PMID- 38244927 OWN - NLM STAT- MEDLINE DCOM- 20240408 LR - 20240424 IS - 1569-8041 (Electronic) IS - 0923-7534 (Linking) VI - 35 IP - 4 DP - 2024 Apr TI - 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: updated safety and efficacy outcomes. PG - 392-401 LID - S0923-7534(24)00009-7 [pii] LID - 10.1016/j.annonc.2024.01.002 [doi] AB - BACKGROUND: Sacituzumab govitecan (SG) is a Trop-2-directed antibody-drug conjugate containing cytotoxic SN-38, the active metabolite of irinotecan. SG received accelerated US Food and Drug Administration approval for locally advanced (LA) or metastatic urothelial carcinoma (mUC) previously treated with platinum-based chemotherapy and a checkpoint inhibitor, based on cohort 1 of the TROPHY-U-01 study. Mutations in the uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) gene are associated with increased adverse events (AEs) with irinotecan-based therapies. Whether UGT1A1 status could impact SG toxicity and efficacy remains unclear. PATIENTS AND METHODS: TROPHY-U-01 (NCT03547973) is a multicohort, open-label, phase II registrational study. Cohort 1 includes patients with LA or mUC who progressed after platinum- and checkpoint inhibitor-based therapies. SG was administered at 10 mg/kg intravenously on days 1 and 8 of 21-day cycles. The primary endpoint was objective response rate (ORR) per central review; secondary endpoints included progression-free survival, overall survival, and safety. Post hoc safety analyses were exploratory with descriptive statistics. Updated analyses include longer follow-up. RESULTS: Cohort 1 included 113 patients. At a median follow-up of 10.5 months, ORR was 28% (95% CI 20.2% to 37.6%). Median progression-free survival and overall survival were 5.4 months (95% CI 3.5-6.9 months) and 10.9 months (95% CI 8.9-13.8 months), respectively. Occurrence of grade >/=3 treatment-related AEs and treatment-related discontinuation were consistent with prior reports. UGT1A1 status was wildtype ( *1| *1) in 40%, heterozygous ( *1| *28) in 42%, homozygous ( *28| *28) in 12%, and missing in 6% of patients. In patients with *1| *1, *1| *28, and *28| *28 genotypes, any grade treatment-related AEs occurred in 93%, 94%, and 100% of patients, respectively, and were managed similarly regardless of UGT1A1 status. CONCLUSIONS: With longer follow-up, the ORR remains high in patients with heavily pretreated LA or mUC. Safety data were consistent with the known SG toxicity profile. AE incidence varied across UGT1A1 subgroups; however, discontinuation rates remained relatively low for all groups. CI - Copyright (c) 2024 The Authors. Published by Elsevier Ltd.. All rights reserved. FAU - Loriot, Y AU - Loriot Y AD - Medical Oncology Department, Institut de Cancerologie Gustave Roussy, Universite Paris-Saclay, Villejuif, France. Electronic address: Yohann.LORIOT@gustaveroussy.fr. FAU - Petrylak, D P AU - Petrylak DP AD - Genitourinary Oncology, Yale School of Medicine, New Haven. FAU - Rezazadeh Kalebasty, A AU - Rezazadeh Kalebasty A AD - School of Medicine, University of California Irvine, Irvine, USA. FAU - Flechon, A AU - Flechon A AD - Department of Medical Oncology, Centre Leon Berard, Lyon, France. FAU - Jain, R K AU - Jain RK AD - Department of Genitourinary Oncology, Moffitt Cancer Center, Tampa. FAU - Gupta, S AU - Gupta S AD - Division of Oncology, Department of Medicine, Huntsman Cancer Institute, Salt Lake City. FAU - Bupathi, M AU - Bupathi M AD - Medical Oncology, Rocky Mountain Cancer Centers, Littleton, USA. FAU - Beuzeboc, P AU - Beuzeboc P AD - Oncology and Supportive Care Department, Hopital Foch, Suresnes, France. FAU - Palmbos, P AU - Palmbos P AD - Urologic Oncology Clinic, Rogel Cancer Center, University of Michigan, Ann Arbor. FAU - Balar, A V AU - Balar AV AD - Genitourinary Oncology Department, New York University Langone Medical Center, New York. FAU - Kyriakopoulos, C E AU - Kyriakopoulos CE AD - Division of Hematology, Oncology and Palliative Care, University of Wisconsin-Madison, Madison, USA. FAU - Pouessel, D AU - Pouessel D AD - Department of Medical Oncology and Clinical Research Unit, Institut Claudius Regaud/Institut Universitaire du Cancer de Toulouse (IUCT-Oncopole), Toulouse, France. FAU - Sternberg, C N AU - Sternberg CN AD - Department of Genitourinary Oncology, Weill Cornell Medical College of Cornell University, New York. FAU - Tonelli, J AU - Tonelli J AD - Clinical Development - Oncology, Gilead Sciences, Inc., Parsippany. FAU - Sierecki, M AU - Sierecki M AD - Clinical Development - Oncology, Gilead Sciences, Inc., Parsippany. FAU - Zhou, H AU - Zhou H AD - Department of Biometrics, Gilead Sciences, Inc., Foster City. FAU - Grivas, P AU - Grivas P AD - Department of Medicine, University of Washington; Clinical Research Division, Fred Hutchinson Cancer Center, Seattle, USA. FAU - Barthelemy, P AU - Barthelemy P AD - Medical Oncology Department, Institut de Cancerologie Strasbourg Europe, Strasbourg, France. FAU - Tagawa, S T AU - Tagawa ST AD - Department of Genitourinary Oncology, Weill Cornell Medical College of Cornell University, New York. LA - eng PT - Clinical Trial, Phase II PT - Journal Article DEP - 20240118 PL - England TA - Ann Oncol JT - Annals of oncology : official journal of the European Society for Medical Oncology JID - 9007735 RN - M9BYU8XDQ6 (sacituzumab govitecan) RN - 7673326042 (Irinotecan) RN - 49DFR088MY (Platinum) RN - XT3Z54Z28A (Camptothecin) RN - 0 (Immunoconjugates) RN - 0 (Antibodies, Monoclonal, Humanized) SB - IM MH - Humans MH - Irinotecan MH - *Carcinoma, Transitional Cell/drug therapy/genetics MH - Platinum/therapeutic use MH - *Urinary Bladder Neoplasms/drug therapy/genetics MH - Camptothecin/*analogs & derivatives MH - *Immunoconjugates/adverse effects MH - *Antibodies, Monoclonal, Humanized OTO - NOTNLM OT - SN-38 OT - antibody-drug conjugate OT - metastatic urothelial carcinoma OT - sacituzumab govitecan OT - topoisomerase I inhibitor EDAT- 2024/01/21 00:42 MHDA- 2024/04/08 06:42 CRDT- 2024/01/20 19:20 PHST- 2023/09/28 00:00 [received] PHST- 2024/01/02 00:00 [revised] PHST- 2024/01/04 00:00 [accepted] PHST- 2024/04/08 06:42 [medline] PHST- 2024/01/21 00:42 [pubmed] PHST- 2024/01/20 19:20 [entrez] AID - S0923-7534(24)00009-7 [pii] AID - 10.1016/j.annonc.2024.01.002 [doi] PST - ppublish SO - Ann Oncol. 2024 Apr;35(4):392-401. doi: 10.1016/j.annonc.2024.01.002. Epub 2024 Jan 18.