Updated outcomes in TROPHY-U-01 cohort 1, a phase 2 study of sacituzumab govitecan (SG) in patients (pts) with metastatic urothelial cancer (mUC) that progressed after platinum (PT)-based chemotherapy and a checkpoint inhibitor (CPI).
Authors: Tagawa Scott T. , Balar Arjun V. , Petrylak Daniel P. , Rezazadeh Arash , Loriot Yohann , Flechon Aude , Jain Rohit K. , Agarwal Neeraj , Bupathi Manojkumar , Barthelemy Philippe , Beuzeboc Philippe , Palmbos Phillip Lee , Kyriakopoulos Christos , Pouessel Damien , Sternberg Cora N. , Tonelli Julia , Sierecki Mitch , Zhou Huafeng , Grivas Petros 
Published: March 2023

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Background: SG is an antibody-drug conjugate composed of an anti-Trop-2 antibody coupled to SN-38, a topoisomerase-I inhibitor, via a proprietary hydrolyzable linker. SG received accelerated FDA approval in April 2021 in pts with mUC who previously received PT-based therapy and a CPI based on the primary analysis of the pivotal TROPHY-U-01 Cohort 1 study. With 9.1 mo median (med) follow-up, SG monotherapy demonstrated a 27% objective response rate (ORR) and med overall survival (OS) of 10.9 mo in 113 pts with locally advanced or mUC progressing after receiving at least a PT-based therapy and a CPI (Tagawa, et al. J Clin Oncol. 2021). Here we report updated Cohort 1 outcomes. Methods: TROPHY-U-01 (NCT03547973) is a multicohort, open-label, phase 2 study. Cohort 1 pts (≥18 y) had progression of mUC following PT (as first-line metastatic therapy or as (neo)adjuvant therapy with recurrence/progression ≤12 mo) and CPI, had ECOG PS 0-1, and creatinine clearance ≥30 mL/min. Pts received 10 mg/kg of SG intravenously on D1 and D8 of 21-D cycles. The primary endpoint was ORR per central review by RECIST 1.1. Key secondary endpoints included duration of response (DOR), progression-free survival (PFS), clinical benefit rate (CBR), OS, and safety. Results: As of July 26, 2022, med follow-up was 10.5 mo (range, 0.3-40.9) for treated pts (N=113). As previously reported, pts (78% men; med age, 66 y; 66% with visceral metastases, 34% liver), were heavily pretreated with a med of 3 prior therapies (range, 1-8). Med time since last prior therapy was 1.5 mo (range, 0-60.0). At data cutoff, per central review, ORR was 28% (95% CI, 20.2-37.6); CBR was 38% (95% CI, 29.1-47.7), med DOR was 6.1 mo (95% CI, 4.7-9.7, n=32) and med PFS was 5.4 mo (95% CI, 3.5-6.9). Med time to response was 1.6 mo (range, 1.2-5.6) and med OS was 10.9 mo (95% CI, 8.9-13.8). DOR, PFS, and OS rates (95% CI) at 12 mo were 30% (13.6-48.8), 14% (7.2-23.3), and 45% (35.4-53.8), respectively, with 7 (6%) pts still receiving SG at 12 mo. In pts who received prior enfortumab vedotin (n=10) and prior PT in the (neo)adjuvant setting (n=39), results were consistent with the overall population. Grade ≥3 treatment-related adverse events (TRAEs) occurred in 65% of pts and were similar to prior reports; the most common Grade ≥3 TRAEs were neutropenia (35%), leukopenia (18%), anemia (14%), diarrhea (10%), and febrile neutropenia (10%). One treatment-related death occurred due to febrile neutropenia-related sepsis. Conclusions: At 10.5-mo med follow-up, the response rate remains high in pts with heavily pretreated mUC, including pts with visceral metastases, prior EV therapy and prior (neo)adjuvant PT therapy. No new safety signals were observed. These data support the use of SG in pts with mUC who received PT and a CPI and further evaluation of SG in earlier lines of therapy. Clinical trial information: NCT03547973 .