Sponsor: Eli Lilly and Company (industry)
Phase: 3
Start date: Dec. 12, 2025
Planned enrollment: 450
Vepugratinib (also known as LY3866288 or LOXO-435) is an investigational oral targeted therapy being developed primarily for FGFR3-altered urothelial carcinoma and other FGFR3-altered solid tumors. Early human data have been reported from the ongoing first-in-human FORAGER-1 phase 1 program, and a registrational phase 3 study (FORAGER-2) has started enrollment in first-line metastatic/locally advanced urothelial cancer with FGFR3 alterations.
- Phase 1 (FORAGER-1; NCT05614739): study description and cohorts include monotherapy dose escalation/optimization plus expansion cohorts including combinations with pembrolizumab ± enfortumab vedotin. (Lilly trial overview, UC BRAID listing)
- Phase 3 (FORAGER-2; NCT07218380): vepugratinib vs placebo combined with enfortumab vedotin + pembrolizumab in previously untreated locally advanced/metastatic urothelial carcinoma with an FGFR3 genetic alteration. (UCSF trial page)
Monotherapy (FORAGER-1)
- ASCO GU 2025 (initial dose-escalation results; metastatic urothelial cancer subset at ≥200 mg BID): In 39 evaluable metastatic urothelial cancer patients with activating FGFR3 mutation/fusion, the confirmed objective response rate (ORR) was 41% (16/39) with disease control rate (DCR) 90%; among those previously treated with an FGFR inhibitor, the confirmed response rate was reported as 50% (6/12). (UroToday ASCO GU 2025 report)
- ESMO 2025 (dose-optimization portion): In metastatic urothelial cancer, vepugratinib monotherapy showed ORRs around the low-to-mid 30% range across evaluated twice-daily doses; for example, ORR 34% at 200 mg BID was reported, with all responses described as partial responses in one summary. (UroToday ESMO 2025 report, OncLive summary of ESMO 2025)
Combination (early signal; FORAGER-1 expansion)
- In a very small early cohort combining vepugratinib 200 mg BID + enfortumab vedotin + pembrolizumab (reported n=5), 4/5 patients responded at first scan (reported as 3 partial responses and 1 complete response). (UroToday ESMO 2025 report)
Monotherapy (FORAGER-1)
- Across dose-optimization/dose-escalation summaries, the most frequently highlighted adverse event has been diarrhea, typically grade 1–2. (UroToday ASCO GU 2025 report)
- ESMO 2025 reporting described uncommon rates of higher-grade adverse events considered typical of pan-FGFR inhibitors (e.g., hyperphosphatemia, nail/skin disorders, ocular toxicities), with examples including hyperphosphatemia 19% (reported as transient and predominantly grade 1) and relatively low discontinuation due to adverse events in one 200 mg BID safety cohort summary. (UroToday ESMO 2025 report)
- A media summary of ESMO 2025 reported high overall rates of treatment-emergent adverse events (TEAEs) with grade ≥3 TEAEs in the ~37–49% range across selected dose groups, with low discontinuation rates in that summary. (OncLive ESMO 2025 summary)
Combination (FORAGER-1 expansion; very limited n)
- In the small combination cohort (n=5) with enfortumab vedotin + pembrolizumab, reported common treatment-related adverse events included nausea, diarrhea, fatigue, decreased appetite, and dry mouth (each reported at 40%), with overall safety described as consistent with the individual agents. (UroToday ESMO 2025 report)
Last updated: Jan 2026
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
Inclusion Criteria:
* Have histologically confirmed, unresectable locally advanced or metastatic urothelial cancer (mUC). Individuals with mixed histology other than small cell or neuroendocrine carcinoma are eligible if a urothelial component is present.
* Have a qualifying fibroblast growth factor receptor 3 (FGFR3) genetic alteration determined via molecular testing from a tumor or blood sample obtained at or any time after diagnosis of advanced or metastatic urothelial cancer.
* Have measurable disease by investigator assessment defined by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1
* Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2.
* Have adequate laboratory parameters
Exclusion Criteria:
* Have received prior systemic therapy for locally advanced or metastatic urothelial cancer (mUC).
* Have any unresolved toxicities greater than Grade 1 Common Terminology Criteria for Adverse Events (\[CTCAE\] version 5.0) from prior neoadjuvant or adjuvant systemic therapy.
* Have ongoing sensory or motor neuropathy of Grade 2 or higher
* Have untreated or uncontrolled central nervous system (CNS) involvement or any history of leptomeningeal disease.
* Current evidence corneal keratopathy or retinal disorder confirmed by ocular examination at screening.
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No email / No phone
Status: Not yet recruiting
Sheffield, S10 2SJ, United Kingdom
No email / No phone
Status: Not yet recruiting
Huntsville, Alabama, 35805, United States
No email / 256-705-4224
Status: Not yet recruiting
Tucson, Arizona, 85719, United States
No email / 520-626-4703
Status: Not yet recruiting
Torrance, California, 90505, United States
No email / 310-750-3300
Status: Not yet recruiting
Los Angeles, California, 90024, United States
No email / No phone
Status: Not yet recruiting
Los Angeles, California, 90404, United States
No email / No phone
Status: Not yet recruiting
San Francisco, California, 94158, United States
No email / 773-837-0783
Status: Not yet recruiting
Denver, Colorado, 80210, United States
No email / 303-715-7030
Status: Not yet recruiting
Grand Junction, Colorado, 81505, United States
No email / 970-644-4460
Status: Not yet recruiting
Orlando, Florida, 32804, United States
No email / 407-303-2024
Status: Not yet recruiting
Boise, Idaho, 83712, United States
No email / No phone
Status: Not yet recruiting
Chicago, Illinois, 60637, United States
No email / 773-702-1152
Status: Not yet recruiting
Chicago, Illinois, 60612, United States
No email / No phone
Status: Not yet recruiting
Indianapolis, Indiana, 46237, United States
No email / No phone
Status: Not yet recruiting
Indianapolis, Indiana, 46202, United States
No email / No phone
Status: Not yet recruiting
Fort Wayne, Indiana, 46845, United States
No email / No phone
Status: Not yet recruiting
Lexington, Kentucky, 40536, United States
No email / No phone
Status: Not yet recruiting
Baton Rouge, Louisiana, 70809, United States
No email / 225-215-1185
Status: Not yet recruiting
Baltimore, Maryland, 21287, United States
No email / No phone
Status: Not yet recruiting
Boston, Massachusetts, 02114, United States
No email / 617-724-4000
Status: Not yet recruiting
Detroit, Michigan, 48201, United States
No email / No phone
Status: Not yet recruiting
St Louis, Missouri, 63108, United States
No email / No phone
Status: Not yet recruiting
New York, New York, 10032, United States
No email / No phone
Status: Not yet recruiting
New York, New York, 10029, United States
No email / No phone
Status: Not yet recruiting
New York, New York, 10065, United States
No email / 646-888-4737
Status: Not yet recruiting
New York, New York, 10065, United States
No email / 317-217-9178
Status: Not yet recruiting
Columbus, Ohio, 43210, United States
No email / No phone
Status: Not yet recruiting
Portland, Oregon, 97227, United States
No email / 503-249-3315
Status: Not yet recruiting
Portland, Oregon, 97239, United States
No email / No phone
Status: Not yet recruiting
Portland, Oregon, 97213, United States
No email / No phone
Status: Not yet recruiting
Portland, Oregon, 97225, United States
No email / No phone
Status: Not yet recruiting
Pittsburgh, Pennsylvania, 15212, United States
No email / 412-325-5700
Status: Not yet recruiting
Lancaster, Pennsylvania, 17601, United States
No email / No phone
Status: Not yet recruiting
Sioux Falls, South Dakota, 57105, United States
No email / No phone
Status: Not yet recruiting
Nashville, Tennessee, 37203, United States
No email / No phone
Status: Not yet recruiting
Nashville, Tennessee, 37203, United States
No email / No phone
Status: Not yet recruiting
Nashville, Tennessee, 37203, United States
No email / No phone
Status: Not yet recruiting
Chattanooga, Tennessee, 37404, United States
No email / No phone
Status: Not yet recruiting
Nashville, Tennessee, 37232, United States
No email / No phone
Status: Not yet recruiting
McAllen, Texas, 78504, United States
No email / 281-944-3610
Status: Not yet recruiting
Dallas, Texas, 75235, United States
No email / 214-648-4180
Status: Not yet recruiting
The Woodlands, Texas, 77380, United States
No email / No phone
Status: Not yet recruiting
Tyler, Texas, 75702, United States
No email / No phone
Status: Not yet recruiting
Austin, Texas, 78731, United States
No email / No phone
Status: Not yet recruiting
Dallas, Texas, 75390, United States
No email / 214-648-4180
Status: Not yet recruiting
Houston, Texas, 77030-4009, United States
No email / No phone
Status: Not yet recruiting
Norfolk, Virginia, 23502, United States
No email / No phone
Status: Not yet recruiting