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Clinical Trial
. 2021 Aug 1;39(22):2474-2485.
doi: 10.1200/JCO.20.03489. Epub 2021 Apr 30.

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

Scott T Tagawa  1 , Arjun V Balar  2 , Daniel P Petrylak  3 , Arash Rezazadeh Kalebasty  4 , Yohann Loriot  5 , Aude Fléchon  6 , Rohit K Jain  7 , Neeraj Agarwal  8 , Manojkumar Bupathi  9 , Philippe Barthelemy  10 , Philippe Beuzeboc  11 , Phillip Palmbos  12 , Christos E Kyriakopoulos  13 , Damien Pouessel  14 , Cora N Sternberg  1 , Quan Hong  15 , Trishna Goswami  15 , Loretta M Itri  15 , Petros Grivas  16
Affiliations
Clinical Trial

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

Scott T Tagawa et al. J Clin Oncol. .

Abstract

Purpose: Patients with metastatic urothelial carcinoma (mUC) who progress on platinum-based combination chemotherapy (PLT) and checkpoint inhibitors (CPIs) have limited options that offer objective response rates (ORRs) of approximately 10% with a median overall survival (OS) of 7-8 months. Sacituzumab govitecan (SG) is a TROP-2-directed antibody-drug conjugate with an SN-38 payload that has shown preliminary activity in mUC.

Methods: TROPHY-U-01 (ClinicalTrials.gov identifier: NCT03547973) is a multicohort, open-label, phase II, registrational study. Cohort 1 includes patients with locally advanced or unresectable or mUC who had progressed after prior PLT and CPI. Patients received SG 10 mg/kg on days 1 and 8 of 21-day cycles. The primary outcome was centrally reviewed ORR; secondary outcomes were progression-free survival, OS, duration of response, and safety.

Results: Cohort 1 included 113 patients (78% men; median age, 66 years; 66.4% visceral metastases; median of three [range, 1-8] prior therapies). At a median follow-up of 9.1 months, the ORR was 27% (31 of 113; 95% CI, 19.5 to 36.6); 77% had decrease in measurable disease. Median duration of response was 7.2 months (95% CI, 4.7 to 8.6 months), with median progression-free survival and OS of 5.4 months (95% CI, 3.5 to 7.2 months) and 10.9 months (95% CI, 9.0 to 13.8 months), respectively. Key grade ≥ 3 treatment-related adverse events included neutropenia (35%), leukopenia (18%), anemia (14%), diarrhea (10%), and febrile neutropenia (10%), with 6% discontinuing treatment because of treatment-related adverse events.

Conclusion: SG is an active drug with a manageable safety profile with most common toxicities of neutropenia and diarrhea. SG has notable efficacy compared with historical controls in pretreated mUC that has progressed on both prior PLT regimens and CPI. The results from this study supported accelerated approval of SG in this population.

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Conflict of interest statement

Scott TagawaConsulting or Advisory Role: Medivation, Astellas Pharma, Dendreon, Janssen, Bayer, Genentech, Endocyte, Immunomedics, Karyopharm Therapeutics, Abbvie, Tolmar, QED Therapeutics, Amgen, Sanofi, Pfizer, Clovis Oncology, Novartis, Genomic Health, POINT Biopharma, Blue Earth Diagnostics, Seattle Genetics, AIkido PharmaResearch Funding: Lilly, Sanofi, Janssen, Astellas Pharma, Progenics, Millennium, Amgen, Bristol-Myers Squibb, Dendreon, Rexahn Pharmaceuticals, Bayer, Genentech, Newlink Genetics, Inovio Pharmaceuticals, AstraZeneca, Immunomedics, Novartis, AVEO, Boehringer Ingelheim, Merck, Stem CentRx, Karyopharm Therapeutics, Abbvie, Medivation, Endocyte, Exelixis, Clovis OncologyTravel, Accommodations, Expenses: Sanofi, Immunomedics, AmgenUncompensated Relationships: Telix Pharmaceuticals, ATLAB Pharma, Phosplatin Therapeutics Arjun BalarHonoraria: Merck, Genentech/Roche, AstraZeneca/MedImmuneConsulting or Advisory Role: Immunomedics, Bristol Myers Squibb, Genentech/Roche, Merck, Cerulean Pharma, AstraZeneca/MedImmune, Pfizer/EMD Serono, Incyte, Seattle Genetics/Astellas, Nektar, Dragonfly Therapeutics, GlaxoSmithKlineResearch Funding: Immunomedics, Merck, Genentech/Roche, AstraZeneca/MedImmune, Seattle Genetics Daniel PetrylakStock and Other Ownership Interests: Bellicum Pharmaceuticals, TYMEConsulting or Advisory Role: Bayer, Exelixis, Pfizer, Roche, Astellas Pharma, AstraZeneca, Lilly, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Clovis Oncology, Incyte, Janssen, Pharmacyclics, Seattle Genetics, Urogen pharma, Advanced Accelerator Applications, Ipsen, Bicycle Therapeutics, Mirati Therapeutics, Monopteros TherapeuticsResearch Funding: Progenics, Sanofi, Endocyte, Genentech, Merck, Astellas Medivation, Novartis, AstraZeneca, Bayer, Lilly, Innocrin Pharma, MedImmune, Pfizer, Roche, Seattle Genetics, Clovis Oncology, Bristol Myers Squibb, Advanced Accelerator Applications, Agensys, BioXCel therapeutics, Eisai, Mirati Therapeutics, ReplimuneExpert Testimony: Celgene, sanofi Arash RezazadehStock and Other Ownership Interests: ECOM MedicalConsulting or Advisory Role: Exelixis, AstraZeneca, Bayer, Pfizer, Novartis, Genentech, Bristol Myers Squibb, EMD Serono, Immunomedics, Gilead SciencesSpeakers' Bureau: Janssen, Astellas Medivation, Pfizer, Novartis, Sanofi, Genentech/Roche, Eisai, AstraZeneca, Bristol Myers Squibb, Amgen, Exelixis, Exelixis, EMD Serono, Merck, Seattle Genetics/Astellas, Seattle Genetics/Astellas, Myovant Sciences, Gilead Sciences, AVEOResearch Funding: Genentech, Exelixis, Janssen, AstraZeneca, Bayer, Bristol Myers Squibb, Eisai, Macrogenics, Astellas Pharma, BeyondSpring Pharmaceuticals, BioClin Therapeutics, Clovis Oncology, Bavarian Nordic, Seattle Genetics, Immunomedics, EpizymeTravel, Accommodations, Expenses: Genentech, Prometheus, Astellas Medivation, Janssen, Eisai, Bayer, Pfizer, Novartis, Exelixis, AstraZeneca Yohann LoriotHonoraria: Sanofi, PfizerConsulting or Advisory Role: Janssen, Astellas Pharma, Roche, AstraZeneca, MSD Oncology, MSD Oncology, Seattle Genetics, Bristol Myers Squibb, Immunomedics, Taiho PharmaceuticalResearch Funding: Sanofi, Janssen Oncology, MSD Oncology, AstraZeneca, Clovis Oncology, Exelixis, Boehringer Ingelheim, Incyte, Pfizer, Oncogenex, Medivation, CureVac, NektarTravel, Accommodations, Expenses: Astellas Pharma, Janssen Oncology, Roche, MSD Oncology, AstraZeneca, Seattle Genetics Aude FlechonHonoraria: MSD Oncology, AstraZeneca, Bristol Myers Squibb, Janssen-Cilag, Astellas Pharma, Pfizer, Sanofi/Aventis, Roche/Genentech, Bayer, Ipsen, AAA HealthCareTravel, Accommodations, Expenses: Astellas Pharma, Sanofi/Aventis, Janssen-Cilag, Bayer, Pfizer, Ipsen, Bristol Myers Squibb, AstraZeneca, MSD Oncology, Roche/Genentech, AAA HealthCare Rohit JainHonoraria: AlphasightsConsulting or Advisory Role: Taiho Oncology, Pfizer, Seattle Genetics/Astellas, Gilead Sciences, EMD SeronoSpeakers' Bureau: Seattle Genetics/Astellas Neeraj AgarwalConsulting or Advisory Role: Pfizer, Medivation/Astellas, Bristol Myers Squibb, AstraZeneca, Nektar, Lilly, Bayer, Foundation One Inc, Pharmacyclics, Foundation Medicine, Astellas Pharma, Lilly, Exelixis, AstraZeneca, Pfizer, Merck, Novartis, Lilly, Eisai, Seattle Genetics, EMD Serono, Janssen Oncology, AVEO, Calithera Biosciences, MEI Pharma, Genentech, Astellas PharmaResearch Funding: Bayer, Bristol Myers Squibb, GlaxoSmithKline, Takeda, Novartis, Pfizer, BN ImmunoTherapeutics, Exelixis, TRACON Pharma, Rexahn Pharmaceuticals, Amgen, AstraZeneca, Active Biotech, Bavarian Nordic, Calithera Biosciences, Celldex, Eisai, Genentech, Immunomedics, Janssen, Merck, Newlink Genetics, Prometheus, Sanofi Manojkumar BupathiHonoraria: Bristol Myers Squibb, Exelixis, AstraZeneca, Pfizer, Astellas PharmaConsulting or Advisory Role: Bristol Myers Squibb, AstraZeneca, ExelixisSpeakers' Bureau: AstraZeneca, Bristol Myers Squibb, Pfizer, Exelixis, Astellas Pharma Philippe BarthelemyHonoraria: Ipsen, Bristol Myers Squibb, MSD, Astellas Pharma, Janssen-Cilag, Pfizer, Merck KGaAConsulting or Advisory Role: Ipsen, Bristol Myers Squibb, MSD Oncology, Pfizer, Janssen-Cilag, AstraZeneca, AmgenTravel, Accommodations, Expenses: Bristol Myers Squibb, Pfizer, Janssen-Cilag, Astellas Pharma, MSD, Ipsen Phillip PalmbosResearch Funding: Roche, Immunomedics Christos KyriakopoulosConsulting or Advisory Role: Exelixis, Sanofi, AVEO, EMD Serono, Janssen OncologyResearch Funding: Sanofi Damien PouesselHonoraria: Ipsen, Janssen Oncology, Bristol Myers Squibb, AstraZeneca, Merck, Astellas PharmaConsulting or Advisory Role: Astellas Pharma, AstraZeneca, Janssen Oncology, Pfizer, SanofiResearch Funding: Incyte, Merck Sharp & Dohme, Roche, Bristol Myers Squibb, AstraZeneca, Janssen Oncology, Seattle GeneticsTravel, Accommodations, Expenses: Janssen Oncology, AstraZeneca, Pfizer Cora SternbergConsulting or Advisory Role: BMS, MSD, Pfizer, Roche-Genentech, Incyte, AstraZeneca, Merck, Medscape, UroToday, Astellas Pharma, Sanofi-Genzyme, Immunomedics, now Gilead, Foundation Medicine, CCO Clinical, Janssen, NCIResearch Funding: Pfizer, MSD, Astellas, BMS, Immunomedics, now Gilead, Arvinas, Mirati Quan HongEmployment: Immunomedics, Gilead SciencesLeadership: ImmunomedicsStock and Other Ownership Interests: Immunomedics Trishna GoswamiEmployment: Immunomedics/GileadLeadership: Immunomedics/GileadStock and Other Ownership Interests: Immunomedics/GileadPatents, Royalties, Other Intellectual Property: Patents around combinations with TrodelvyTravel, Accommodations, Expenses: Immunomedics/Gilead Loretta ItriEmployment: Immunomedics/GileadLeadership: Immunomedics/GileadStock and Other Ownership Interests: ImmunomedicsConsulting or Advisory Role: ImmunomedicsTravel, Accommodations, Expenses: Immunomedics Petros GrivasConsulting or Advisory Role: Merck, Bristol Myers Squibb, AstraZeneca, Clovis Oncology, EMD Serono, Seattle Genetics, Foundation Medicine, Pfizer, Janssen, Bayer, Genzyme, Mirati Therapeutics, Exelixis, Roche, GlaxoSmithKline, Genentech, Immunomedics, Dyania Health, Infinity Pharmaceuticals, QED Therapeutics, 4D Pharma PLCResearch Funding: Pfizer, Clovis Oncology, Bavarian Nordic, Immunomedics, Bristol Myers Squibb, Debiopharm Group, Merck, QED Therapeutics, Kure It Cancer Research, GlaxoSmithKline, Mirati TherapeuticsNo other potential conflicts of interest were reported.

Figures

FIG 1.
FIG 1.
CONSORT diagram. CPI, checkpoint inhibitor; IV, intravenous; mUC, metastatic urothelial cancer.
FIG 2.
FIG 2.
Tumor response to sacituzumab govitecan. (A) Waterfall plot showing best percent change from baseline in the sum of the diameters of the target lesions (longest for non-nodal and short axis for nodal lesions) in 94 patients (excludes 19 patients; 15 patients did not have post-baseline radiologic assessments and four patients lacked or had unevaluable target lesions at baseline or post-baseline). The dashed lines at +20% and −30% indicate thresholds for PD and partial response, respectively, according to RECIST v1.1. Target lesions were reduced in 77% of patients (72 of 94) with at least 1 post-baseline target lesion measurement. (B) Spider plot of tumor response by week. (C) Swimmer plot of response and duration. PD, progressive disease.
FIG 3.
FIG 3.
Kaplan-Meier analysis of (A) PFS, (B) OS, and (C) DOR. DOR, duration of response; OS, overall survival; PFS, progression-free survival.
FIG A1.
FIG A1.
TROPHY-U-01 study design. EudraCT Number: 2018-001167-23; ClinicalTrials.gov identifier: NCT03547973; IMMU-132-06 study. CPI, checkpoint inhibitor; DOR, duration of response; mUC, metastatic urothelial cancer; ORR, objective response rate; OS, overall survival; PD-1, programmed death-1; PD-L1, programmed death-ligand 1; PFS, progression-free survival; SG, sacituzumab govitecan.
FIG A2.
FIG A2.
Forest plot showing ORR in different subgroups. Horizontal line represents CI. ECOG, Eastern Cooperative Oncology Group; NA, not available; ORR, objective response rate.
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