TROPHY U-01 (NCT03547973) COHORT 1 is a phase 2 open-label study of sacituzumab govitecan (SG) in patients with metastatic urothelial cancer (mUC) and disease progression after both platinum-based regimens and checkpoint inhibitors (CPIs).

SG is a Trop-2–directed antibody-drug conjugate (ADC). It is a humanized anti–Trop-2 antibody, which is an epithelial antigen expressed on many solid tumors and is highly expressed in urothelial cancer. SG is distinct from other ADCs because there is a high drug-to-antibody ratio, and there is a bystander effect due to its hydrolysable linker. When SG’s SN-38 payload, which is a more potent parent compound than irinotecan, is released, the hydrolysable payload allows drugs to get into the tumor cells and the microenvironment around the tumor cells, making SG unique. This attribute has significant activity across several tumors, and SG has recently been approved for triple-negative breast cancer and received fast track designation for mUC. A phase 3 trial in urothelial cancer is under way.

Cohort 1 consisted of 100 patients with mUC who progressed after prior platinum-based and CPI-based therapy. Patients were given 10 mg/kg on days 1 and 8 of an every- 21-day cycle, and the primary objective was overall response rate (ORR) by central review. The cohort was conducted in 2 stages. Scott T. Tagawa, MD, MS, FACP, presented the first 35 patients at the European Society for Medical Oncology (ESMO) 2019 meeting, which led to a continued enrollment of cohort 1 up to the intention-to-treat analysis of 113 patients based on a blinded independent central assessment of data for RECIST v1. The data cutoff for the report was May 18, 2020.

Regarding patient disposition, 66% of patients in the trial stopped treatment because of progressive disease versus 14% who have continued treatment. Comparatively, there are still patients in follow-up for survival in 50% of the cases. The median treatment time was 3.7 months. Although the patient population was highly pretreated, 28% had liver metastases, and 48% had lung or pleural metastases. The median number of anticancer regimens was 3, and more than 50% of patients had more than 3 regimens. This treatment was a fourth line therapy, and 72% percent of patients had had cisplatin and 35% had carboplatin.

At the ESMO virtual meeting, Yohann Loriot, MD, PhD, presented a 27% ORR, which included a 5% conversion rate and a 22% partial remission rate. The median duration of response was 5.9 months. Reduction in tumor size was also observed in the study. Specifically, 76% of patients had reduction in their tumor size as it relates to primarily third- and fourth-line therapy.

Many of the patients from the study are still alive. Twenty-seven of 31 responders are alive, and 8 have an ongoing response and were still on treatment as of the data cutoff. Additionally, many of the patients by the May 20, 2020, cutoff were still on treatment.

The median progression-free survival (PFS) was 5.4 months. The median overall survival was 10.5 months. Comparatively, second-line therapy in this case has been historically 7 to 9 months in duration. Therefore, having a fourth-line therapy with a median overall survival of 10.5 months and a PFS of 5.4 months is excellent for that sick patient population with widely metastatic visceral disease.

Adverse effects included mostly neutropenia, leukopenia, and anemia. A portion of patients experienced diarrhea, but few reached grade 3 and 4. Other adverse effects included nausea and fatigue, but the majority of symptoms were not grade 3 or 4. These results may have been due to the drug irinotecan and UGT1A1 genotypes being homozygous; therefore, this population was most likely to have the neutropenia, which additionally was not associated with diarrhea in this study. Moreover, there was a 30% granulocyte colony-stimulating factor usage in the study.

In conclusion, the TROPHY U-01 cohort 1 results confirm the interim findings presented by Tagawa and prior phase 1 and 2 study results. SG has significant activity and is safe in patients with heavily pretreated mUC who progress on platinum, cisplatin, carboplatin, and a CPI. The results of SG were a 27% overall response rate, 5.9 months’ median duration of response, and 5.4 months’ median PFS. Additionally, the therapies compare favorably with single-agent chemotherapy that is typically given in the second or third line, such as the taxanes or vinflunine. SG has received fast track designation in this indication and may have the potential to change practice in this setting. A phase 3 confirmatory trial in mUC called TROPiCS-04 (NCT04527991) is under way.

The TROPiCS-04 study design is for patients with mUC on the upper tract or urothelial tract. Mixed histological types will be allowed, but if the urothelial cancer is predominant, patients will have progressed after platinum-based therapy and a CPI or platinum in the neoadjuvant adjuvant setting within 12 months and will be randomized, specifically 482 patients to SG and investigators’ choice of either docetaxel, paclitaxel, or vinflunine. Currently, the primary end point is overall survival.

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TROPHY U-01 cohort 1 is a phase 2 open-label study of sacituzumab govitecan in patients with metastatic urothelial cancer and disease progression after both platinum-based regimens and checkpoint inhibitors.

Cora Sternberg, MD, FACP, Weill Cornell Medicine

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