Trial: FORAGER-1: A Study of LOXO-435 (LY38662…

Trial Details

Sponsor: Eli Lilly and Company (industry)

Phase: 1

Start date: Jan. 12, 2023

Planned enrollment: 535

Trial ID: NCT05614739

More trial details at ClinicalTrials.gov

Show Summary from Sponsor

Investigational Drug AI Analysis

Show for: LOXO-435 (LY3866288, LOX-24350)

Overview

LOXO-435 (LY3866288; LOX-24350) is an oral, investigational, isoform‑selective inhibitor of FGFR3 being developed by Loxo Oncology at Lilly/Eli Lilly. A first‑in‑human phase 1 study (FORAGER‑1; NCT05614739) is enrolling patients with advanced solid tumors harboring FGFR3 alterations, with a focus on metastatic urothelial cancer (mUC). Initial clinical results were presented at the 2025 ASCO Genitourinary Cancers Symposium. (ascopubs.org)

Mechanism of action

LOXO-435 is designed to potently and selectively inhibit FGFR3 while sparing other FGFR isoforms and to retain activity against acquired FGFR3 “gatekeeper” resistance mutations (for example V555M). Preclinical characterization publicly reported by the sponsor supports high FGFR3 selectivity and activity against gatekeeper variants. (investor.lilly.com)

Efficacy

Early phase 1 dose-escalation data (cutoff August 27, 2024) from FORAGER-1 reported the following among patients treated at doses ≥200 mg twice daily:
- In mUC with activating FGFR3 mutation or fusion, objective response rate (ORR) was 42% (14/33; 10 confirmed; 4 pending confirmation as of September 6, 2024). Responses were seen across multiple mutations (e.g., S249C, Y373C, R248C, S371C) and FGFR3–TACC3 fusions.
- In mUC previously treated with an FGFR inhibitor, ORR was 45% (5/11).
- Partial responses were also observed in single patients with NSCLC (FGFR3 S249C) and biliary tract cancer (FGFR3–TACC3).
- Circulating tumor DNA analyses showed reductions in FGFR3 variant allele frequency in 92% (12/13) of evaluable patients at cycle 2 or 3; 8 achieved clearance (5 with PR; 3 with SD).
Most responses (88%, 14/16 PRs) were ongoing at the cutoff. (ascopubs.org)

Safety

Across 101 treated patients in dose escalation (6 mg QD to 400 mg BID), no dose‑limiting toxicities were observed. At doses ≥200 mg BID, the most common treatment‑emergent adverse events were diarrhea (67%), hyperphosphatemia (28%), fatigue (23%), and elevations in ALT (22%) and AST (22%); most events were grade 1–2. Adverse events frequently associated with pan‑FGFR inhibitors (e.g., retinopathy, onycholysis, hand‑foot syndrome) were ≤5% and low grade. Treatment‑related AEs led to dose reductions in 5% and no discontinuations. Trough concentrations exceeded the IC90 for FGFR3 S249C at doses ≥200 mg BID; exposures were similar in patients with moderate renal impairment. (ascopubs.org)

Ongoing clinical development

FORAGER‑1 is an open‑label phase 1 study with dose escalation/optimization followed by expansion cohorts evaluating LOXO‑435 as monotherapy and in combinations (including pembrolizumab with or without enfortumab vedotin) in FGFR3‑altered tumors. The study started in January 2023; the current estimated primary completion is June 2027. (ichgcp.net)

HealthScout AI Analysis

Goal: Evaluate the safety, tolerability, pharmacokinetics, and preliminary antitumor activity of the selective FGFR3 inhibitor LOXO-435 as monotherapy and in combination with pembrolizumab with or without enfortumab vedotin, and determine an optimal dose for further study in FGFR3-altered advanced solid tumors, including metastatic urothelial cancer.

Patients: Adults with locally advanced or metastatic solid tumors harboring actionable FGFR3 pathway alterations, with emphasis on urothelial cancer. Expansion cohorts include: FGFR inhibitor–naïve and FGFR inhibitor–pretreated metastatic urothelial cancer, treatment-naïve metastatic urothelial cancer for combination cohorts, and non-urothelial solid tumors with qualifying FGFR3 alterations. ECOG 0–1 for dose-escalation/optimization and select expansion cohorts; up to ECOG 2 allowed in other expansion cohorts. Measurable disease per RECIST v1.1 is required in most cohorts. Prior therapy requirements vary by cohort, including prior erdafitinib exposure for specific monotherapy expansions and FGFR inhibitor–naïve status for others. Key exclusions include primary CNS malignancy, uncontrolled CNS metastases, significant ophthalmic or cardiovascular disease, prolonged QTcF, unresolved toxicities, and uncontrolled infection.

Design: Phase 1, open-label, multicenter, non-randomized study with dose escalation and optimization (Phase 1a) followed by multiple dose-expansion cohorts (Phase 1b). Estimated enrollment approximately 535 participants. Phase 1a defines the recommended dose based on safety, tolerability, and PK; Phase 1b evaluates antitumor activity and safety of monotherapy and combinations.

Treatments: LOXO-435 oral monotherapy across dose-escalation/optimization and several expansion cohorts; LOXO-435 plus pembrolizumab; and LOXO-435 plus pembrolizumab plus enfortumab vedotin. LOXO-435 (LY3866288) is an oral, highly isoform-selective FGFR3 inhibitor designed to spare FGFR1/2/4 and mitigate off-target toxicities such as FGFR1-mediated hyperphosphatemia. It has preclinical activity against FGFR3 point mutations and fusions and is engineered to retain potency against FGFR3 resistance mutations. Early phase 1 readouts presented in 2025 reported encouraging activity in metastatic urothelial cancer with FGFR3 alterations, including responses after prior FGFR inhibitor exposure, and a favorable tolerability profile with predominantly low-grade adverse events. Pembrolizumab is a standard PD-1 inhibitor used across urothelial cancer settings. Enfortumab vedotin is a Nectin-4–directed antibody–drug conjugate approved for urothelial cancer; here it is combined with pembrolizumab and LOXO-435 in a first-line cohort.

Outcomes: Primary outcomes include dose-limiting toxicities in Phase 1a to establish the recommended dose, overall response rate per investigator-assessed RECIST v1.1 in Phase 1b, and the incidence of treatment-emergent and serious adverse events. Secondary outcomes include pharmacokinetics of LOXO-435 (AUC, Cmin), objective response rate in supportive analyses, duration of response, time to response, progression-free survival, overall survival, disease control rate, and patient-reported outcomes including bladder-related symptoms (FACT-Bl subscale) and physical well-being (FACT-PWB).

Burden on patient: High. As a first-in-human/early phase study with dose escalation and PK characterization, participants should expect frequent clinic visits, intensive safety monitoring, serial pharmacokinetic blood draws, and mandated ophthalmologic and cardiac assessments due to class effects and QTcF monitoring. Most cohorts require measurable disease assessments with regular imaging per RECIST, and tissue availability is requested; additional biopsies may be required or strongly encouraged in some sites. Combination cohorts add infusion visits for pembrolizumab (every 3 or 6 weeks per protocol) and enfortumab vedotin (typically days 1 and 8 of 21- or 28-day cycles), increasing visit frequency and potential infusion-related monitoring. Travel demands and time on study could extend up to 30 months, contributing to substantial logistical and procedural burden.

Last updated: Oct 2025

Eligibility

Show Criteria

Inclusion Criteria:

* Have solid tumor cancer with an FGFR3 pathway alteration on molecular testing in tumor or blood sample that is deemed as actionable

* Cohort A1: Presence of an alteration in FGFR3 or its ligands

* Cohort A2, B2, B3, and B5: Histological diagnosis of urothelial cancer (UC) that is locally advanced or metastatic with a qualifying FGFR3 genetic alteration

* Cohorts B1 and B4: Histological diagnosis of urothelial cancer that is locally advanced or metastatic

* Cohort C1: Must have histological diagnosis of a non-urothelial solid tumor malignancy that is locally advanced or metastatic with a qualifying FGFR3 genetic alteration

* Measurability of disease:

* Cohort A1 and B3: Measurable or non-measurable disease as defined by Response Evaluation Criteria in Solid Tumors v 1.1 (RECIST v1.1)

* Cohorts A2, B1, B2, B4, B5, and C1: Measurable disease required as defined by RECIST v1.1

* Have adequate tumor tissue sample available. Participants with inadequate tissue sample availability may still be considered for enrollment upon review

* Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 for Cohorts A1, A2, B3, and B5

* Less than or equal to 2 for Cohorts B1, B2, B4, and C1

* Prior Systemic Therapy Criteria:

* Cohort A1/C1: Participant has received all standard therapies for which the participant was deemed to be an appropriate candidate by the treating Investigator; OR the participant is refusing the remaining most appropriate standard of care treatment; OR there is no standard therapy available for the disease. There is no restriction on number of prior therapies.

* Cohort A2, B2, B3 participants must have received at least one prior regimen, and cohorts B1 and B4 participants at least 2 prior regimens, in the locally advanced or metastatic setting

* There is no restriction on number of prior therapies

* Cohort B5: Participants have not received prior systemic therapy for locally advanced or metastatic UC

* FGFR inhibitor specific requirements:

* Cohort A1/A2/B3: Prior FGFR inhibitor treatment is permitted but not required

* Cohort B1/B4: Participants must have been previously treated with erdafitinib

* Cohort B2, B5, and C1: Participants must be FGFR inhibitor naïve

Exclusion Criteria:

* Participants with primary central nervous system (CNS) malignancy

* Untreated or uncontrolled CNS metastases

* Current evidence of corneal keratopathy or retinal disorder. Individuals with asymptomatic ophthalmic conditions may be eligible

* Any serious unresolved toxicities from prior therapy

* Significant cardiovascular disease

* Prolongation of the QT interval corrected for heart rate using Fridericia's formula (QTcF)

* Active uncontrolled systemic infection or other clinically significant medical conditions

Falls Church, Virginia, 22042, United States

No email / No phone

Status: Not yet recruiting

FORAGER-1: A Phase 1, Open-Label, Multicenter Study of LOXO-435 (LY3866288) in Locally Advanced or Metastatic Solid Tumors Including Urothelial Cancer With FGFR3 Alterations

Trial Details

Show Summary from Sponsor

More details:

Investigational Drug AI Analysis

Show for: LOXO-435 (LY3866288, LOX-24350)

Overview

Mechanism of action

Efficacy

Safety

Ongoing clinical development

Further reading

HealthScout AI Analysis

Eligibility

Show Criteria

Sites (84)

St Vincent's Hospital

Macquarie University

GenesisCare North Shore

Calvary Mater Newcastle

British Columbia Cancer Agency

Princess Margaret Hospital

Beijing Hospital

Beijing Cancer hospital

Zhejiang Provincial People's Hospital

First Affiliated Hospital of Medical College of Xian jiaotong University

Tianjin Medical University Cancer Institute & Hospital

Renji Hospital, Shanghai Jiaotong University School of Medicine

Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University

Sun Yat-Sen University- Cancer Center

Institut Bergonie

Institut Gustave Roussy

Centre Leon Berard

Universitaetsklinikum Schleswig-Holstein - Campus Luebeck

Universitaetsklinikum Tuebingen

Klinikum der Technischen Universitaet Muenchen (TUM Klinikum)

Sheba Medical Center

Rabin Medical Center, Beilinson Hospital

UOC Fase I - Fondazione Policlinico Universitario A. Gemelli IRCCS - Universita Cattolica del Sacro Cuore

IRCCS Ospedale San Raffaele

Cancer Institute Hospital of JFCR

National Cancer Center Hospital

Aichi Cancer Center Hospital

National Cancer Center Hospital East

Erasmus MC

Oslo University Hospital

Haukeland University Hospital

Seoul National University Hospital

Severance Hospital, Yonsei University Health System

Asan Medical Center

Samsung Medical Center

Hospital Universitario Marques De Valdecilla

South Texas Accelerated Research Therapeutics (START) Madrid - CIOCC

Hospital Universitario 12 de Octubre

Fundacion MD Anderson International Espana

Institut Catala d'Oncologia - L'Hospitalet

Sheffield Teaching Hospitals NHS Foundation Trust

The Christie NHS Foundation Trust

University of Arizona - Cancer Center

University of California (UC) Davis Comprehensive Cancer Center

City of Hope

University of California, Los Angeles (UCLA) - Division of Hematology-Oncology

University of California - Irvine

Stanford Cancer Center

Advent Health

Emory University Hospital

The University of Chicago Medical Center (UCMC)

Indiana University (IU) Melvin and Bren Simon Cancer Center

Mary Bird Perkins Cancer Center

Ochsner Clinic Foundation

Johns Hopkins Kimmel Cancer Center

Massachusetts General Hospital

Barbara Ann Karmanos Cancer Institute

Washington University in St. Louis

New York University (NYU)

Weill Cornell Medicine

Icahn School of Medicine at Mount Sinai

Columbia University

David H. Koch Center for Cancer Care at Memorial Sloan Kettering Cancer Center

University of Rochester - Wilmot Cancer Institute