A Phase I, Open-Label, Multicenter, Dose-escalation Study of the Oral Selective FGFR Inhibitor Debio 1347 in Patients with Advanced Solid Tumors Harboring FGFR Gene Alterations

Abstract

Purpose: To investigate tolerability, efficacy, and pharmacokinetics/pharmacodynamics of Debio 1347, a selective FGFR inhibitor.Patients and Methods: This was a first-in-human, multicenter, open-label study in patients with advanced solid tumors harboring FGFR1-3 gene alterations. Eligible patients received oral Debio 1347 at escalating doses once daily until disease progression or intolerable toxicity. Dose-limiting toxicities (DLT) were evaluated during the first 4 weeks on treatment, pharmacokinetics/pharmacodynamics postfirst dose and after 4 weeks.Results: A total of 71 patients were screened and 58 treated with Debio 1347 at doses from 10 to 150 mg/day. Predominant tumor types were breast and biliary duct cancer, most common gene alterations were FGFR1 amplifications (40%) and mutations in FGFR2 (12%) and FGFR3 (17%); 12 patients (21%) showed FGFR fusions. Five patients at three dose levels had six DLTs (dry mouth/eyes, hyperamylasemia, hypercalcemia, hyperbilirubinemia, hyperphosphatemia, and stomatitis). The maximum tolerated dose was not reached, but dermatologic toxicity became sometimes dose limiting beyond the DLT period at !80 mg/day. Adverse events required dose modifications in 52% of patients, mostly due to dose-dependent, asymptomatic hyperphosphatemia (22%). RECIST responses were seen across tumor types and mechanisms of FGFR activation. Six patients, 3 with FGFR fusions, demonstrated partial responses, 10 additional patients' tumor size regressions of 30%. Plasma half-life was 11.5 hours. Serum phosphate increased with Debio 1347 plasma levels and confirmed target engagement at doses !60 mg/day.Conclusions: Preliminary efficacy was encouraging and tolerability acceptable up to 80 mg/day, which is now used in an extension part of the study.

Futibatinib Is a Novel Irreversible FGFR 1–4 Inhibitor That Shows Selective Antitumor Activity against FGFR-Deregulated Tumors

“…Several selective small-molecule FGFR inhibitors entered clinical development in the past few years and have shown responses in patients with FGFR signaling pathway aberrations in phase 1/2 clinical studies (14)(15)(16)(17)(18)(19)(20). However, the majority of these agents bind reversibly to the adenosine triphosphate (ATP)-binding pocket of FGFRs.…”

FGFR inhibitors in cholangiocarcinoma: what’s now and what’s next?

“… 32 In a recently published phase I study with debio 1347, RECIST responses were seen across tumor types and mechanisms of FGFR activation, that is, FGFR1-3 amplification, mutation and fusions. 33 – 35 Currently, two FGFR inhibitors have gained FDA approval: pemigatinib was approved in April 2020 for the treatment of advanced iCCA, whereas erdafitinib was approved for therapy-resistant urothelial cancers harboring FGFR2/3 genetic alterations. 36 In CCA, a phase I as well as a phase IIa study in Asian patients showed promising results for erdafitinib, but due to the low patient numbers the clinical data available thus far cannot be considered fully conclusive yet [ClinicalTrials.gov identifier: NCT01703481] and [ClinicalTrials.gov identifier: NCT02699606].…”

Fibroblast Growth Factor Receptor (FGFR) Inhibitors in Urothelial Cancer

“…Debio‐1347 is a small, oral molecule that selectively inhibits the ATP binding site of FGFR1–3 [38]. A phase I clinical trial evaluated the safety and antitumor activity of debio‐1347 in 58 patients with solid tumors including breast (21%), biliary tract (14%), bladder (10%), uterine (9%), squamous cell lung cancer (7%), gastric cancer (7%), prostate cancer (3%), and cervical cancer (3%) with known FGFR 1–3 alterations [39]. FGFR1 amplification was most common (40%), followed by FGFR fusion (21%), FGFR2 mutation (12%), and FGFR3 mutation (17%).…”