Debio 1347 in patients with gastrointestinal cancers harboring an FGFR gene fusion: preliminary results

Aberrant FGFR signaling has been implicated in GI cancer carcinogenesis especially in biliary tract, gastro-esophageal, and colon cancers. Debio 1347 is an orally available selective FGFR inhibitor with potent antitumor effect in preclinical models of cancer bearing FGFR alterations. Debio 1347 showed encouraging preliminary clinical activity and manageable treatment-emergent adverse events (TEAE) in its first-in-human (FIH) ph1 study (NCT1948297). Here we report results from the patients with GI cancers harboring an FGFR fusion.

This FIH study enrolled patients with advanced solid malignancies harboring activating alterations of FGFR 1, 2, or 3. A confirmatory post-hoc genetic analysis was performed centrally for all available biopsies. Patients received Debio 1347 at doses between 60 and 150 mg orally daily in 28-day cycles. Pharmacokinetics and pharmacodynamics were serially evaluated in blood, skin and/or tumor tissue. The primary endpoints were to investigate the safety and to determine the MTD in the dose-escalation part of the study. Objective response rate (ORR) assessed per RECIST 1.1 and safety were the primary endpoints in the expansion part.

A total of 18 patients harboring FGFR1-3 fusions were enrolled as of March 11, 2019. Among 13 patients with GI cancers, 8 had intrahepatic cholangiocarcinoma (7 FGFR2 and one FGFR1 fusion), 1 had a gallbladder cancer (FGFR3 fusion), 2 had colon cancer (FGFR2 fusion), and 2 had gastric cancer (FGFR2 and FGFR3 fusion). All had prior systemic therapy (mostly 2 or 3 lines; range 1-5). Partial responses were observed in 3 out of 10 evaluable patients, 2 with colon cancer and one with cholangiocarcinoma. An additional 6 patients had target lesions regression < 30% (SD). Overall disease control was observed in 9 out of 10 evaluable patients. The median duration of treatment was 24 weeks (range 4-47). The most common TEAEs were hyperphosphatemia, nausea, constipation, fatigue and nail changes. Grade 3 TEAEs were hyperphosphatemia in 4 patients (30.8%), and anemia, hydronephrosis, increased transaminases in one patient each.

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).