(UPDATE) Sacituzumab Govitecan-hziy

Commentary by Bladder Cancer Site Editor for JNCCN 360

Thomas Flaig, MD

Professor, Medicine-Medical Oncology and Vice Chancellor for Research, Anschutz Medical Campus, Aurora, Colorado

Clinicians are rapidly gaining experience in the use of sacituzumab govitecan-hziy as a subsequent therapy in patients with advanced bladder cancer, based on accelerated approval by the U.S. Food and Drug Administration. Encouraging anticancer activity of approximately 30% was observed in the initial trial groups. There are currently many ongoing clinical investigations examining sacituzumab govitecan in combination with several other agents that will provide additional insights. There is much anticipation of the results of the ongoing phase III TROPiCS-04 trial, which will provide high-level evidence of the safety and efficacy of the agent in this setting. 

DISCLOSURES

Dr. Flaig has received clinical research support/data safety monitoring board from Agensys, Astellas Pharma US, AstraZeneca, Bristol Myers Squibb, Genentech, Janssen Pharmaceutica Products, Merck & Co, sanofi-aventis U.S., and Seattle Genetics; has served on a scientific advisory board or as a consultant or expert witness for Aurora Oncology (founder), Janssen Pharmaceutica Products, and Seattle Genetics; and was issued patent for work done at the University of Colorado and now Aurora Oncology.

In April 2021, the U.S. Food and Drug Administration (FDA) granted accelerated approval to the Trop-2–directed antibody-drug conjugate sacituzumab govitecan-hziy for adults with locally advanced or metastatic urothelial cancer who previously received a platinum-containing chemotherapy and PD-1 or PD-L1 inhibitors, based on the final results from cohort 1 of the phase II TROPHY-U-01 trial.^1,2 Since the Spotlight was posted in July 2021, data from cohorts 2 and 3 have shed further light on the safety and antitumor activity of this agent; however, full FDA approval hinges on the results of the ongoing confirmatory phase III TROPiCS-04 trial.

TROPHY-U-01 Trial Updates

Based on the preliminary results from cohort 2 of the TROPHY-U-01 trial, sacituzumab govitecan demonstrated an “encouraging” objective response rate of 28% in patients with platinum-ineligible metastatic urothelial cancer whose disease progressed after prior checkpoint inhibitor therapy.³ The primary analysis revealed an objective response rate of 32%.⁴ The median durations of response, progression-free survival, and overall survival were 5.6, 5.6, and 13.5 months, respectively. No new safety signals were observed. Treatment-related adverse events of grade 3 or higher occurred in 68% of patients.  

Second-line therapy with sacituzumab govitecan plus pembrolizumab showed activity in patients with platinum-refractory, checkpoint inhibitor–naive metastatic urothelial cancer, based on the interim results from cohort 3.⁵ The investigator-assessed objective response, clinical benefit, and progression-free survival rates were 34%, 44%, and 47%, respectively. No new safety signals were observed; diarrhea (76%), nausea (59%), anemia (56%), neutropenia (44%), and asthenia (41%) were the most frequently reported treatment-emergent adverse events. A total of 59% of patients experienced a treatment-related adverse event of grade 3 or higher.

Next Steps

Clinicians are eagerly awaiting the results from the remaining cohorts of the TROPHY-U-01 trial to further clarify the role of sacituzumab govitecan in the treatment of metastatic urothelial cancer. Cohort 4 will evaluate the novel agent in combination with cisplatin in platinum-naive patients.⁶ In cohort 5, maintenance therapy with sacituzumab govitecan plus zimberelimab will be compared with both zimberelimab and avelumab monotherapy in patients whose disease did not progress after prior chemotherapy with gemcitabine plus cisplatin.⁷ Treatment-naive, cisplatin-ineligible patients in cohort 6 will be randomly assigned to receive sacituzumab govitecan monotherapy, sacituzumab govitecan plus zimberelimab, sacituzumab govitecan plus zimberelimab and domvanalimab, or carboplatin plus gemcitabine.⁸

Although the published results from the TROPHY-U-01 trial have shed light on the optimal use of sacituzumab govitecan, continued FDA approval in patients with locally advanced or metastatic bladder cancer will be contingent upon verification of clinical benefit in the TROPiCS-04 trial (ClinicalTrials.gov identifier NCT04527991).⁹ A phase I study (NCT04724018) is also planned to evaluate sacituzumab govitecan in combination with the Nectin-4–directed antibody-drug conjugate enfortumab vedotin-ejfv in the setting of metastatic disease.

References

1. S. Department of Health and Human Services. U.S. Food and Drug Administration. FDA grants accelerated approval to sacituzumab govitecan for advanced urothelial cancer. Available at https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-sacituzumab-govitecan-advanced-urothelial-cancer. Accessed February 6, 2023.
2. Loriot Y, Balar AV, Petrylak DP, et al. TROPHY-U-01 cohort 1 final results: a phase II study of sacituzumab govitecan in metastatic urothelial cancer that has progressed after platinum and checkpoint inhibitors. Ann Oncol 2020;31(suppl):Abstract LBA24.
3. Petrylak DP, Tagawa ST, Jain RK, et al. Early results of TROPHY-U-01 cohort 2: sacituzumab govitecan in platinum-ineligible patients with metastatic urothelial cancer who progressed after prior checkpoint inhibitor therapy. J Clin Oncol 2020;38(suppl):Abstract 5027.
4. Petrylak DP, Tagawa ST, Jain RK, et al. Primary analysis of TROPHY-U-01 cohort 2, a phase 2 study of sacituzumab govitecan in platinum-ineligible patients with metastatic urothelial cancer that progressed after prior checkpoint inhibitor therapy. 2023 ASCO Genitourinary Cancers Symposium. Abstract 520.
5. Grivas P, Pouessel D, Park CH, et al. TROPHY-U-01 cohort 3: sacituzumab govitecan in combination with pembrolizumab in patients with metastatic urothelial cancer who progressed after platinum-based regimens. J Clin Oncol 2022;40(suppl):Abstract 434.
6. Tagawa ST, Grivas P, Petrylak DP, et al. TROPHY-U-01 cohort 4: sacituzumab govitecan in combination with cisplatin in platinum-naive patients with metastatic urothelial cancer. J Clin Oncol 2022;40(suppl):Abstract TPS581.
7. Powles T, Necchi A, Duran I, et al. TROPHY-U-01 cohort 5: evaluation of maintenance sacituzumab govitecan plus zimberelimab, zimberelimab, or avelumab in cisplatin-eligible patients with unresectable or metastatic urothelial cancer. 2023 ASCO Genitourinary Cancers Symposium. Abstract TPS598.
8. Duran I, Necchi A, Powles T, et al. TROPHY-U-01 cohort 6: sacituzumab govitecan, sacituzumab govitecan plus zimberelimab, sacituzumab govitecan plus zimberelimab plus domvanalimab, or carboplatin + gemcitabine in cisplatin-ineligible patients with treatment-naive metastatic urothelial cancer. 2023 ASCO Genitourinary Cancers Symposium. Abstract TPS592.
9. Grivas P, Tagawa ST, Bellmunt J, et al. TROPiCS-04: study of sacituzumab govitecan in metastatic or locally advanced unresectable urothelial cancer that has progressed after platinum and checkpoint inhibitor therapy. J Clin Oncol 2021;39(suppl):Abstract TPS498.