Debio 1347, an oral FGFR inhibitor: Results from a first-in-human, phase I dose-escalation study in patients with FGFR genomically activated advanced solid tumors.

Abstract

2500 Background: Oncogenic alterations in fibroblast growth factor receptors (FGFR) are seen across multiple solid tumor malignancies. Debio 1347 is an orally available, highly selective panFGFR inhibitor with potent antitumor effect in preclinical models bearing FGFR1-3 genetic alterations. Methods: Patients harboring defined FGFR 1, 2 or 3 alterations received escalating doses of Debio 1347 starting from 10 mg once daily. Dose escalation followed a 3+3+3 algorithm based on a modified Fibonacci sequence. The MTD was defined as the level where ≥ 3/9 patients suffer a DLT. Pharmacokinetics (PK) and pharmacodynamic were serially evaluated in blood, skin and/or tumor tissue. Results: Fifty-six patients were enrolled, including patients with mutations (n = 17), amplifications (n = 28) and fusions (n = 11). The dose was escalated up to 150 mg over 8 cohorts. DLTs were experienced by 4/56 patients, including G2 intolerable dry mouth + eyes at 60 mg, G3 hypercalcemia + hyperamylasemia at 80 mg, and G3 bilirubin increase at 110 mg. At data cut-off, the most common treatment-emergent adverse events (TEAE) were hyperphosphatemia (73%), fatigue (41%), diarrhea (39%), nausea (37%), and inappetence (32%). Fifteen patients (27%) experienced a grade ≥ 3 related TEAE. Twenty-five patients (47%) required dose modification, primarily due to hyperphosphatemia and cutaneous toxicity. An MTD has not been reached. PK appeared overall linear, with a half-life of 14 hours; hyperphosphatemia was dose-dependent. Among the 54 response-evaluable patients, 4 confirmed and 1 unconfirmed partial responses were observed in patients with cholangiocarcinoma (FGFR2 mutant), uterine (FGFR2 and FGFR1 amplified), colon (FGFR2 fusion), and urothelial cancer (FGFR3 fusion); an additional 10 patients had target regression < 30%. Conclusions: Debio 1347 had a tolerable and manageable safety profile. Encouraging antitumor activity was seen in several tumor types, mainly in patients with FGFR2 or 3 gene alterations, including fusion events, treated at 80 mg and 110 mg daily. Efficacy will be further explored in disease-specific and molecularly defined expansion cohorts. Clinical trial information: NCT1948297.

Multicenter Phase I Study of Erdafitinib (JNJ-42756493), Oral Pan-Fibroblast Growth Factor Receptor Inhibitor, in Patients with Advanced or Refractory Solid Tumors

“…For cholangiocarcinoma, in which all patients were treated at 10-mg intermittent except for one patient who received 9 mg daily, the sample size was smaller and the ORR was lower relative to urothelial carcinoma; however, the duration of response was notable at 11.4 months. Although other clinical trial data regarding the antitumor activity of FGFR inhibition in urothelial carcinoma and cholangiocarcinoma remain limited, emerging data are showing responses across several investigational anti-FGFR compounds in early clinical development, including BGJ398 (20) and AZD4547 (21) in urothelial carcinoma, ARQ 087 (22) in cholangiocarcinoma, and Debio 1347 (23) in both urothelial carcinoma and in cholangiocarcinoma. Across clinical trials of FGFR inhibitors irrespective of histology, it appears that the most common type of alteration (FGFR1 amplification) is not the most sensitive to treatment and that identifying patients with relatively uncommon FGFR mutations and FGFR gene fusions may provide the highest likelihood for clinical response, posing some challenges with respect to clinical trial designs while reinforcing the importance for comprehensive screening (24,25).…”

TAS-120 Overcomes Resistance to ATP-Competitive FGFR Inhibitors in Patients with FGFR2 Fusion–Positive Intrahepatic Cholangiocarcinoma

“…A phase I dose-escalation trial using another ATP-competitive FGFR1-3 inhibitor, Debio 1347 (CH5183284; ref. 15 ), has also reported early evidence of antitumor activity in a few tumor types including ICC ( 16 ). However, rapid emergence of acquired resistance has frequently www.aacrjournals.org been observed, with a 5.8-month median progression-free survival in the BGJ398 trial (14).…”

Precision oncology in urothelial cancer

“…In an unselected cohort of patients who progressed following first-line chemotherapy, dovitinib disappointingly showed limited activity 17. Another study investigated the use of debio 1347, a panFGFR inhibitor across 56 patients with a range of solid tumours 18. Preliminary responses have been seen in patients with cholangiocarcinoma, uterine, colon and urothelial cancer 18…”

“…Another study investigated the use of debio 1347, a panFGFR inhibitor across 56 patients with a range of solid tumours 18. Preliminary responses have been seen in patients with cholangiocarcinoma, uterine, colon and urothelial cancer 18…”