Advanced urothelial cancer (aUC) has seen remarkable progress in recent years with the emergence of antibody-drug conjugates (ADCs) targeting specific antigens. Trop-2, a cell surface antigen highly expressed in UC, has become a promising therapeutic target. Sacituzumab govitecan (SG), a next-generation Trop-2 ADC, received accelerated approval from the US FDA in April 2021 for treating adult patients with locally advanced or metastatic UC who had prior platinum-based chemotherapy and PD-(L)1 inhibitors. The 2023 ASCO-GU conference unveiled data from various cohorts of the TROPHY-U-01 trial and the latest advancements in UC treatment, encompassing late-line monotherapy, combination therapy, first-line combination therapy, and first-line maintenance therapy. Here, we summarize essential findings from these presentations, anticipating further insights after the conference.
Late-Line Monotherapy or Combination Therapy:
Updated Results from TROPHY-U-01 Cohort 1
Background: SG is an ADC comprising an anti-Trop-2 antibody linked to the topoisomerase I inhibitor SN-38. Initial results from the pivotal TROPHY-U-01 cohort 1 study led to SG’s accelerated FDA approval for treating patients with metastatic UC (mUC) who had previously received platinum-based and CPI therapy. This section presents updated findings from cohort 1.
Methods: TROPHY-U-01 is a multicohort phase 2 study involving adult patients with mUC who progressed after platinum-based and CPI therapy. Patients received SG intravenously on Days 1 and 8 of each 21-day cycle. The primary endpoint was the centrally reviewed objective response rate (ORR) per RECIST 1.1, with key secondary endpoints including duration of response (DOR), progression-free survival (PFS), clinical benefit rate (CBR), overall survival (OS), and safety.
Results: As of July 26, 2022, 113 treated patients exhibited a median follow-up of 10.5 months. The centrally reviewed ORR was 28%, with a CBR of 38%. Median DOR was 6.1 months, median PFS was 5.4 months, and median OS was 10.9 months. Notably, 12-month rates for DOR, PFS, and OS were 30%, 14%, and 45%, respectively. Treatment-related adverse events (TRAEs) of grade ≥3 occurred in 65% of patients, with common ones including neutropenia, leukopenia, anemia, diarrhea, and febrile neutropenia.
Conclusion:SG continues to exhibit a robust response rate in mUC patients who underwent multiple prior lines of therapy. These data endorse SG’s use in patients previously treated with platinum and CPI therapy, warranting further evaluation in front-line settings.
Second-Line Treatment with Sacituzumab Govitecan (SG) in Platinum-Intolerant and CPI-Treated Metastatic Urothelial Cancer (mUC) Patients: Key Analysis of TROPHY-U-01 Cohort 2
Background: Platinum-intolerant mUC patients face limited treatment options post-CPI therapy. Preliminary results from TROPHY-U-01 cohort 2 demonstrated an ORR of 28% with SG in this population.
Methods:Cohort 2 included adult patients with platinum-intolerant mUC who had previously received platinum-based treatment. Patients received SG, with the primary endpoint being centrally reviewed ORR.
Conclusion: SG remains promising in platinum-intolerant and CPI-treated mUC patients, with a 28% ORR.
Evaluation of Clinical Benefits of Enfortumab Vedotin (EV) Sequential Sacituzumab Govitecan (SG) Therapy in Advanced Urothelial Carcinoma (UC) – Real-World Experience
Background:This analysis explores the effectiveness of SG following EV treatment in patients with advanced UC. SG received accelerated FDA approval for refractory UC, with a 27% ORR.
Methods:A retrospective study involved 17 UC patients who received sequential SG therapy after EV treatment.
Conclusion:Sequential SG therapy demonstrates a clinical benefit rate of 42.8% for advanced UC patients who had progression after EV treatment, even with lower SG doses.
First-Line Combination Therapy: A Phase I/II Study of Atezolizumab (Atezo) + Nivolumab (Nivo) in Combination with Sacituzumab Govitecan (SG) for Cisplatin-Ineligible Metastatic Urothelial Carcinoma (mUC) After Progression
Background:SG, when combined with checkpoint inhibitors, demonstrates promise for cisplatin-ineligible mUC patients. Early signals of treatment activity were observed.
Methods:The study assessed SG in combination with atezolizumab (Atezo) and nivolumab (Nivo) as first-line treatment for cisplatin-ineligible mUC patients.
Conclusion:SG in combination with Atezo and Nivo showed early treatment activity, with further exploration in Phase II.
TROPHY-U-01 Cohort 6: Sacituzumab Govitecan (SG), SG + Zimberelimab (ZIM), SF + ZIM + Domvanalimab (DOM), or Carboplatin (CARBO) + Gemcitabine (GEM) for First-Line Treatment of Cisplatin-Ineligible Locally Advanced or mUC Patients
Background: Cohort 6 of TROPHY-U-01 evaluates SG as monotherapy and in combination with checkpoint inhibitors or chemotherapy for first-line treatment of cisplatin-ineligible locally advanced or mUC patients.
Methods:This multicohort, open-label phase II trial explores various treatment approaches for cisplatin-ineligible UC patients.
Conclusion:Results from this ongoing trial will provide insights into first-line treatment options for cisplatin-ineligible UC patients.
First-Line Maintenance Therapy: TROPHY-U-01 Cohort 5: Sacituzumab Govitecan (SG) in Combination with Zimberelimab (ZIM), ZIM, or Avelumab for Maintenance Treatment in Platinum-Ineligible, Unresectable or Metastatic Urothelial Carcinoma (mUC)
Background: Cohort 5 evaluates SG in combination with checkpoint inhibitors or as monotherapy for maintenance treatment in platinum-ineligible, unresectable, or metastatic UC patients.
Methods:The study aims to assess safety, tolerability, and efficacy of these maintenance treatments.
Conclusion: This ongoing trial will provide insights into maintenance therapy options for platinum-ineligible UC patients.
Conclusion:The 2023 ASCO-GU conference showcased significant advancements in the treatment of advanced urothelial cancer, particularly with sacituzumab govitecan (SG). These findings highlight SG’s potential across various treatment modalities, from late-line monotherapy to first-line combination therapy and maintenance therapy, offering hope for improved outcomes in UC patients. Further research and clinical trials will continue to shape the landscape of UC treatment.
