Sacituzumab govitecan is an antibody-drug conjugate that recognizes Trop-2, a cell-surface glycoprotein highly expressed in aggressive bladder cancers. The antibody to Trop-2 is conjugated with a linker to a payload consisting of SN-38, the active metabolite of irinotecan. On April 22, 2020, this agent attained accelerated FDA approval for patients with metastatic triple-negative breast cancer who have previously received at least two prior therapies for metastatic disease.3
In a Phase I/II solid tumor basket trial, 45 patients with metastatic urothelial carcinoma who progressed after one or more lines of prior systemic therapy were treated with sacituzumab govitecan at the 10 mg/kg dose level on days 1 and 8, of every 21-day cycles.4 The objective response rate, by RECIST 1.1 criteria, to sacituzumab govitecan was 31%, with median progression-free and overall survival of 7.3 and 18.9 months, respectively. The agent was well-tolerated with grade 3 or greater adverse events of neutropenia (38%), anemia (11%), hypophosphatemia (11%), diarrhea (9%), fatigue (9%), and febrile neutropenia (7%).
This promising data led to the development of the TROPHY-U-01 open-label Phase II trial with multiple cohorts. Cohort 1 enrolled 113 patients who experienced prior progression after platinum-based chemotherapy and a checkpoint inhibitor.5 Final results were presented at the European Society of Medical Oncology (ESMO) 2020 Congress. The objective response rate was consistent with the Phase I/II basket trial, with a 27% objective response rate. However, 76% of patients impressively had some reduction in tumor size. Median progression-free and overall survival were 5.4 and 10.5 months, respectively. The safety data were consistent with prior trial results.
As a result of this trial, sacituzumab govitecan has received fast track designation from the FDA, and a randomized, Phase III trial, termed TROPiCS-04 (NCT04527991) is underway. This trial randomizes locally-advanced or metastatic urothelial carcinoma patients who have previously progressed after platinum-based chemotherapy and prior anti-PD-(L)1 therapy. Patients will either receive sacituzumab govitecan with the above-described dosing schedule vs. docetaxel, paclitaxel, or vinflunine. The primary endpoint is overall survival.
Cohort 2 of the TROPHY-U-01 trial (NCT03547973) is still actively accruing patients, and early results were presented at the 2020 American Society of Clinical Oncology (ASCO) Meeting.6 This cohort includes cisplatin-ineligible patients who have received checkpoint inhibitors for first-line metastatic urothelial carcinoma. The first 18 patients of a planned 40 patient cohort have demonstrated an objective response rate of 28%. Target lesion reduction of any amount was reported in 61%. No new safety signals have been identified.
Cohort 3 of the TROPHY-U-01 trial (NCT03547973) is also actively accruing patients,7 and we have yet to see results. This cohort is planning to accrue up to 61 locally-advanced or metastatic urothelial carcinoma patients who progressed after platinum-based chemotherapy, yet who are checkpoint inhibitor-naïve. Patients will receive sacituzumab govitecan in combination with pembrolizumab in this second-line setting.
Please see below for select trials of sacituzumab govitecan for patients with genitourinary malignancies. Although most activity is ongoing for urothelial carcinoma, there are trials that allow other solid tumors, and one trial that is specific to patients with metastatic castration-resistant prostate cancer.
Select trials with sacituzumab govitecan that allow genitourinary malignancies:
- TROPiCS-04 – Randomized Phase III trial of sacituzumab govitecan vs. taxane in post-platinum, post PD-(L)1 antibody therapy setting (NCT04527991)
- TROPHY-U-01 - Phase II trial of sacituzumab govitecan (NCT03547973)
- Cohort 2 for platinum ineligible metastatic urothelial carcinoma post-PD-(L)1 antibody therapy
- Cohort 3 for post-platinum metastatic urothelial carcinoma in combination with pembrolizumab
- MORPHEUS mUC – Phase I/II trial of sacituzumab govitecan plus atezolizumab for metastatic urothelial carcinoma post platinum chemotherapy (NCT03869190)
- SEASTAR - Phase I/II trial of sacituzumab govitecan plus Rucaparib for metastatic urothelial carcinoma or a tumor with DNA repair deficiency (NCT03992131)
- Phase I trial of sacituzumab govitecan in solid tumors and moderate hepatic impairment (NCT04617522)
- Phase II trial of sacituzumab govitecan for metastatic castration-resistant prostate cancer who have progressed on second-generation androgen receptor-directed therapy (NCT03725761)
- Yu, Evan. “Antibody Drug Conjugates for Urothelial Carcinoma, a Cool Technology with Promising Results.” Accessed January 29, 2021.
- Yu, Evan. “Enfortumab Vedotin – Changing the Way We Think About Urothelial Cancer.” Accessed January 29, 2021.
- Tagawa, Scott T., Bishoy Morris Faltas, Elaine Tat Lam, Philip James Saylor, Aditya Bardia, Julio Hajdenberg, Alicia K. Morgans et al. "Sacituzumab govitecan (IMMU-132) in patients with previously treated metastatic urothelial cancer (mUC): Results from a phase I/II study." (2019): 354-354.
- Loriot, Y., A. V. Balar, D. P. Petrylak, S. T. Tagawa, A. Rezazadeh, A. Fléchon, R. Jain et al. "LBA24 TROPHY-U-01 cohort 1 final results: A phase II study of sacituzumab govitecan (SG) in metastatic urothelial cancer (mUC) that has progressed after platinum (PLT) and checkpoint inhibitors (CPI)."Annals of Oncology 31 (2020): S1156.
- Petrylak, Daniel Peter, Scott T. Tagawa, Rohit K. Jain, Manojkumar Bupathi, Arjun Vasant Balar, Arash Rezazadeh, Saby George et al. "Early results of TROPHY-U-01 Cohort 2: Sacituzumab govitecan (SG) in platinum-ineligible patients (pts) with metastatic urothelial cancer (mUC) who progressed after prior checkpoint inhibitor (CPI) therapy." (2020): 5027-5027.
- Grivas, P., C. N. Sternberg, N. Agarwal, D. P. Petrylak, S. T. Tagawa, Q. Hong, A. Gladden, C. Kanwal, T. Goswami, and Y. Loriot. "796TiP TROPHY-U-01 Cohort 3: Sacituzumab govitecan (SG) and pembrolizumab (pembro) in patients (pts) with progression or recurrence of metastatic urothelial cancer (mUC) after platinum (PLT)-based therapy." Annals of Oncology31 (2020): S604-S605.