zoligratinib (Debio 1347) / Debiopharm - LARVOL DELTA

Structure-based drug-development study against fibroblast growth factor receptor 2: molecular docking and Molecular dynamics simulation approaches. (PubMed, Sci Rep) - "This compound indicates a higher potential for inhibiting FGFR2 than the control inhibitor, Zoligratinib...ADMET analysis showed promising pharmacokinetic potential of the screened compound. Overall, the findings indicate that the compound CID:507883 may have promising potential to serve as a lead candidate against FGFR2 and could be further exploited in therapeutic development."

Journal • Oncology • FGFR2

Targeting the FGFR Pathway in Patients with Advanced Solid Tumors. (PubMed, Clin Cancer Res) - "In the phase II FUZE trial targeting the FGFR pathway, Debio 1347 showed limited antitumor activity and manageable toxicity in patients with advanced solid tumors. Results from transcriptomic-based analysis enhanced our understanding of the genomic landscape of FGFR fusion-driven tumors, informing clinical trial design and generating hypotheses for resistance mechanisms."

Journal • Metastases • Oncology • Solid Tumor

Evaluating Debio 1347 in Patients with FGFR Fusion-Positive Advanced Solid Tumors from the FUZE Multicenter, Open-Label, Phase II Basket Trial. (PubMed, Clin Cancer Res) - "Debio 1347 had manageable toxicity; however, the efficacy in patients with tumors harboring FGFR fusions did not support further clinical evaluation in this setting. Our transcriptomic-based analysis characterized in detail the incidence and nature of FGFR fusions across solid tumors."

Journal • Metastases • P2 data • Pan tumor • Biliary Cancer • Biliary Tract Cancer • Dental Disorders • Metabolic Disorders • Nephrology • Oncology • Renal Disease • Solid Tumor • Stomatitis • FGFR

Targeting the fibroblast growth factor pathway in molecular subtypes of castration-resistant prostate cancer. (PubMed, Prostate) - "Although FGFRi treatments suppressed tumor growth across CRPC phenotypes, our analyses did not identify a single pathway or biomarker that would identify tumor response to FGFRi. This is very likely due to the array of FGFR1-4 expression and tumor phenotypes present in CRPC. Nevertheless, our data nominate the FGFR pathway as a clinically actionable target that promotes tumor growth in diverse phenotypes of treatment-refractory metastatic CRPC."

Journal • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Neuroendocrine Tumor • Oncology • Prostate Cancer • Solid Tumor • FGFR1

Dose-Dependent and Reversible Serous Retinal Detachments in Fibroblast Growth Factor Receptor Inhibitor-Associated Retinopathy. (PubMed, Ophthalmic Surg Lasers Imaging Retina) - "We report two cases of fibroblast growth factor receptor (FGFR) inhibitor-associated retinopathy, including the first case of Debio 1347 associated retinopathy manifesting with bilateral serous retinal detachments along the superotemporal arcades and a case of erdafitinib associated retinopathy manifesting with classic foveal serous retinal detachments. FGFR inhibitor-associated retinopathy appears to manifest differently among patients. [Ophthalmic Surg Lasers Imaging Retina 2023;54:xx-xx.]."

Journal • Ophthalmology • Retinal Disorders • FGFR

Covalent FGFR inhibitor futibatinib exhibits sustained antitumor effects compared with ATP-competitive inhibitors by being less prone to on-target resistance (AACR-NCI-EORTC 2022) - "Using this as a model system for clonal selection, cells were exposed to futibatinib, pemigatinib and erdafitinib, and cell count measured over time...Sequencing of the resistant clones for these three FGFR inhibitors identified mutations at the following key amino acid residues: N550, E566 and K642 (regulatory triad), V565 (gatekeeper region), and K660 (activation loop); these were also identified previously in patients who developed resistance to pemigatinib, infigratinib, and Debio1347... Futibatinib, a covalent FGFR1-4 inhibitor, exhibited sustained antitumor effects compared to ATP-competitive inhibitors with fewer and later onset of acquired FGFR2 kinase resistance mutations. These data may potentially explain the numerically favorable differences in duration of response for futibatinib compared with ATP-competitive FGFR inhibitors for treatment of cholangiocarcinoma patients. No"

Biliary Cancer • Cholangiocarcinoma • Gastrointestinal Cancer • Oncology • Solid Tumor • FGFR2

FGFR2 Extracellular Domain In-Frame Deletions are Therapeutically Targetable Genomic Alterations that Function as Oncogenic Drivers in Cholangiocarcinoma. (PubMed, Cancer Discov) - "Three patients with FGFR2 EIDs were treated with Debio 1347, an oral FGFR-1/2/3 inhibitor, and all showed partial responses. One patient developed an acquired L618F FGFR2 kinase domain mutation at disease progression and experienced a further partial response for 17 months to an irreversible FGFR2 inhibitor, futibatinib. Together, these findings reveal FGFR2 EIDs as an alternative mechanism of FGFR2 activation in IHCC that predict sensitivity to FGFR inhibitors in the clinic."

Journal • Biliary Cancer • Biliary Tract Cancer • Cholangiocarcinoma • Gastrointestinal Cancer • Oncology • Solid Tumor • FGFR2

Clinical outcomes and genomic evolution of FGFR2 fusions/rearrangements in intrahepatic cholangiocarcinoma (AACR 2022) - "Forty two (42) patients with FGFR2 fusions and 9 patients with FGFR2 rearrangements received FGFR inhibitors: these include infigratinib (13), pemigatinib (17), futibatinib (14), derazantinib (5), and zoligratinib (2). The genomic evolution post-progression on FGFR inhibition involves acquired resistance in multiple pathways. Targeting co-alterations acquired post-progression with drug combination may overcome these resistance mechanisms and potentiate the efficacy of FGFR inhibition."

Clinical • Clinical data • Biliary Cancer • Cholangiocarcinoma • Gastrointestinal Cancer • Oncology • Solid Tumor • BAP1 • BICC1 • BRAF • FGFR2 • GNAS • NRAS • PIK3CA • TACC2 • TP53

Preclinical evaluation of a panel of FGFR inhibitors for their normal brain and brain tumor distribution (AACR 2022) - "In this study, seven pan-FGFR inhibitors (infigratinib, AZD4547, debio1347, erdafitinib, LY2874455, pemigatinib, and TAS-120) were evaluated for their brain penetration ability employing cassette dosing strategy with an aim to identify the optimal candidates for brain tumor targeting. The predictive parameters of brain penetration calculated based on physico-chemical properties have been estimated and shown not to correlate with the experimentally obtained neuro-pharmacokinetic values. In summary, our study provides comprehensive evaluation of neuro-pharmacokinetic behavior of seven FGFR inhibitors and delivers rationale for selection of most optimal candidates for future investigation in brain tumor clinical trials."

Preclinical • Brain Cancer • Glioblastoma • Oncology • Solid Tumor • ABCB1

Basket Trial in Solid Tumors Harboring a Fusion of FGFR1, FGFR2 or FGFR3- (FUZE Clinical Trial) (clinicaltrials.gov) - P2 | N=63 | Terminated | Sponsor: Debiopharm International SA | Completed ➔ Terminated; Due to lower antitumor activity than expected

Pan tumor • Trial termination • Oncology • Solid Tumor

Basket Trial in Solid Tumors Harboring a Fusion of FGFR1, FGFR2 or FGFR3- (FUZE Clinical Trial) (clinicaltrials.gov) - P2; N=63; Completed; Sponsor: Debiopharm International SA; Active, not recruiting ➔ Completed

Pan tumor • Trial completion • Oncology • Solid Tumor

Debio 1347 in patients with gastrointestinal cancers harboring an FGFR gene fusion: preliminary results (ESMO-GI 2019) - P2; " Debio 1347 demonstrated promising antitumor activity in patients with GI cancers harboring FGFR fusions, with an acceptable initial safety profile. The FUZE clinical trial of Debio 1347 for patients with advanced solid tumors harboring FGFR fusions includes patients with GI cancers (NCT03834220)."

Clinical

FUZE clinical trial: A Phase 2 study of Debio 1347 in FGFR fusion-positive advanced solid tumors irrespectively oftumor histology. (ASCO 2019) - P2; "Accrual is opened in US, EU, Asia and Australia. Clinical trial information: NCT03834220"

Clinical • P2 data

[VIRTUAL] Final results from the phase I study expansion cohort of the selective FGFR inhibitor Debio 1,347 in patients with solid tumors harboring an FGFR gene fusion. (ASCO 2020) - P1 | "Debio 1347 at the recommended dose of 80 mg qd was generally well tolerated and showed signs of activity in solid tumors harboring an FGFR fusion. The FUZE phase 2 clinical trial of Debio 1347 is recruiting FGFR fusion-positive advanced solid tumors irrespectively of tumor histology, excluding PBT. Research Funding: Debiopharm International SA"

Clinical • P1 data • Alopecia • Biliary Cancer • Bladder Cancer • Brain Cancer • Cholangiocarcinoma • Colon Cancer • Colorectal Cancer • Constipation • Dermatopathology • Endometrial Cancer • Fatigue • Gastric Cancer • Gastrointestinal Cancer • Genito-urinary Cancer • Gynecologic Cancers • Hematological Disorders • Lung Cancer • Nephrology • Oncology • Ophthalmology • Renal Disease • Retinal Disorders • Solid Tumor • Squamous Cell Carcinoma • Thoracic Cancer • Urothelial Cancer • FGFR2 • FGFR3 • TACC3

Safety and efficacy of the selective FGFR inhibitor debio 1347 in phase I study patients with FGFR genomically activated advanced biliary tract cancer (BTC). (ASCO-GI 2018) - "These results suggest that BTC pts with genomic events leading to activation of FGFR2/3 may benefit from treatment with Debio 1347. Further study is ongoing in the expansion cohort of this trial."

Clinical • P1 data • Biliary Cancer • Urothelial Cancer

A Study of Debio 1347 Plus Fulvestrant in Patients With Metastatic Breast Cancer (clinicaltrials.gov) - P1/2; N=10; Completed; Sponsor: Memorial Sloan Kettering Cancer Center; Active, not recruiting ➔ Completed

Trial completion • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • CCND1 • ER • FGF3 • FGFR • HER-2 • PGR

Targeting the Fibroblast Growth Factor Receptor (FGFR) in Advanced Cholangiocarcinoma: Clinical Trial Progress and Future Considerations. (PubMed, Cancers (Basel)) - "We review the FGFR pathway and discuss emerging issues including resistance to FGFR inhibitors. We end with a discussion on future considerations to optimize the potential of this class of therapeutics in advanced cholangiocarcinoma."

Clinical • Journal • Review • Biliary Cancer • Cholangiocarcinoma • Gastrointestinal Cancer • Oncology • Solid Tumor • FGFR

[VIRTUAL] Acquired resistance to ATP-competitive and irreversible FGFR inhibitors (FGFRi’s): A library-based approach (AACR 2021) - "Using an unbiased library-based approach, we examined the development of acquired resistance with the irreversible FGFRi futibatinib and the ATP-competitive FGFRi’s erdafitinib (ERD) and pemigatinib (PEM). Mutant (mt) libraries were generated with random mutagenesis in two FGFR2 KD regions: #1 (amino acids [aa] 540-569), and #2 (aa 640-669)...Sequencing (table) identified, among others, the following aa mutations: N549, E565, and K641 (regulatory triad), V564 (gatekeeper region) and K659 (activation loop), also seen in patients who developed resistance to Debio1347, infigratinib, and PEM... Resistance mutations identified with this unbiased library-based in vitro approach were consistent with those observed in the clinic. Acquired drug resistance mutations were less frequent with futibatinib than with ATP-competitive FGFRi’s. Futibatinib demonstrated the most robust inhibition of drug resistant mts."

Preclinical • Oncology • FGFR2

[VIRTUAL] Targeting fibroblast growth factor receptors in castration-resistant prostate cancer (AACR 2021) - "Although AR signaling inhibitors (ARSI), such as enzalutamide (ENZ) and abiraterone (ABI), extend survival in recurrent and castration-resistant prostate cancer (CRPC), durable complete responses are rare...In vitro/ex vivo analysis of FGFRi (erdafitinib, CH5183284 and rogaratinib) demonstrated robust growth suppression in DNPC and moderate growth suppression in SCNPC...Furthermore, in vitro/ex vivo analysis of AR-expressing CRPC models determined that combination ARSI (ENZ, ABI or darolutamide) with FGFRi was superior to ARSI or FGFRi monotherapies in a subset of models... The emergence of bypass mechanisms that subvert AR-dependence in mCRPC highlights a need for novel therapeutic strategies. Our data nominate the FGF pathway as an actionable target in diverse phenotypes of treatment-refractory mCRPC."

Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • FGFR

A Study of Debio 1347 Plus Fulvestrant in Patients With Metastatic Breast Cancer (clinicaltrials.gov) - P1/2; N=10; Active, not recruiting; Sponsor: Memorial Sloan Kettering Cancer Center; Trial completion date: Nov 2020 ➔ Nov 2021; Trial primary completion date: Nov 2020 ➔ Nov 2021

Clinical • Trial completion date • Trial primary completion date • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • CCND1 • ER • FGF3 • FGFR • HER-2 • PGR

Defining the molecular phenotypes of metastatic castration-resistant prostate cancer sensitive to FGF pathway inhibition (AACR 2018) - "Our data highlight the importance of AR and REST transcriptional programs in maintaining phenotypic stability in mCRPC and explain the phenotypic heterogeneity of mCRPC in the post-abiraterone/enzalutamide era. Understanding the mCRPC subtypes that depend on the FGF pathway for survival and proliferation will inform treatment and lead to the development of novel therapies for advanced disease."

IO Biomarker • Prostate Cancer

[VIRTUAL] Acquired resistance to selective FGFR Inhibitors in FGFR-Altered cholangiocarcinoma (AACR-NCI-EORTC 2020) - "Pts received an ATP-competitive, reversible FGFRi including infigratinib (19%), pemigatinib (5%), Debio1347 (2%), ponatinib (2%), or AZD4547 (2%), or the covalently-binding, irreversible inhibitor futibatinib (69%) as their first FGFRi. On-target resistance with acquired mutations in the FGFR2 kinase domain emerges over time in pts experiencing clinical benefit from FGFRi, suggesting FGFR pathway dependence in these patients. Only ~40% of pts on futibatinib developed FGFR2 KDmuts, suggesting that most may have off-target mechanisms of resistance. Mutation of the cysteine residue to which futibatinib binds was not a common mechanism of resistance in this small series."

Preclinical • Biliary Cancer • Cholangiocarcinoma • Gastrointestinal Cancer • Oncology • Solid Tumor • FGFR2

[VIRTUAL] Debio1347, an oral FGFR inhibitor: results from a single center study in pediatric patients with recurrent/refractory FGFR altered gliomas (SNO 2020) - "FGFR targeted therapy with Debio1347 demonstrated tolerable toxicity and promising anti-tumor efficacy in pediatric patients with recurrent/refractory FGFR altered gliomas. Further studies in this population are warranted."

Clinical • Astrocytoma • CNS Tumor • Glioma • Metabolic Disorders • Nephrology • Oncology • Pediatrics • Renal Disease • Solid Tumor • FGFR3 • TACC3

[VIRTUAL] DEBIO1347, AN ORAL FGFR INHIBITOR: RESULTS FROM A SINGLE CENTER STUDY IN RECURRENT/REFRACTORY FGFR ALTERED PEDIATRIC GLIOMAS (SIOP 2020) - "Conclusions Debio1347 demonstrated tolerable toxicity and promising anti-tumor efficacy in pediatric patients with refractory FGFR altered gliomas. Further studies in this population are warranted."

Clinical • Astrocytoma • CNS Tumor • Glioma • Metabolic Disorders • Nephrology • Oncology • Pediatrics • Renal Disease • Solid Tumor • FGFR • FGFR3 • TACC3

Basket Trial in Solid Tumors Harboring a Fusion of FGFR1, FGFR2 or FGFR3- (FUZE Clinical Trial) (clinicaltrials.gov) - P2; N=63; Active, not recruiting; Sponsor: Debiopharm International SA; Trial completion date: Aug 2022 ➔ Dec 2021; Trial primary completion date: Aug 2020 ➔ Dec 2020

Clinical • Pan Tumor • Trial completion date • Trial primary completion date • Oncology • Solid Tumor • FGFR