FORAGER-2: A Phase 3, Randomized, Double-blind, Placebo-controlled Study Evaluating the Efficacy and Safety of Vepugratinib Combined With Enfortumab Vedotin and Pembrolizumab in Adults With Untreated Locally Advanced or Metastatic Urothelial Carcinoma With an FGFR3 Genetic Alteration

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Investigational drug late phase More information Active drug More information Moderate burden on patient More information

Trial Details

Sponsor: Eli Lilly and Company (industry)

Phase: 3

Start date: Dec. 12, 2025

Planned enrollment: 450

Trial ID: NCT07218380
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More trial details at ClinicalTrials.gov More info

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chevron Show for: Vepugratinib

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Goal: To determine whether adding the investigational FGFR3 inhibitor vepugratinib to first-line enfortumab vedotin plus pembrolizumab improves clinical outcomes and is tolerable versus placebo plus enfortumab vedotin plus pembrolizumab in FGFR3-altered unresectable locally advanced or metastatic urothelial carcinoma.

Patients: Adults with histologically confirmed unresectable locally advanced or metastatic urothelial carcinoma (mixed histology allowed if a urothelial component is present; small cell/neuroendocrine excluded) whose tumor or blood testing demonstrates a qualifying FGFR3 genetic alteration. Patients must have measurable disease by RECIST v1.1, ECOG 0–2, and adequate organ function. Key exclusions include any prior systemic therapy for locally advanced/metastatic disease, unresolved >Grade 1 toxicities from prior perioperative therapy, baseline Grade ≥2 neuropathy, untreated/uncontrolled CNS disease or leptomeningeal disease, and certain ocular disorders (corneal keratopathy/retinal disorder) at screening.

Design: Phase 3, randomized, double-blind, placebo-controlled, multicenter study with an initial safety lead-in cohort. Efficacy includes blinded independent central review for progression-free survival and key response endpoints, with follow-up planned up to approximately 6 years.

Treatments: Patients receive oral vepugratinib or matched oral placebo in combination with intravenous enfortumab vedotin (a nectin-4–directed antibody–drug conjugate) plus intravenous pembrolizumab (anti–PD-1). Vepugratinib (LY3866288; LOXO-435) is a potent, highly FGFR3-selective oral kinase inhibitor designed to target FGFR3-altered tumors while potentially reducing off-target toxicities seen with less selective/pan-FGFR inhibition; preclinical work supports combination with enfortumab vedotin by increasing nectin-4 expression in FGFR3-altered urothelial cancer models. Early phase 1 data in FGFR3-altered metastatic urothelial cancer reported objective responses in roughly one-third to ~40% of evaluable patients at active doses, and a very small early triplet cohort with enfortumab vedotin plus pembrolizumab showed responses in most patients at first assessment; these findings underpin the phase 3 strategy but remain preliminary.

Outcomes: Primary assessments include treatment-related adverse events attributed to vepugratinib when combined with enfortumab vedotin and pembrolizumab, overall response rate during the safety lead-in, and progression-free survival by blinded independent central review. Key secondary endpoints include overall survival, objective response rate (by central review and by investigator), duration of response (central review and investigator), investigator-assessed progression-free survival, PFS2, safety lead-in disease control rate and time to response, patient-reported global health status/quality of life and physical function (EORTC QLQ-C30), and pharmacokinetics of vepugratinib via serial plasma sampling.

Burden on patient: Overall burden is moderate. Treatment involves an oral study drug taken continuously plus frequent clinic visits for standard enfortumab vedotin and pembrolizumab infusions, with corresponding routine labs and toxicity monitoring typical for this backbone (including attention to neuropathy and ocular symptoms). There is added study burden from the double-blind placebo-controlled design, scheduled response assessments over a long follow-up horizon, and protocolized pharmacokinetic blood draws every other cycle (odd cycles) while on treatment; molecular confirmation of FGFR3 alteration is required but can be done from tumor or blood and does not necessarily mandate a new biopsy.

Last updated: Jan 2026

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Tokushima, 770-8503, Japan

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Tsukuba, 305-8576, Japan

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Warsaw, 02-798, Poland

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Krakow, 30-727, Poland

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Warsaw, 02-786, Poland

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Seoul, 05505, South Korea

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Junggu, 35015, South Korea

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Seoul, 07985, South Korea

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Namdong-gu, 21565, South Korea

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Goyang-si, 10408, South Korea

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Seoul, 06351, South Korea

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Seongnam, 13620, South Korea

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Seoul, 03080, South Korea

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Seoul, 03722, South Korea

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Seoul, 06591, South Korea

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Santiago de Compostela, 15706, Spain

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Pamplona, 31009, Spain

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Status: Not yet recruiting

H.R.U Málaga - Hospital General

Málaga, 29011, Spain

No email / 951308130

Status: Not yet recruiting

Hospital Arnau de Vilanova

Valencia, 46015, Spain

No email / 679370073

Status: Not yet recruiting

Hospital Clinico San Carlos

Madrid, 28040, Spain

No email / 913307545

Status: Not yet recruiting

Hospital Clínic de Barcelona

Barcelona, 08036, Spain

No email / 34 932275402

Status: Not yet recruiting

Hospital General Universitario Gregorio Marañon

Madrid, 28009, Spain

No email / 34914265238

Status: Not yet recruiting

Hospital General Universitario de Elche

Elche, 03202, Spain

No email / No phone

Status: Not yet recruiting

Hospital Infanta Cristina

Badajoz, 06006, Spain

No email / 924218040

Status: Not yet recruiting

Hospital Insular de Gran Canaria

Las Palmas de Gran Canaria, 35016, Spain

No email / No phone

Status: Not yet recruiting

Hospital La Princesa

Madrid, 28006, Spain

No email / +34915202200

Status: Not yet recruiting

Hospital Universitari Sant Joan de Reus

Reus, 43204, Spain

No email / No phone

Status: Not yet recruiting

Hospital Universitari Vall d'Hebron

Barcelona, 08035, Spain

No email / 932746000 x 4350

Status: Not yet recruiting

Hospital Universitario 12 de Octubre

Madrid, 28041, Spain

No email / 0034 91 390 83 39

Status: Not yet recruiting

Hospital Universitario La Paz

Madrid, 28046, Spain

No email / 917277516

Status: Not yet recruiting

Hospital Universitario Marqués de Valdecilla

Santander, 39008, Spain

No email / 607552230

Status: Not yet recruiting

Hospital Universitario Quironsalud Madrid

Pozuelo de Alarcón, 28223, Spain

No email / +34914521987

Status: Not yet recruiting

Hospital Universitario Ramón y Cajal

Madrid, 28034, Spain

No email / (+34) 913368263

Status: Not yet recruiting

Hospital Universitario Reina Sofia

Córdoba, 14004, Spain

No email / No phone

Status: Not yet recruiting

Hospital Universitario Virgen Del Rocio

Seville, 41013, Spain

No email / 34955013068

Status: Not yet recruiting

Hospital de la Santa Creu i Sant Pau

Barcelona, 08041, Spain

No email / 34935565638

Status: Not yet recruiting

Institut Català d'Oncologia (ICO) - Badalona

Badalona, 08916, Spain

No email / 34 934978925

Status: Not yet recruiting

Institut Català d'Oncologia (ICO) - Girona

Girona, 17007, Spain

No email / 34972225834

Status: Not yet recruiting

Instituto Catalan de Oncologia - Hospital Duran i Reynals

Hospitalet, 08907, Spain

No email / +34 932603261

Status: Not yet recruiting

MD Anderson Cancer Center

Madrid, 28033, Spain

No email / No phone

Status: Not yet recruiting

OSI Ezkerraldea-Enkarterri-Cruces - Hospital Universitario Cruces

Barakaldo, 48903, Spain

No email / No phone

Status: Not yet recruiting

Chang Gung Medical Foundation-Linkou Branch

Taoyuan District, 333, Taiwan

No email / 886-3-3281200

Status: Not yet recruiting

Chang Gung Memorial Hospital at Kaohsiung

Kaohsiung Niao Sung Dist, 83301, Taiwan

No email / 886-972919696

Status: Not yet recruiting

Chi Mei Hospital - Liouying Branch

Tainan, 73657, Taiwan

No email / No phone

Status: Not yet recruiting

Chi Mei Medical Center

Tainan, 71004, Taiwan

No email / No phone

Status: Not yet recruiting

China Medical University Hospital

Taichung, 404332, Taiwan

No email / +886422052121

Status: Not yet recruiting

Kaohsiung Medical University Chung-Ho Memorial Hospital

Kaohsiung City, 807, Taiwan

No email / No phone

Status: Not yet recruiting

National Cheng Kung University Hospital

Tainan, 704, Taiwan

No email / 0980971870

Status: Not yet recruiting

National Taiwan University Cancer Center (NTUCC)

Taipei, 106, Taiwan

No email / No phone

Status: Not yet recruiting

National Taiwan University Hospital

Taipei, 10002, Taiwan

No email / No phone

Status: Not yet recruiting

Taichung Veterans General Hospital

Taichung, 407, Taiwan

No email / No phone

Status: Not yet recruiting

Taipei Veterans General Hospital

Taipei, 11217, Taiwan

No email / 886228757519-323

Status: Not yet recruiting

Adana Medical Park Seyhan Hastanesi

Adana, 01140, Turkey (Türkiye)

No email / 905325005269

Status: Not yet recruiting

Ankara Bilkent Şehir Hastanesi

Ankara, 06800, Turkey (Türkiye)

No email / 905555306271

Status: Not yet recruiting

Ankara University Health Practice and Research Hospitals

Ankara, 06100, Turkey (Türkiye)

No email / 00903125957321

Status: Not yet recruiting

Antalya Egitim ve Arastırma Hastanesi

Antalya, 07100, Turkey (Türkiye)

No email / 905336488217

Status: Not yet recruiting

Dicle Üniversitesi

Diyarbakır, 21200, Turkey (Türkiye)

No email / 90 5337677131

Status: Not yet recruiting

Dr. Lutfi Kirdar Kartal Training and Research Hospital

Istanbul, 34890, Turkey (Türkiye)

No email / No phone

Status: Not yet recruiting

Gaziantep Universitesi Sahinbey Arastirma ve Uygulama Hastanesi

Gaziantep, 27310, Turkey (Türkiye)

No email / 05065118207

Status: Not yet recruiting

Marmara Universitesi Pendik Egitim Arastirma Hastanesi

Istanbul, 34899, Turkey (Türkiye)

No email / 905433389339

Status: Not yet recruiting

Sakarya University School of Medicine

Adapazarı, 54100, Turkey (Türkiye)

No email / +90 5054785576

Status: Not yet recruiting

Trakya University

Edirne, 22030, Turkey (Türkiye)

No email / 90 5334364678

Status: Not yet recruiting

zmir Katip Çelebi Üniversitesi Atatürk Eitim Ve Aratrma Hastanesi

Izmir, 35360, Turkey (Türkiye)

No email / 905324078648

Status: Not yet recruiting

Huddersfield Royal Infirmary

Huddersfield, HD3 3EA, United Kingdom

No email / No phone

Status: Not yet recruiting

Royal Marsden Hospital (Chelsea)

London, SW3 6JJ, United Kingdom

No email / +44 (0) 2086613529

Status: Not yet recruiting

Royal Marsden Hospital (Sutton)

London, SM2 5PT, United Kingdom

No email / +44 (0) 2086613529

Status: Not yet recruiting

St Bartholomew's Hospital

London, EC1A 7BE, United Kingdom

No email / 02078828494

Status: Not yet recruiting

The Christie NHS Foundation Trust

Manchester, M20 4BX, United Kingdom

No email / 01614468409

Status: Not yet recruiting

University College London Hospital

London, NW1 2PG, United Kingdom

No email / No phone

Status: Not yet recruiting

Weston Park Hospital

Sheffield, S10 2SJ, United Kingdom

No email / No phone

Status: Not yet recruiting

Clearview Cancer Institute

Huntsville, Alabama, 35805, United States

No email / 256-705-4224

Status: Not yet recruiting

The University of Arizona Cancer Center - North Campus

Tucson, Arizona, 85719, United States

No email / 520-626-4703

Status: Not yet recruiting

Hunt Cancer Institute, an Affiliate of Cedars-Sinai Cancer (TMPN)

Torrance, California, 90505, United States

No email / 310-750-3300

Status: Not yet recruiting

TRIO-US (Translational Research in Oncology-US)

Los Angeles, California, 90024, United States

No email / No phone

Status: Not yet recruiting

UCLA Hematology/Oncology - Santa Monica

Los Angeles, California, 90404, United States

No email / No phone

Status: Not yet recruiting

UCSF Medical Center at Mission Bay

San Francisco, California, 94158, United States

No email / 773-837-0783

Status: Not yet recruiting

AdventHealth Medical Group - Porter

Denver, Colorado, 80210, United States

No email / 303-715-7030

Status: Not yet recruiting

Colorado West Healthcare System - Grand Valley Oncology

Grand Junction, Colorado, 81505, United States

No email / 970-644-4460

Status: Not yet recruiting

AdventHealth Orlando

Orlando, Florida, 32804, United States

No email / 407-303-2024

Status: Not yet recruiting

St. Luke's Cancer Institute: Boise

Boise, Idaho, 83712, United States

No email / No phone

Status: Not yet recruiting

University of Chicago Medical Center

Chicago, Illinois, 60637, United States

No email / 773-702-1152

Status: Not yet recruiting

University of Illinois at Chicago

Chicago, Illinois, 60612, United States

No email / No phone

Status: Not yet recruiting

Franciscan Health

Indianapolis, Indiana, 46237, United States

No email / No phone

Status: Not yet recruiting

Indiana University Melvin and Bren Simon Cancer Center

Indianapolis, Indiana, 46202, United States

No email / No phone

Status: Not yet recruiting

Parkview Research Center at Parkview Regional Medical Center

Fort Wayne, Indiana, 46845, United States

No email / No phone

Status: Not yet recruiting

University of Kentucky Chandler Medical Center

Lexington, Kentucky, 40536, United States

No email / No phone

Status: Not yet recruiting

Mary Bird Perkins Cancer Center

Baton Rouge, Louisiana, 70809, United States

No email / 225-215-1185

Status: Not yet recruiting

Johns Hopkins Hospital

Baltimore, Maryland, 21287, United States

No email / No phone

Status: Not yet recruiting

Massachusetts General Hospital

Boston, Massachusetts, 02114, United States

No email / 617-724-4000

Status: Not yet recruiting

Karmanos Cancer Institute

Detroit, Michigan, 48201, United States

No email / No phone

Status: Not yet recruiting

Washington University School of Medicine

St Louis, Missouri, 63108, United States

No email / No phone

Status: Not yet recruiting

Columbia University Irving Medical Center

New York, New York, 10032, United States

No email / No phone

Status: Not yet recruiting

Icahn School of Medicine at Mount Sinai

New York, New York, 10029, United States

No email / No phone

Status: Not yet recruiting

Memorial Sloan Kettering Cancer Center

New York, New York, 10065, United States

No email / 646-888-4737

Status: Not yet recruiting

Weill Cornell Medical College

New York, New York, 10065, United States

No email / 317-217-9178

Status: Not yet recruiting

The James Cancer Hospital and Solove Research Institute at The Ohio State University Comprehensive Cancer -T

Columbus, Ohio, 43210, United States

No email / No phone

Status: Not yet recruiting

Kaiser Permanente Interstate Medical Office Central

Portland, Oregon, 97227, United States

No email / 503-249-3315

Status: Not yet recruiting

Oregon Health and Science University

Portland, Oregon, 97239, United States

No email / No phone

Status: Not yet recruiting

Providence Portland Medical Center

Portland, Oregon, 97213, United States

No email / No phone

Status: Not yet recruiting

Providence St. Vincent Medical Center

Portland, Oregon, 97225, United States

No email / No phone

Status: Not yet recruiting

AHN Allegheny General Hospital

Pittsburgh, Pennsylvania, 15212, United States

No email / 412-325-5700

Status: Not yet recruiting

Lancaster General Hospital - Ann B Barshinger Cancer Institute

Lancaster, Pennsylvania, 17601, United States

No email / No phone

Status: Not yet recruiting

Avera Cancer Institute- Research

Sioux Falls, South Dakota, 57105, United States

No email / No phone

Status: Not yet recruiting

SCRI Oncology Partners

Nashville, Tennessee, 37203, United States

No email / No phone

Status: Not yet recruiting

Sarah Cannon Research Institute

Nashville, Tennessee, 37203, United States

No email / No phone

Status: Not yet recruiting

Tennessee Oncology

Nashville, Tennessee, 37203, United States

No email / No phone

Status: Not yet recruiting

Tennessee Oncology Chattanooga

Chattanooga, Tennessee, 37404, United States

No email / No phone

Status: Not yet recruiting

Vanderbilt University Medical Center

Nashville, Tennessee, 37232, United States

No email / No phone

Status: Not yet recruiting

Nova Oncology

McAllen, Texas, 78504, United States

No email / 281-944-3610

Status: Not yet recruiting

Parkland Health and Hospital System

Dallas, Texas, 75235, United States

No email / 214-648-4180

Status: Not yet recruiting

US Oncology Research Network

The Woodlands, Texas, 77380, United States

No email / No phone

Status: Not yet recruiting

USO - Texas Oncology - Northeast Texas

Tyler, Texas, 75702, United States

No email / No phone

Status: Not yet recruiting

USO-Texas Oncology-Central/South Texas

Austin, Texas, 78731, United States

No email / No phone

Status: Not yet recruiting

UT Southwestern Medical Center

Dallas, Texas, 75390, United States

No email / 214-648-4180

Status: Not yet recruiting

University of Texas MD Anderson Cancer Center

Houston, Texas, 77030-4009, United States

No email / No phone

Status: Not yet recruiting

USO - Virginia Oncology Associates

Norfolk, Virginia, 23502, United States

No email / No phone

Status: Not yet recruiting

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