Current and emerging role of sacituzumab govitecan in the management of urothelial carcinoma

ABSTRACT

Introduction

Despite rapid advances in the treatment landscape of urothelial cancer, there is a substantial unmet need for safe and effective therapies for patients with locally advanced and metastatic urothelial cancer. Sacituzumab govitecan (SG) is an antibody-drug conjugate, consisting of a Trop-2 directed monoclonal antibody linked to SN-38, the active metabolite of irinotecan. Trop-2 is a glycoprotein overexpressed in various carcinomas, including urothelial carcinomas.

Areas covered

We review the available data on SG, including mechanism of action, pharmacology, efficacy, safety, and clinical studies regarding locally advanced or metastatic urothelial cancer.

Expert opinion

SG performed well in the TROPHY-U-01 phase II trial with an objective response rate of 27%. The most common adverse effects were diarrhea, nausea, fatigue, alopecia, and neutropenia, with the most common grade ≥ 3 treatment-related AEs being neutropenia, leukopenia, anemia, diarrhea, and febrile neutropenia. However, these effects were managed effectively with supportive care. SG currently has an accelerated approval for patients with locally advanced or metastatic urothelial cancer who have received platinum-based chemotherapy and either programmed cell death receptor-1 (PD-1) or programmed death-ligand 1 (PD-L1) inhibitor. Several studies are evaluating SG in urothelial cancers as single-agent or in combination with other agents.

KEYWORDS:

• Antibody drug conjugate (ADC)
• IMMU-132
• sacituzumab govitecan
• SN-38
• trophoblastic cell-surface antigen 2 (trop-2)
• urothelial carcinoma

Article highlights

• Sacituzumab govitecan (SG) is an antibody-drug conjugate consisting of a Trop-2 directed monoclonal antibody linked to the drug SN-38, a topoisomerase inhibitor, by a hydrolysable linker (CL2A).

• SG targets trophoblastic cell-surface antigen 2 (Trop-2), a glycoprotein overexpressed in various carcinomas, including urothelial carcinomas.

• The IMMU-132-01 phase I/II basket trial evaluated SG in advanced relapsed/refractory metastatic epithelial cancers.

• Among the 45 patients with metastatic urothelial carcinoma treated on the IMMU-132-01 phase, an objective response rate (ORR) of 31% (14/45) was noted.

• In the phase II TROPHY-U-01 trial, SG demonstrated an ORR of 27.4% in patients with locally advanced or metastatic urothelial cancer who had received prior treatment with a platinum chemotherapy and either programmed cell death receptor-1 (PD-1) or programmed death-ligand 1 (PD-L1) inhibitor.

• The most common adverse effects were diarrhea, nausea, fatigue, alopecia, and neutropenia which can be managed effectively with supportive care measures.

• The U.S Food and Drug Administration has granted accelerated approval to SG in patients with locally advanced or metastatic urothelial cancers who had prior treatment with platinum chemotherapy and PD-1/L1 inhibitor.

• Several clinical trials are currently evaluating the effectiveness of SG as a single agent or in combination with other agents in urothelial cancer.

Declaration of interest

N Agarwal reports consultancy to Astellas, Astra Zeneca, Aveo, Bayer, Bristol Myers Squibb, Calithera, Clovis, Eisai, Eli Lilly, EMD Serono, Exelixis, Foundation Medicine, Genentech, Gilead, Janssen, Merck, MEI Pharma, Nektar, Novartis, Pfizer, Pharmacyclics, and Seattle Genetics and research funding to institution from Astellas, Astra Zeneca, Bavarian Nordic, Bayer, Bristol Myers Squibb, Calithera, Celldex, Clovis, Eisai, Eli Lilly, EMD Serono, Exelixis, Genentech, Gilead, Glaxo Smith Kline, Immunomedics, Janssen, Medivation, Merck, Nektar, New Link Genetics, Novartis, Pfizer, Prometheus, Rexahn, Roche, Sanofi, Seattle Genetics, Takeda, and Tracon. U Swami reports consultancy to Astellas and Seattle Genetics and research funding to institute from Janssen and Astellas/Seattle Genetics. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.