LY3866288 / Eli Lilly - LARVOL DELTA

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

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 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

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

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

New P1 trial

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

FGFR-targeted therapeutics: clinical activity, mechanisms of resistance and new directions. (PubMed, Nat Rev Clin Oncol) - "Various agents, including pan-FGFR inhibitors (erdafitinib and futibatinib), FGFR1/2/3 inhibitors (infigratinib and pemigatinib), as well as a range of more-specific agents, have been developed and several have entered clinical use. The next generation of small-molecule inhibitors, such as lirafugratinib and LOXO-435, and the FGFR2-specific antibody bemarituzumab are expected to have a reduced risk of hyperphosphataemia and the ability to overcome certain resistance mutations. In this Review, we describe the development and current clinical role of FGFR inhibitors and provide perspective on future research directions including expansion of the therapeutic indications for use of FGFR inhibitors, combination of these agents with immune-checkpoint inhibitors and the application of novel technologies, such as artificial intelligence."

Journal • Review • Biliary Cancer • Cholangiocarcinoma • Gastrointestinal Cancer • Oncology • Renal Disease • Solid Tumor • Urothelial Cancer • FGFR • FGFR2 • TP53

Development of a novel RNA-based fibroblast growth factor receptor response signature (FGFR-PRS) for use in patients with urothelial cancer (UC). (ASCO-GU 2024) - P1, P2, P3 | "Background: Interest in FGFR-targeted (FGFRi) therapies for UC or pan-tumor use is growing (ongoing clinical studies include erdafitinib (NCT05316155; NCT04172675; NCT03390504; NCT04083976), LOXO-435 (NCT05614739), and pemigatinib (NCT03914794) following accelerated approval of erdafitinib in locally advanced/metastatic (m) post-chemotherapy UC patients with FGFR2/3 (i.e., DNA mutations and fusions) alterations (ALT). FGFR-PRS (+) captured most ALT (+) tumors and an additional 2X more with similar FGFR pathway activation. FGFR-PRS (+) tumors were associated with gene enrichments for ontologies linked to FGFR3 signaling. The correlation of FGFR-PRS score with in vitro FGFRi activity provided initial utility of the signature, which is undergoing clinical evaluation in the ALAMANCE retrospective study of UC patients treated with FGFRi or other standard-of-care therapies."

Clinical • Bladder Cancer • Genito-urinary Cancer • Oncology • Solid Tumor • Urothelial Cancer • BAIAP2 • BAIAP2L1 • FGFR • FGFR1 • FGFR2 • FGFR3 • FOXA1 • TACC3

A first-in-human phase 1 study of LOXO-435, a potent, highly isoform-selective FGFR3 inhibitor in advanced solid tumors with FGFR3 alterations (trial in progress) (AACR 2023) - P1 | "Cohort B will enroll pts with mUC and include 2 cohorts to evaluate LOXO-435 as monotherapy (B1, B2) and 1 cohort to evaluate LOXO-435 in combination with pembrolizumab (B3). Pts in cohort B1 must have progressed on or were intolerant to a prior FGFR inhibitor, and pts in cohorts B2, B3, and C1 must be FGFR inhibitor treatment naive. Dose expansion will evaluate the safety, PK/PD, and antitumor activity (per RECIST v1.1) of LOXO-435 at the RP2D."

Metastases • P1 data • Oncology • Solid Tumor • Urothelial Cancer • FGFR1 • FGFR3

A Study of LOXO-435 in Patients With Cancer With a Change in a Gene Called FGFR3 (clinicaltrials.gov) - P1 | N=140 | Recruiting | Sponsor: Eli Lilly and Company | Not yet recruiting ➔ Recruiting

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

A Study of LOXO-435 in Patients With Cancer With a Change in a Gene Called FGFR3 (clinicaltrials.gov) - P1 | N=140 | Not yet recruiting | Sponsor: Eli Lilly and Company

New P1 trial • Bladder Cancer • Oncology • Solid Tumor • Urothelial Cancer