Phase II Open Label, Study of IMMU-132 in Metastatic Urothelial Cancer After Failure of Platinum-Based Regimen or Anti-PD-1/ PD-L1 Based Immunotherapy (TROPHY-U-01 Cohort 1)

Immunomedics, Inc.
Study Design: 
This was a phase II, multicenter single-arm trial and updated data for the cohort of 113 patients with metastatic UC that progressed on prior platinum and immune checkpoint therapy were presented at ESMO 2020. Patients received IMMU-132 10mg/kg days 1 and 8 of a 21-day cycle that was continued until toxicity or disease progression. The null hypothesis was an overall response rate 12%.
Although patients with metastatic UC have multiple options for therapy, patients who do not respond to platinum-based chemotherapy and/or anti-PD-1/PD-L1 based immunotherapy have had few treatment options until recently (enfortumab vedoin and erdafitinib). Antibody-drug conjugates (ADCs) are monoclonal antibodies (mABs) conjugated to cytotoxic drugs that can deliver a toxic payload to tumor cells expressing a specific tumor target. Enfortumab vedotin is a well-known ADC targeting Nectin 4 that is now FDA-approved. In this specific trial, a different ADC, Sacituzumab govitecan (SG), also known as IMMU-132, is evaluated containing an antibody against the epithelial cell surface molecule Trop-2 conjugated SN-38 (a potent derivative of the cytotoxic drug irinotecan). Trop-2 is overexpressed in bladder cancer and SN-38 inhibits DNA topoisomerase 1 thereby preventing DNA unwinding which results in irreversible double strand DNA breaks and eventually cytotoxic cell death. SG is distinct from other ADCs, with a high drug-to-antibody ratio.
The primary objective was overall response rate (ORR) and the secondary outcomes are duration of response (DOR), PFS and OS.
The results are encouraging given the fact that the patients were heavily pre-treated. In fact, 10 patients in the cohort were previously treated with enfortumab vedotin and despite that 3 of these patients had a partial response to SG. ADCs may represent a new salvage therapy option for patients with metastatic UC with progression after checkpoint inhibition therapy and chemotherapy.
The group was heavily pre-treated with a median number of 3 prior anti-cancer therapies and the median age of the cohort was 66. There was a 27% overall response rate. The median duration of response was 5.9 months and 76% of patients had a reduction in tumor size. As of data cut-off, 16 of the 113 patients were continuing on treatment. Overall two-thirds of patients discontinued therapy due to progressive disease. Median PFS was 5.4 months and median OS was 10.5 months. Of note, 28% of patients had liver metastases. The most common treatment-related adverse event was diarrhea with 9% of patients having a grade 3 event.