Vepugratinib-Based Therapy Displays Potential in Metastatic FGFR3+ Urothelial Cancer

Treatment with vepugratinib (LY3866288) monotherapy yielded responses and displayed tolerability in patients with metastatic urothelial carcinoma harboring FGFR3 alterations, according to data from the dose-optimization portion of the phase 1 FORAGER-1 trial (NCT05614739).1 Furthermore, preliminary from an expansion cohort showed that vepugratinib plus enfortumab vedotin-ejfv (Padcev) and pembrolizumab (Keytruda) was safe and active in the first-line treatment of patients with FGFR3-altered urothelial cancer.

Data presented at the 2025 ESMO Congress demonstrated that vepugratinib yielded an overall response rate of 34% when given at 200 mg twice per day (n = 35), 30% when administered at 300 mg twice per day (n = 37), and 33% when given at 400 mg twice per day (n = 30). All responses were partial, and the respective rates of stable disease were 60%, 54%, and 43%. The disease control rate was 94% in the 200-mg arm, 84% in the 300-mg arm, and 77% in the 400-mg arm.

“With 8 months of median follow-up, [61%] of [responders] continued…on the study, and we feel comfortable combining vepugratinib with other agents because it is a safe drug,” lead study author Alexandra Drakaki, MD, said in a presentation of the data. Drakaki is an associate professor of hematology/oncology and urology at the University of California, Los Angeles David Geffen School of Medicine.

Regarding safety, 38% of patients treated across the 3 monotherapy doses remained on treatment at data cutoff. Any-grade treatment-emergent adverse effects (TEAEs) occurred in 97% of among patients with all FGFR3-altered solid tumors treated at 200 mg twice per day (n = 59), 100% in those treated at 300 mg twice per day (n = 65), and 100% in patients treated at 400 mg twice per day (n = 62). The rates of grade 3 or higher TEAEs were 37%, 49%, and 45%, respectively. TEAEs led to dose reductions in 14%, 35%, and 29% of patients respectively; these toxicities led to treatment discontinuation in 3%, 3%, and 0% of patients, respectively.

What differentiates vepugratinib from other FGFR inhibitors?

Drakaki explained that FGFR3 alterations are present in approximately 15% to 20% of patients with metastatic urothelial cancer. Vepugratinib is an oral, highly potent, isoform-selective, small molecule FGFR3 inhibitor intended to limit off-target toxicities associated with other pan-FGFR inhibitors.

Notably, preclinical studies showed that the use of FGFR3 inhibition in FGFR3-altered urothelial cancer cell lines induced NECTIN-4 expression, which is the target of enfortumab vedotin. The combination of vepugratinib, enfortumab vedotin, and pembrolizumab subsequently displayed robust antitumor activity in these cell lines, Drakaki noted. Enfortumab vedotin plus pembrolizumab is currently approved by the FDA for the treatment of patients with locally advanced or metastatic urothelial cancer.2

How was the FORAGER-1 trial designed?

During the phase 1 dose-escalation portion of the study, investigators enrolled patients (n = 223) with advanced solid tumors harboring FGFR3 alterations per local testing.1 Patients were required to have an ECOG performance status of 0 to 2, and prior treatment with an FGFR inhibitor was permitted. Vepugratinib was evaluated at 10 dose levels in the initial A1 cohort, ranging from 6 mg once per day to 400 mg twice per day.

Cohort A2 served as a randomized, dose-optimization group where patients with urothelial cancer received the agent as monotherapy at 200 mg, 300 mg, or 400 mg twice per day.

In dose-expansion, cohort B includes patients with metastatic urothelial cancer who are being assigned to 1 of 5 sub-cohorts, including cohort B5 evaluating vepugratinib at 200 mg twice per day in combination with enfortumab vedotin and pembrolizumab as first-line treatment.

The primary end points of both portions of the study include safety/tolerability, determining the optimal dose of vepugratinib, pharmacokinetics, and preliminary efficacy per RECIST 1.1 criteria. The data cutoff for this analysis was August 29, 2025.

Patients with metastatic urothelial cancer treated with vepugratinib monotherapy at 200 mg twice per day (n = 46), 300 mg twice per day (n = 52), and 400 mg twice per day (n = 40) had a median age of 67 years (range, 35-88), 72 years (range, 42-93), and 70 years (range, 26-89), respectively. The majority of patients in all 3 groups were male (67%; 60%; 73%), were White (46%; 58%; 70%), had an ECOG performance status of 1 (70%; 73%; 63%), had primary tumors located in the lower tract (54%; 58%; 65%), harbored FGFR3 mutations rather than fusions (70%; 88%; 78%), and had a creatinine clearance of at least 60 mL/min.

What additional safety data were reported for vepugratinib monotherapy?

Among evaluable patients with any solid tumor treated with vepugratinib monotherapy at 200 mg, 300 mg, or 400 mg twice per day, the most common any-grade TEAEs comprised diarrhea (200 mg, 59%; 300 mg, 77%; 400 mg, 79%), fatigue (34%; 34%; 27%), increased alanine aminotransferase levels (27%; 34%; 31%), decreased appetite (24%; 23%; 31%), increased aspartate aminotransferase levels (22%; 31%; 32%), nausea (17%; 19%; 24%), vomiting (17%; 17%; 16%), constipation (15%; 8%; 18%), increased blood creatinine levels (15%; 14%; 11%), and urinary tract infection (8%; 15%; 18%).

Any-grade TEAEs of special interest included skin disorders (34%; 46%; 47%), palmar-plantar erythrodysesthesia (10%; 11%; 15%), oral mucositis (25%; 35%; 27%), stomatitis (22%; 35%; 26%), hyperphosphatemia (19%; 37%; 34%), nail disorders (17%;20%; 26%), dry mouth (7%; 20%; 21%) eye disorders (5%; 31%; 18%), and retinopathy (2%; 9%; 5%).

What preliminary data were reported for vepugratinib plus enfortumab vedotin and pembrolizumab?

Among 5 evaluable patients treated with vepugratinib plus enfortumab vedotin and pembrolizumab, 3 achieved a response at their first scan, including 1 complete response and 3 partial responses.

The safety of the combination was in line with the known profiles of the 3 agents. The most common treatment-related AEs included nausea, diarrhea, fatigue, decreased appetite, and dry mouth, with all of these toxicities occurring at a rate of 40%.

Disclosures: Drakaki reported receiving institutional/grant funding from Pfizer, AstraZeneca, Daichi Sankyo, Eli Lilly/Loxo, Arcus, Merck, Roche, and Adcentrix; and serving as a consultant or advisor for AstraZeneca, Pfizer, Daichi Sankyo, Eli Lilly, Jansen, Exelixis, EMD Serono, and Merck.

References

1. Drakaki A, Park SH, Castellano D, et al. Phase 1 study of vepugratinib (LY3866288), a potent, highly isoform-selective FGFR3 inhibitor in FGFR3-altered advanced solid tumors (FORAGER-1): dose optimization. Presented at: 2025 ESMO Congress; October 17-21, 2025; Berlin, Germany. Abstract 3070MO.
2. FDA approves enfortumab vedotin-ejfv with pembrolizumab for locally advanced or metastatic urothelial cancer. FDA. December 15, 2023. Accessed October 28, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-enfortumab-vedotin-ejfv-pembrolizumab-locally-advanced-or-metastatic-urothelial-cancer