab govitecan with 1 mg/kg of enfortumab vedotin; dose level 2 increased the dose of enfortumab vedotin to 1.25 mg/kg plus the same dose of sacituzumab govitecan; dose level 3 utilized the full 10 mg/kg dose of sacituzumab govitecan and 1.25 mg/kg dose of enfortumab vedotin.
Findings presented at the 2023 ESMO Congress showed that the maximum tolerated dose (MTD) was achieved at dose level 3 with G-CSF support, McGregor begins. However, the recommended phase 2 dose was determined to be dose level 2, as it demonstrated manageable toxicity, patients were able to receive treatment for multiple cycles, and enfortumab vedotin is already approved at 1.25 mg/kg based on phase 3 data, he explains.
Overall, the combination therapy exhibited a tolerable toxicity profile, with no new or unexpected toxicities observed compared with monotherapy of either drug, McGregor continues. The most common adverse events included diarrhea, anemia, and neutropenia, while rates of neuropathy were not significantly elevated, he states.
At a median follow-up of 14.9 months, the regimen demonstrated an overall response rate of 70%, including 3 complete responses and 13 partial responses, McGregor detailed. Notably, ongoing responses were observed in 9 patients, and additional analysis revealed shrinkage in target lesions for 20 patients across all dose levels. Response rates were high and achieved early across all 3 dose levels, underscoring the potential efficacy of the combination therapy in this patient population, McGregor concludes.