(UroToday.com) Dr. Loriot presented the safety data of the TROPHY-U-01 cohort 1, stratified by UGT1A1 status. TROPHY-U-01 was a phase 2 study of sacituzumab govitecan (SG) in patients (pts) with metastatic urothelial cancer (mUC) who progressed after platinum (PT)-based chemotherapy and a checkpoint inhibitor (CPI).
As some background, sacituzumab govitecan (SG) is a Trop-2–directed antibody-drug conjugate that was granted FDA accelerated approval for patients with mUC previously treated with platinum-based chemotherapy and a CPI. Approval was based on the pivotal TROPHY-U-01 Cohort 1 study of 113 pts, where SG demonstrated an objective response rate (ORR) of 27%, a median overall survival (OS) of 10.9 mo, and a manageable safety profile (median follow up 9.1 mo [range, 0-19.9]). Updated results were just presented as GU ASCO 2023. ORR was now 28%, median PFS 54 months and median OS was 10.9 months. Landmark DOR, PFS, and OS rates (95% CI) at 12 months were 30% (13.6-48.8), 14% (7.2-23.3), and 45% (35.4-53.8), respectively, with 7 (6%) patients still receiving sacituzumab govitecan at 12 months.
A phase 3 confirmatory study TROPiCS-04 (NCT04527991) is ongoing.
Herein, Dr. Loriot presents updated safety outcomes by UGT1A1 status. This is due the fact that hepatic UGT1A1 and UGT1A9 play a major role in the detoxification of SN-38. UGT1A1*28 is the most common polymorphism and approximately 10% of patients have the homozygotic form in Western countries.
The study design for TROPHY-U-01 is shown below:
Patients in Cohort 1 were specifically patients that had progressed following platinum-based chemo and a CPI. They received SG 10 mg/kg on D1 and D8 of 21-D cycles. The primary endpoint was ORR per central review by RECIST 1.1.
For the purposes of this abstract, post hoc safety analyses were exploratory with descriptive statistics reported.
Focusing on the safety profile, Grade 3 or higher treatment-related adverse events (TRAEs) occurrence and treatment-related discontinuation were consistent with prior reports.
In total, 94% of treated patients (n=106) had an evaluable UGT1A1 status, of which 45 were wild type, 47 were heterozygous, and 14 were homozygous.
- Gr ≥3 TRAEs occurred in 62% of wild-type, 60% of heterozygous, and 79% of homozygous patients
Breaking down the types of AEs (any grade):
- Any Gr diarrhea was 53%, 72%, and 71%, respectively
- Any Gr neutropenia was 38%, 55%, and 50%, respectively
- Any Gr anemia was 38%, 32%, and 29%, respectively
Focusing on Grade 3+ AEs:
- Diarrhea: 4%, 15%, and 7%, respectively;
- Neutropenia: 31%, 36%, and 50%, respectively
- Anemia: 13%, 19%, and 29%
TRAEs leading to SG discontinuation occurred in 7%, 6%, and 14% of pts with wild-type, heterozygous, and homozygous status, respectively.
In this exploratory analysis of safety profile stratified by UGT1A1 status, Dr. Loriot and team report that the incidence of adverse events varied across UGT1A1 subgroups, with dose interruptions being more frequently observed in homozygous pts. However they note that this is limited by the fact that there were low numbers in each subgroup, so further studies will be needed to confirm the impact of this UGT1A1 status on safety outcomes. however if validated, it may impact the decision to use SG in certain populations.
Presented by: Yohann Loriot, MD, PhD, Physician Scientist, Director of Bladder Cancer Program, Gustave Roussy; Université Paris-Saclay, Villejuif, France
Written by: Thenappan (Thenu) Chandrasekar, MD – Urologic Oncologist, Associate Professor of Urology, University of California, Davis, @tchandra_uromd @UCDavisUrology on Twitter during the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting, Chicago, IL, Fri, June 2 – Tues, June 6, 2023.
References:- Tagawa ST, Balar AV, Petrylak DP, et al. TROPHY-U-01: A Phase II Open-Label Study of Sacituzumab Govitecan in Patients With Metastatic Urothelial Carcinoma Progressing After Platinum-Based Chemotherapy and Checkpoint Inhibitors. J Clin Oncol. 2021 Aug 1;39(22):2474-2485. doi: 10.1200/JCO.20.03489. Epub 2021 Apr 30. PMID: 33929895; PMCID: PMC8315301.