SUMMARY: The FDA on April 13, 2021, granted accelerated approval to TRODELVY® (Sacituzumab Govitecan) for patients with locally advanced or metastatic Urothelial Cancer who previously received a Platinum-containing chemotherapy, and either a Programmed Death receptor-1 (PD-1) or a Programmed Death-Ligand 1 (PD-L1) inhibitor. The American Cancer Society estimates that in the United States for 2021, about 83,730 new cases of bladder cancer will be diagnosed and approximately 17,200 patients will die of the disease. Bladder cancer is the fourth most common cancer in men, but it is less common in women. A third of the patients initially present with locally invasive or metastatic disease. Patients with Urothelial Carcinoma are currently treated in the first line setting with a Platinum based chemotherapy regimen, and a checkpoint Inhibitor (PD-1 or PD-L1 inhibitor) in the second line setting. Treatment options for patients who progress after first and second line therapies are limited, with poor outcomes. The response rates with standard chemotherapy in this patient population, is about 10%, with a median Overall Survival (OS) of 7-8 months.
Two new agents approved by the FDA include BALVERSA® (Erdafitinib), a pan-Fibroblast Growth Factor Receptor (FGFR) inhibitor, for patients with locally advanced or metastatic Urothelial Carcinoma with susceptible FGFR3 or FGFR2 genetic alterations, that has progressed during or following Platinum-containing chemotherapy, as well as PADCEV® (Enfortumab Vedotin), an Antibody-Drug Conjugate (ADC) that targets Nectin-4, a cell adhesion molecule, highly expressed in Urothelial Cancers and other solid tumors. These two agents have Objective Response Rates (ORRs) of approximately 40%, and most patients will progress on these therapies. Further, FGFR alterations occur in only 20% of patients with metastatic Urothelial Carcinoma, limiting the use of BALVERSA®. Hence, there is an unmet need for novel therapies.
Trop-2 is a transmembrane glycoprotein and calcium signal transducer. It stimulates cancer-cell growth, and this cell surface receptor is overexpressed in several epithelial cancers including cancers of the Breast, Colon, Lung and Urothelial Cancer, and has limited expression in normal human tissues. TRODELVY® is an Antibody-Drug Conjugate (ADC) in which SN-38, an active metabolite of Irinotecan, a Topoisomerase I inhibitor, is coupled to the humanized Anti-Trophoblast cell-surface antigen 2 (Trop-2) monoclonal antibody (hRS7 IgG1κ), through the cleavable CL2A linker. SN-38 cannot be given directly to patients because of its toxicity and poor solubility. Upon binding to Trop-2, the anti-TROP-2 monoclonal antibody is internalized and delivers SN-38 directly into the tumor cell, making it a suitable transporter for the delivery of cytotoxic drugs. Further, the cleavable linker enables SN-38 to be released both intracellularly into the tumor cells, as well as the tumor microenvironment, thereby allowing for the delivery of therapeutic concentrations of the active drug in bystander cells to which the conjugate has not bound. Thus, TRODELVY®-bound tumor cells are killed by intracellular uptake of SN-38, whereas the adjacent tumor cells are killed by the extracellular release of SN-38.
TRODELVY® in a Phase I/II trial involving patients with advanced epithelial cancers, showed encouraging clinical activity across various solid tumors and was associated with a Objective Response Rate (ORR) of 31% in patients with relapsed or refractory metastatic Urothelial Carcinoma, including a 27% ORR among patients who had received prior checkpoint inhibitor and Platinum based therapy. The TROPHY-U-01 Phase II trial was designed to assess the activity of TRODELVY® and confirm these findings in patients with locally advanced unresectable or metastatic Urothelial Carcinoma. This trial includes 5 patient cohorts, evaluating the role of TRODELVY® in various groups of patients and in combination with various agents including checkpoint inhibitors. The authors in this publication reported the primary results from the full Cohort 1 of the TROPHY-U-01 study in patients with metastatic Urothelial Cancer who progressed after prior Platinum based and checkpoint inhibitor based therapies.
Cohort 1 included 113 patients who had received a median of three prior therapies. Patients received TRODELVY® 10 mg/kg IV, on days 1 and 8 of a 21-day treatment cycle, until disease progression or unacceptable toxicities. The median patient age was 66 years and 66% of patients had visceral metastases. The main efficacy endpoints were Objective Response Rate (ORR) and Duration of Response (DOR), evaluated by Independent Review, using RECIST 1.1 criteria.
At a median follow up of 9.1 months, the ORR was 27.7%, and 77% of patients had decrease in measurable disease. The Complete Response rate was 5.4% and 22.3% had Partial Responses. The median DOR was 7.2 months. The median Progression Free Survival was 5.4 months and Overall Survival was 10.9 months. Important Grade 3 or more treatment related adverse events included, neutropenia, anemia, diarrhea, and febrile neutropenia, with 6% of patients discontinuing treatment due to adverse events because of treatment-related adverse events.
It was concluded that TRODELVY® is an active agent and has notable efficacy, compared with historical controls, in pretreated metastatic Urothelial Cancer, that has progressed on both prior Platinum regimens and checkpoint inhibitors, and has manageable safety profile.
TROPHY-U-01: A Phase II Open-Label Study of Sacituzumab Govitecan in Patients With Metastatic Urothelial Carcinoma Progressing After Platinum-Based Chemotherapy and Checkpoint Inhibitors. Tagawa, ST, Balar AV, Petrylak DP, et al. J Clin Oncol. 2021;39:2474-2485.