Scott Tagawa, MD
Sacituzumab govitecan exhibited significant clinical activity in an open-label, single-arm phase I/II basket study (IMMU 132-01) of patients with heavily pretreated, relapsed/refractory metastatic urothelial cancer.
Among the 45 patients with metastatic urothelial cancer enrolled in the phase II portion of the basket trial, 14 had an objective response to sacituzumab govitecan, for an objective response rate (ORR) of 31.1%, said Scott T. Tagawa, MD, at the 2019 Genitourinary Cancers Symposium.
The activity of sacituzumab govitecan in the study extended to the post-checkpoint inhibitor setting. Among the 17 patients who received prior checkpoint inhibition, 4 patients had responses for an ORR of 23.5%. Further, the ORR was 33.3% (5 of 15) among patients with liver involvement at study entry.
The median progression-free survival was 7.3 months (95% CI, 5.0-10.7) and the median overall survival was 16.3 months (95% CI, 9.0-31.0).
The responses occurred “in the setting of reasonable drug tolerance,” said Tagawa, associate professor of clinical oncology and medical director, Genitourinary Oncology Research Program, Weill Cornell School of Medicine. Sacituzumab govitecan was well tolerated, with a manageable and predictable safety profile, with “a relatively low rate of discontinuations due to adverse events, none due to neutropenia.”
Sacituzumab govitecan is a novel antibody drug conjugate (ADC) directed against Trop-2. Trop-2 is a cell surface antigen present on the surface of multiple types of epithelial tumors, including urothelial carcinoma, in which it particularly overexpressed in invasive tumors. “The ADC is comprised of the humanized anti-Trop-2 antibody with a linker that is designed to release the payload inside Trop-2-expressing cells as well as around stroma, and in a high drug-to-antibody ratio, SN-38 is linked to the antibody,” Tagawa said. SN-38 is the most active metabolite of irinotecan.
The initial part of the dose-escalation phase of IMMU 132-01 enrolled patients with advanced epithelial malignancies of various types that were treatment-refractory, unselected for Trop-2 expression. The recommended phase II dosage to emerge was 10 mg/kg given on days 1 and 8 every 21 days. Within that phase, the efficacy signal appeared promising in the subset of patients with advanced urothelial carcinoma.
Tagawa presented data from an expansion cohort of 45 patients with urothelial cancer, who were required to have treatment-refractory disease, an ECOG performance status of 0-1, and measurable disease. They received sacituzumab govitecan at the recommended phase II dosage until progression or unacceptable toxicity.
Median patient age was 67 years, 91% were male, 87% were white, 69% had an ECOG performance status of 1, and 73% had visceral sites of metastatic disease, including 33% with liver metastases. The median number of prior therapies was 2 (range, 1-6); 62% received ≤2 prior lines of therapy and 38% received ≥3 prior lines. Seventeen patients had prior checkpoint inhibitor therapy, 71% of whom had ≥3 prior lines of therapy.
The median duration of follow-up was 15.7 months and the median number of treatment cycles was 8, with a relative dose intensity of 95.2%. Five patients remained on treatment at the time of data cutoff, 3 of whom had ongoing response.
The most frequent treatment-emergent adverse events (AEs) across all grades were diarrhea (69%), nausea (67%), fatigue (58%), and neutropenia (51%), for which at any time during the study, 24% of patients received at least 1 dose of granulocyte-colony stimulating factor.
Of the 14 responders, there were 2 (4%) complete responses and 12 (27%) partial responses. Most patients had some decrease in tumor burden. Most of the patients who responded did so early, with a median time to onset of response of 1.9 months, with 1 patient having an onset of response at 7.4 months. The median duration of response was 12.9 months.
When the ORR was stratified by number of prior lines of therapy, the ORR was 39.3% (11 of 28) in patients receiving ≤2 prior lines and 17.6% (3 of 17) in those receiving ≥3 prior lines.
“The grade-3 and -4 adverse events were largely restricted to laboratory-based AEs, including a 38% incidence of grade-3 or -4 neutropenia, but only a 7% rate of febrile neutropenia,” said Tagawa. The most frequent grade ≥3 AEs were neutropenia and anemia (13%). Five patients discontinued due to potential drug-related AEs, none due to neutropenia. There were no treatment-related deaths.
“We believe that the activity in this modest subset of patients deserves further study, so the TROPHY-U-01 study has been activated,” he said. TROPHY-U-01 (NCT03547973) is an international, single-arm, open-label phase II study evaluating sacituzumab govitecan in 100 patients with urothelial cancer that has progressed despite prior platinum therapy and immune checkpoint inhibition. A second cohort will consist of 40 patients unfit for prior platinum-based therapy and who progressed after immune checkpoint therapy.