vepugratinib (LY3866288) / Eli Lilly - LARVOL DELTA

FORAY: A Study of Vepugratinib (LY3866288) in Adults With Non-Muscle Invasive Bladder Cancer and Upper Tract Urothelial Cancer (clinicaltrials.gov) - P2 | N=161 | Not yet recruiting | Sponsor: Eli Lilly and Company

New P2 trial • Bladder Cancer • Genito-urinary Cancer • Oncology • Solid Tumor • Urethral Cancer • Urothelial Cancer

FORAGER-2: A randomized phase 3 study evaluating the efficacy and safety of vepugratinib combined with enfortumab vedotin and pembrolizumab in untreated locally advanced or metastatic urothelial carcinoma with an FGFR3 genetic alteration. (ASCO-GU 2026) - P1, P3 | "The randomized portion of FORAGER-2 will be preceded by a single-arm safety lead-in. Enrollment is ongoing and will be opened in approximately 19 countries."

Clinical • Metastases • P3 data • Genito-urinary Cancer • Oncology • Solid Tumor • Urothelial Cancer • FGFR3 • NECTIN4

A first-in-human phase 1 study of LY3866288 (LOXO-435), a potent, highly isoform-selective FGFR3 inhibitor (FGFR3i) in advanced solid tumors with FGFR3 alterations: Initial results from FORAGER-1. (ASCO-GU 2025) - P1 | "LY3866288 is well-tolerated with robust clinical activity at multiple DLs, including in erdafitinib refractory mUC. Randomized dose optimization is ongoing and updated results will be presented."

Metastases • P1 data • Genito-urinary Cancer • Oncology • Solid Tumor • Urothelial Cancer • FGFR3 • TACC3

Phase I study of LY3866288, a potent, highly isoform-selective FGFR3 inhibitor in FGFR3-altered advanced solid tumors (FORAGER-1): Dose optimization (ESMO 2025) - P1 | "Preclinically, LY increases nectin 4 cell surface expression and enhances the antitumor activity of enfortumab vedotin (EV) in FGFR3 -altered mUC in vivo models...LY plus EV and pembrolizumab (EVP) is being studied in 1L mUC (B5)...TEAEs associated with poor tolerance and compliance to erdafitinib were uncommon (PPE 7%, onycholysis 0%, retinopathy 0%)...Cohort B5 opened at 200 mg BID and updated data will be presented. Conclusions LY3866288 at 200 mg BID was well-tolerated and demonstrated promising antitumor activity in FGFRi pretreated and naive pts with FGFR3 -altered mUC, warranting further study as monotherapy and combined with EVP."

Metastases • P1 data • Genito-urinary Cancer • Oncology • Solid Tumor • Urothelial Cancer • FGFR3 • NECTIN4

Vepugratinib-induced receptor tyrosine kinase (RTK) rewiring sensitizes FGFR3-altered urothelial cancer cells to HER2-targeted therapies (EORTC-NCI-AACR 2026) - "Abstract will be available as of 4 November (with consent of the author)"

Genito-urinary Cancer • Oncology • Solid Tumor • Urothelial Cancer • FGFR3

Update: Evolution in the management of metastatic urothelial carcinomas (PubMed, Bull Cancer) - "The combination of enfortumab-vedotin and pembrolizumab, established in 2024 as the first-line standard of care, has demonstrated impressive survival benefits at 30 months of follow-up and is now the preferred regimen, regardless of cisplatin eligibility. Beyond enfortumab-vedotin, the development of antibody-drug conjugates opens up a field for rapid innovation: next-generation anti-nectin-4 agents, anti-TROP2 strategies, and anti-HER2 agents such as trastuzumab deruxtecan or disitamab vedotin, including in HER2-"low" disease...Erdafitinib is now reimbursed in France for FGFR3-altered tumors, while more selective inhibitors (such as LOXO-435) are currently under investigation. In addition, novel approaches including bispecific antibodies and bicyclic peptides are being evaluated in early-phase trials, reflecting the dynamism of this evolving field. Altogether, metastatic urothelium carcinoma has become a paradigm of rapidly evolving oncology, driven by..."

Journal • Review • Oncology • Solid Tumor • Urothelial Cancer • FGFR3 • NECTIN4

FORAGER-2: A Study of Vepugratinib (LY3866288) in Participants With Cancer in the Urinary Tract (clinicaltrials.gov) - P3 | N=450 | Not yet recruiting | Sponsor: Eli Lilly and Company

New P3 trial • Bladder Cancer • Oncology • Solid Tumor • Urothelial Cancer

FORAGER-2: A Study of Vepugratinib (LY3866288) in Participants With Cancer in the Urinary Tract (clinicaltrials.gov) - P3 | N=450 | Recruiting | Sponsor: Eli Lilly and Company | Not yet recruiting ➔ Recruiting

Enrollment open • Bladder Cancer • Oncology • Solid Tumor • Urothelial Cancer

Expanded Access for Vepugratinib (LY3866288) in Participants With Fibroblast Growth Factor Receptor 3 (FGFR3) Altered Solid Tumors (clinicaltrials.gov) - P=N/A | N=0 | Available | Sponsor: Eli Lilly and Company

New trial • Bladder Cancer • Oncology • Solid Tumor

J4G-MC-JZVD: A Study of Vepugratinib (LY3866288) in Participants with Cancer in the Urinary Tract ( FORAGER-2 ) (clinicaltrialsregister.eu) - P2/3 | N=197 | Not yet recruiting | Sponsor: Eli Lilly & Co.

New P2/3 trial • Bladder Cancer • Oncology • Solid Tumor • Urothelial Cancer

Discovery and preclinical characterization of ISM8001, a covalent and selective FGFR2/FGFR3 dual inhibitor with strong monotherapy anti-tumor activity against advanced solid tumors (AACR 2024) - "The second generation of FGFR inhibitors currently undergoing clinical evaluation such as RLY-4008 and LOXO-435 are primarily focused on achieving selectivity against either the FGFR2 or FGFR3 isoform, which may narrow their clinical potential. Results of 28-day non-clinical toxicology studies in rat and dog showed a safety window of approximately 2-5 fold based on efficacious exposure in different models. Taken together, these data support the clinical development of ISM8001 as a novel, selective FGFR2/FGFR3 dual inhibitor for the potential tissue-agnostic therapy of advanced solid tumors with FGFR2/3 aberrations."

Metastases • Monotherapy • Preclinical • Biliary Cancer • Bladder Cancer • Cholangiocarcinoma • Endometrial Cancer • Gastric Cancer • Gastrointestinal Cancer • Genito-urinary Cancer • Oncology • Solid Tumor • Urothelial Cancer • FGFR1 • FGFR2 • FGFR3 • FGFR4

GSC000829, a novel selective FGFR2/3 inhibitor, displays superior antitumor activity in preclinical FGFR-driven neoplasms models (AACR 2025) - "It also demonstrates enhanced antitumor activity at lower dosage in FGFR3-driven CDX models compared to the pan-FGFR inhibitor Erdafitinib, as well as other FGFR3-selective inhibitors such as TYRA300 and LOXO-435. GSC000829 exhibits favorable physicochemical and pharmacokinetic properties along with an excellent preclinical toxicity profile with no obvious phosphate increase at quite high exposure level in rats. Taken together, these findings bolster the rationale for advancing GSC000829 into clinical trials as a potential best-in-class FGFR isoform-selective inhibitors, offering an approach for treating advanced solid tumors harboring FGFR2/3 aberrations."

Preclinical • Oncology • Solid Tumor • FGFR1 • FGFR2 • FGFR3 • FGFR4

Phase 1 study of LY3866288, a potent, highly isoform-selective FGFR3 inhibitor in FGFR3-altered advanced solid tumors (FORAGER-1): Dose optimization (DKK 2026) - "Preclinically, LY increases nectin-4 cell surface expression and enhances the antitumor activity of enfortumab vedotin (EV) in FGFR3-altered mUC in vivo models...LY plus EV and pembrolizumab (EVP) is being studied in 1L mUC (B5)...TEAEs associated with poor tolerance and compliance to erdafitinib were uncommon (PPE 7%, onycholysis 0%, retinopathy (0%)...In pts treated with ≥200 mg BID, ORR was 38% (24 cPR [confirmed PR], 7 uPR [pending/ongoing]) and ORR at 200 mg BID was 43% (11 cPR, 1 uPR) including 43% (3/7 cPR) in FGFRi pretreated pts. LY3866288 at 200 mg BID was well-tolerated and demonstrated promising antitumor activity in FGFRi pretreated and naive pts with FGFR3-altered mUC, warranting further study as monotherapy and combined with EV."

Metastases • P1 data • Dental Disorders • Genito-urinary Cancer • Metabolic Disorders • Nephrology • Oncology • Renal Disease • Retinal Disorders • Solid Tumor • Stomatitis • Urothelial Cancer • FGFR3 • NECTIN4

Vepugratinib-Based Therapy Displays Potential in Metastatic FGFR3+ Urothelial Cancer (OncLive) - "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."

Audio

Vepugratinib (LY3866288), a potent highly isoform-selective FGFR3 inhibitor, enhances the activity of enfortumab vedotin (EV) in FGFR3-altered metastatic urothelial cancer (mUC) models (AACR-NCI-EORTC 2025) - P1 | "Here, we report results from in vitro and in vivo UC models when vepugratinib was combined with EV (NECTIN4 ADC), with or without pembrolizumab (P). Vepugratinib upregulates NECTIN4 in FGFR3-altered mUC models, enhancing the activity of standard of care EV+P and supporting the investigation of this combination clinically. FORAGER-1 is investigating the combination of vepugratinib with EV+P in patients with untreated locally advanced or mUC with an FGFR3 genetic alteration (NCT05614739)."

Metastases • Bladder Cancer • Genito-urinary Cancer • Oncology • Solid Tumor • Urothelial Cancer • ANXA5 • CD34 • FGFR3 • TACC3

Discovery of a highly potent and selective covalent FGFR3 inhibitor (AACR-NCI-EORTC 2025) - "Among emerging agents, LOXO-435 stands out as the most selective FGFR3 inhibitor in clinical trials, showing best-in-class safety and efficacy to date...BGP-31172 demonstrates exceptional potency and selectivity as a covalent FGFR3 inhibitor, with strong in vitro activity across FGFR3-driven cancer models. BridGene is actively optimizing this promising compound series to meet the urgent clinical need in FGFR3-altered malignancies."

Bladder Cancer • Genito-urinary Cancer • Oncology • Solid Tumor • Urothelial Cancer • ETV6 • FGFR2 • FGFR3 • FGFR4 • TACC3

Vepugratinib (investigational FGFR3 inhibitor) (PRNewswire) - "In a mini oral presentation, Lilly will share updated results from the FORAGER-1 study, a first-in-human Phase 1 study of vepugratinib (LY3866288), a potent, highly isoform-selective FGFR3 inhibitor, in FGFR3-altered urothelial cancer."

P1 data • Bladder Cancer • Urothelial Cancer

Next-generation isoform-selective fibroblast growth factor receptor inhibitors. (PubMed, Trends Pharmacol Sci) - "Pan-FGFR-selective inhibitors (erdafitinib, pemigatinib, and futibatinib) have been developed in clinical practice...FGFR2-selective inhibitor lirafugratinib, FGFR3-selective inhibitors LOXO-435 and TYRA-300, FGFR2/3-selective inhibitor ABSK061, and FGFR4-selective inhibitors are in clinical development. Additionally, novel isoform-selective FGFR-targeting degraders, FGFR2b/FGFR3-selective antibodies, and de novo-designed 'c' isoform-selective proteins provide novel treatment strategies. This review provides an overview of the current FGFR-targeted therapeutics and limitations and evaluates next-generation inhibitor development to guide future research."

Journal • Review • Oncology • FGFR • FGFR2 • FGFR3 • FGFR4

FORAGER-1: A Study of LOXO-435 (LY3866288) in Participants With Cancer With a Change in a Gene Called FGFR3 (clinicaltrials.gov) - P1 | N=535 | Recruiting | Sponsor: Eli Lilly and Company | Trial completion date: Jun 2025 ➔ Jun 2027 | Trial primary completion date: Jun 2025 ➔ Jun 2027

Trial completion date • Trial primary completion date • Bladder Cancer • Genito-urinary Cancer • Oncology • Solid Tumor • Urothelial Cancer

FORAGER-1: A Study of LOXO-435 (LY3866288) in Participants With Cancer With a Change in a Gene Called FGFR3 (clinicaltrials.gov) - P1 | N=535 | Recruiting | Sponsor: Eli Lilly and Company | N=180 ➔ 535

Enrollment change • Bladder Cancer • Genito-urinary Cancer • Oncology • Solid Tumor • Urothelial Cancer

A Study of LY3866288 in Healthy Participants (clinicaltrials.gov) - P1 | N=15 | Completed | Sponsor: Eli Lilly and Company | N=30 ➔ 15 | Recruiting ➔ Completed

Enrollment change • Trial completion

A Study of [14C]-LY3866288 in Healthy Participants (clinicaltrials.gov) - P1 | N=15 | Completed | Sponsor: Eli Lilly and Company | Recruiting ➔ Completed

Trial completion

A Study of [14C]-LY3866288 in Healthy Participants (clinicaltrials.gov) - P1 | N=16 | Recruiting | Sponsor: Eli Lilly and Company | Not yet recruiting ➔ Recruiting

Enrollment open

A Study of LY3866288 in Healthy Participants (clinicaltrials.gov) - P1 | N=30 | Recruiting | Sponsor: Eli Lilly and Company | Not yet recruiting ➔ Recruiting

Enrollment open

A Study of [14C]-LY3866288 in Healthy Participants (clinicaltrials.gov) - P1 | N=16 | Not yet recruiting | Sponsor: Eli Lilly and Company

New P1 trial