Sacituzumab govitecan (IMMU-132) in patients with previously treated metastatic urothelial cancer (mUC): Results from a phase I/II study.

Abstract

354 Background: Patients (pts) with mUC who progress after platinum (PLT)-based chemotherapy and immune checkpoint inhibitor (CPI) therapy have poor outcomes and limited treatment options. Sacituzumab govitecan (SG) is a novel antibody-drug conjugate. It consists of a monoclonal antibody targeting Trop-2, an epithelial cell surface antigen overexpressed in UC, conjugated to the active metabolite of irinotecan (SN38). Methods: We performed a phase I/II basket study in pts with advanced solid tumors receiving intravenous SG administered on day 1 and 8 of 21-day cycles, until progression or unacceptable toxicity. CT/MRI scans were obtained at 8-week intervals for response assessment. We evaluated pts with mUC who progressed after ≥1 prior systemic therapy and were treated with SG at the 10 mg/kg dose level. Endpoints included safety, objective response rate (ORR) by RECIST 1.1, clinical benefit rate (CBR; complete response [CR], partial response [PR], or else SD ≥6-mo), and Kaplan-Meier estimated duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Results: 45 pts (41M/4F; median age 67, range 49-90; ECOG 0/1: 31%/69%) received a median of 2 (range: 1-6) prior treatment lines, including PLT-based chemotherapy (95%) and CPI (38%). 33 had visceral metastases involving liver (n=15), lung (n=27), and other organs (n=5). The ORR was 31% (14/45), with 2 CR and 12 PR. In pts with visceral involvement, the ORR was 27% (9/33). The ORR in CPI-treated pts was 23% (4/17). The median DOR was 12.6 mo (2 pts continuing >2 y), and the CBR was 47% (21/45). Median PFS and OS were 7.3 mo and 18.9 mo, respectively. The AE profile was consistent with prior reports. Grade ≥3 AEs in ≥5% of pts were neutropenia/neutrophil count decreased (38%), anemia (11%), hypophosphatemia (11%), diarrhea (9%), fatigue (9%), and febrile neutropenia (7%). Conclusions: SG demonstrated clinical activity in pts with relapsed/refractory mUC, including CPI-treated pts and pts with visceral disease. A single-arm, open-label, global phase 2 trial is underway to evaluate antitumor activity and safety of SG in advanced UC.(TROPHY-U-01; NCT03547973). Clinical trial information: NCT03547973.

Cervical carcinomas that overexpress human trophoblast cell-surface marker (Trop-2) are highly sensitive to the antibody-drug conjugate sacituzumab govitecan

“…Results from the phase II dose expansion portion identified the 10 mg/kg dose for further evaluation 20 . Findings from the individual cohorts from the phase I/II basket study including breast, urothelial, non-small cell and small cell lung cancer patients showed overall response rates ranging from 14% to 33% [9][10][11][12][13] . In the cohort of 108 patients with triple negative breast cancer, who had received at least 2 prior lines of chemotherapy (median 3, range 2-10), the response rate (3 complete and 33 partial responses) was 33.3% (95% confidence interval [CI], 24.6 to 43.1), and the median duration of response was 7.7 months (95% CI, 4.9 to 10.8) 9 .…”

“…Once the tumor volume reached 0.2 cm 3 , the mice were randomized into four groups (4 mice/group): saline control, sacituzumab govitecan, control ADC and hRS7. Sacituzumab govitecan, control ADC, and hRS7 were given at the dose of 500 μg IV twice per week for three weeks i.e., day 1,4,8,11,15,18 . Tumor volume was measured twice weekly and obtained with the following formula: (A 2 x B)/2.…”

“…Low expression levels in normal healthy tissues make Trop-2 a suitable target for ADCs in cancer treatment 8 . Sacituzumab govitecan has shown promising activity in a recent phase I/II trial including patients with triple negative breast cancer 9 , hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) breast cancer 10 , urothelial cancer 11 , small cell 12 and non-small cell lung cancers 13 . Several registrational clinical trials are also underway in patients with metastatic urothelial cancer (TROPHY U-01; NCT03547973), triple-negative breast cancer (ASCENT; NCT02574455), and HR + /HER2-breast cancer (TROPICS-02; NCT03901339)…”

Targeted Molecular Therapeutics for Bladder Cancer—A New Option beyond the Mixed Fortunes of Immune Checkpoint Inhibitors?

“…SG was evaluated in the phase I/II IMMU-132 clinical trial in patients with advanced bladder cancer that received prior platinum-based treatment ( Table 1 ) [ 35 ]. Patient tumors were determined as positive if >10% of tumor cells had anti-Trop-2 staining.…”

“…Patient tumors were determined as positive if >10% of tumor cells had anti-Trop-2 staining. Expression was scored as 3+ (strong), 2+ (moderate), and 1+ (weak) [ 35 ]. Tumors with <10% tumor cells that stained for Trop-2 were considered Trop-2-negative tumors.…”