In a cohort of the phase II TROPHY-U-01 trial reported in the Journal of Clinical Oncology, Scott T. Tagawa, MD, MS, and colleagues found that the antibody-drug conjugate sacituzumab govitecan-hziy produced responses in patients with metastatic urothelial carcinoma progressing after platinum-based chemotherapy and PD-1 or PD-L1 inhibitor therapy.

The trial supported the April 2021 accelerated approval of sacituzumab govitecan in this setting.

Scott T. Tagawa, MD, MS

As explained by the investigators, sacituzumab govitecan is a Trop-2–directed antibody-drug conjugate consisting of an anti–Trop-2 humanized monoclonal antibody coupled to SN-38 (active metabolite of the topoisomerase 1 inhibitor irinotecan) with a high drug-to-antibody ratio. The hydrolyzable linker permits a dual mechanism of action: internalization of Trop-2-bound sacituzumab govitecan delivers SN-38 inside tumor cells, resulting in cell death; the hydrolyzable linker enables SN-38 to be released into the tumor microenvironment, resulting in killing of adjacent tumor cells.

As stated by the investigators, “Patients with metastatic urothelial carcinoma who progress on platinum-based combination chemotherapy and checkpoint inhibitors have limited options that offer objective response rates of approximately 10% with a median overall survival of 7 to 8 months.”

Study Details

The current report presents findings in a cohort (cohort 1) of the multicohort trial enrolled from August 2018 to November 2019. In the cohort, 113 patients with locally advanced unresectable (4%) or metastatic disease (96%) received sacituzumab govitecan at 10 mg/kg on days 1 and 8 of 21-day cycles until loss of clinical benefit or unacceptable toxicity. The primary outcome measure was overall response rate on blinded independent central review.

Responses

Objective response was observed in 31 patients (27.4%, 95% confidence interval [CI] = 19.5%–36.6%), including complete response in 6 (5.3%). Stable disease was observed in an additional 38 patients (33.6%). The clinical benefit rate (objective response plus stable disease ≥ 6 months) was 37.2% (95% CI = 28.3%–46.8%). A reduction in the size of target lesions was observed in 72 (77%) of 94 patients with at least one post-baseline target lesion measurement.

Median time to objective response was 1.6 months (range = 1.2–5.5 months). At a median follow-up of 9.1 months (range = 0–19.9 months), median duration of response was 7.2 months (95% CI = 4.7–8.6 months). Response durations ranged from 1.4 to 13.7 months among patients with complete response. Responses were observed in all evaluated subgroups, including patients with two or more prior lines of therapy, those with visceral and liver metastases at baseline, and in all Bellmunt risk groups. At data cutoff, 30 of 31 patients with objective response remained alive, and 4 had ongoing response.

Median progression-free survival was 5.4 months (95% CI = 3.5–7.2 months; range = 2.4–8.9 months). Median overall survival was 10.9 months (95% CI = 9.0–13.8 months; range = 3.8–19.8 months).

Adverse Events

The most common treatment-related adverse events of any grade were diarrhea (65%), nausea (60%), fatigue (52%), alopecia (47%), and neutropenia (46%). The most common grade ≥ 3 treatment-related adverse events were neutropenia (35%), leukopenia (18%), anemia (14%), diarrhea (10%), febrile neutropenia (10%), lymphopenia (7%), and urinary tract infection (6%). Grade ≥ 3 serious treatment-related adverse events occurring in more than one patient included febrile neutropenia (n = 10), diarrhea (n = 4), urinary tract infection (n = 4), sepsis (n = 2), and thrombocytopenia (n = 2). One case of interstitial lung disease (grade 2) was observed. Treatment-related adverse events led to discontinuation of treatment in seven patients (6%), most commonly due to neutropenia, febrile neutropenia, and sepsis. One treatment-related death occurred, due to febrile neutropenia and sepsis.

The investigators concluded, “Sacituzumab govitecan is an active drug with a manageable safety profile with most common toxicities of neutropenia and diarrhea. Sacituzumab govitecan has notable efficacy compared with historical controls in pretreated metastatic urothelial carcinoma that has progressed on both prior platinum-based combination chemotherapy regimens and checkpoint inhibitors. The results from this study supported accelerated approval of sacituzumab govitecan in this population.”

Dr. Tagawa, of Weill Cornell Medicine, New York, is the corresponding author for the Journal of Clinical Oncology article.

Disclosure: The study was supported by Immunomedics Inc, a subsidiary of Gilead Sciences, Inc. For full disclosures of the study authors, visit ascopubs.org.