Treatment with the antibody-drug conjugate sacituzumab govitecan-hziy achieved an objective response rate of 32% in platinum-ineligible patients with metastatic urothelial cancer who experienced disease progression on an immune checkpoint inhibitor, according to the primary analysis of the TROPHY-U-01 cohort 2, which was presented at the 2023 ASCO Genitourinary (GU) Cancers Symposium.¹ This study provides new data on the potential sequencing of agents after disease progression with checkpoint inhibition.

In cohort 2 of the study (n = 38), all 12 responses to sacituzumab govitecan were partial and lasted for a median duration of 5.6 months. After a median follow-up of 9.3 months, the median progression-free survival was 5.6 months, and the median overall survival was 13.5 months. Two-thirds of patients (68%) experienced a grade 3 or higher treatment-related adverse event. 

“These data support further evaluation of sacituzumab govitecan—alone or in combination—in patients with metastatic urothelial carcinoma who experience disease progression after prior checkpoint inhibitor therapy,” said lead investigator Daniel P. Petrylak, MD, Professor and Chief of Genitourinary Oncology at Yale School of Medicine, New Haven, Connecticut. “Sacituzumab govitecan had a manageable safety profile, with no new safety signals and no treatment-related deaths.”

In fact, the phase III TROPiCS-04 study is currently evaluating sacituzumab govitecan vs physician’s choice of single-agent chemotherapy in patients who experience disease progression on prior platinum therapy and checkpoint inhibitor therapy.

There are no randomized data or molecular markers to guide treatment selection. In patients with neuropathy, I generally use sacituzumab govitecan first.

— Daniel P. Petrylak, MD

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Study Details

Sacituzumab govitecan was granted accelerated approval by the U.S. Food and Drug Administration in April 2021 for patients with advanced urothelial cancer. This approval was based on findings from 112 patients in cohort 1 of the TROPHY-U-01 study in patients who had experienced disease progression after platinum therapy and a checkpoint inhibitor.²

Patients in cohort 2 received treatment with sacituzumab govitecan at 10 mg/kg subcutaneously on days 1 and 8 of a 21-day cycle. At baseline, the median patient age was 73 years, and most patients were men (61%). At baseline, two-thirds of patients (66%) had visceral metastases, and 29% had liver metastasis. About one-third of patients (34%) had locoregional disease.

The median number of prior therapies was two, and 50% had received prior neoadjuvant platinum. Most patients (97%) had received a prior checkpoint inhibitor. A total of 18% of patients received prior enfortumab vedotin-ejfv, and 3% had received erdafitinib. The median time from the last therapy to study drug administration was 1.6 months. The median duration of the last therapy was 4.2 months, and the best response achieved was a complete response in one patient (3%) and a partial response in six patients (16%).

Key Findings and Toxicity

In addition to the objective response rate of 32%, in 13 patients with no prior exposure to platinum or enfortumab vedotin, the objective response rate was 53.8%. The median time to response with sacitizumab govitecan was 1.4 months, and the median duration of response was 5.6 months. The clinical benefit rate, defined as responses plus stable disease for at least 6 months, was 42%. Many patients (69%) had some reduction in target lesion size.

“Responses were largely similar across prespecified subgroups, regardless of the number of prior anticancer therapies, although some of the subgroups were limited by very small patient numbers,” Dr. Petrylak commented.

At a median follow-up of 9.3 months, progression-free survival was 5.6 months, and median overall survival was 13.5 months.

A total of 68% of patients experienced a grade > 3 treatment-related adverse event: neutropenia (34%), anemia (21%), leukopenia (18%), fatigue (18%), and diarrhea (16%). About 8% of patients experienced treatment-related febrile neutropenia (two were grade 3 and one was grade 4).

Dose reductions because of treatment-related adverse events were needed in 14 patients (37%), and treatment discontinuations because of treatment-related adverse events occurred in 7 patients (18%). Granulocyte colony-stimulating factor (G-CSF) was used as primary prophylaxis in 7 patients (18%) and as secondary prophylaxis in 10 patients (26%).

The study had six cohorts. Cohorts 4, 5, and 6 of TROPHY-U-01 continue to enroll patients and are evaluating sacituzumab govitecan as first-line therapy.

Discussion Points

During the discussion period following his presentation, Dr. Petrylak responded to a question about the levels of myelotoxicity with sacituzumab govitecan and the need for G-CSF. “In practice, as well as in the trial, primary prophylaxis was allowed, and I do this [in clinical practice] because this simply avoids the problem,” he stated.

Dr. Petrylak noted that a response rate of about 30% in patients treated with other agents was “consistent.” He continued: “You would expect that, because the mechanisms of action are different, and the targets are different. At Yale, we see about 30% with patients treated with prior enfortumab vedotin.”

Regarding the optimal sequencing of newer drugs, Dr. Petrylak said “there are no randomized data or molecular markers to guide treatment selection. In patients with neuropathy, I generally use sacituzumab govitecan first. Enfortumab vedotin is approved in the third line. If patients are refractory to enfortumab vedotin, I use sacituzumab govitecan,” he commented. 

DISCLOSURE: Gilead Sciences provided research funding for the TROPHY-U-01 trial. Dr. Petrylak has received grant or research support from Advanced Accelerator Applications, Agensys, Astellas Pharma, AstraZeneca, Bayer, BioXcel Therapeutics, Bristol Myers Squibb, Clovis Oncology, Eisai, Eli Lilly and Company, Endocyte, Genentech, Gilead Sciences, Innocrin Pharmaceuticals, MedImmune, Medivation, Merck & Co., Mirati Therapeutics, Novartis, Pfizer, Progenics Pharmaceuticals, Replimune Group, and Roche; and has served as a consultant to Advanced Accelerator Applications, Amgen, Astellas Pharma, AstraZeneca, Bayer, Bicycle Therapeutics, Boehringer Ingelheim, Bristol Myers Squibb, Clovis Oncology, Eli Lilly and Company, Exelixis, Gilead Sciences, Incyte, Ipsen, Janssen, Mirati Therapeutics, Monopteros Therapeutics, Pfizer, Pharmacyclics, Regeneron Pharmaceuticals, Roche, Seagen, and UroGen Pharma.

REFERENCES

1. 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 GU Cancers Symposium. Abstract 520. Presented February 18, 2023.

2. Tagawa ST, Balar AV, Petrylak DP, et al: Updated outcomes in TROPHY-U-01 cohort 1, a phase 2 study of sacituzumab govitecan in patients with metastatic urothelial cancer that progressed after platinum-based chemotherapy and a checkpoint inhibitor. 2023 ASCO GU Cancers Symposium. Abstract 526. Presented February 18, 2023.