Final results from a phase II study of infigratinib (BGJ398), an FGFR-selective tyrosine kinase inhibitor, in patients with previously treated advanced cholangiocarcinoma harboring an FGFR2 gene fusion or rearrangement.

Abstract

265 Background: Treatment options for cholangiocarcinoma (CCA) after progression on first-line gemcitabine-based therapy are limited. Fibroblast growth factor receptor 2 ( FGFR2) gene fusions occur in 13–17% of intrahepatic CCA. A single-arm, phase II study (NCT02150967) evaluated infigratinib, an ATP-competitive FGFR1–3-selective oral tyrosine kinase inhibitor, in previously-treated advanced CCA with FGFR fusions/rearrangements. Methods: Adult patients with advanced/metastatic CCA with progression on ≥1 line of systemic therapy received infigratinib 125 mg orally for 21 days of each 28-day cycle until unacceptable toxicity or disease progression. All patients received prophylaxis with the oral phosphate binder sevelamer. Primary endpoint: objective response rate (ORR) by independent central review per RECIST v1.1, with duration of response (DOR). Secondary endpoints: progression-free survival (PFS), disease control rate, overall survival, safety, pharmacokinetics. Approximately 160 patients are planned (120/20/20 patients in Cohorts 1/2/3). This analysis focuses on Cohort 1 (patients with FGFR2 gene fusions or rearrangements without receiving a prior FGFR inhibitor). Results: As of 31 March 2020, 108 patients, including 83 (77%) with FGFR2 fusions, received infigratinib: median age 53 years (range 23–81 years); 54% had received ≥2 prior treatment lines. Median follow-up was 10.6 months (range 1.1–55.9 months). 96 patients (88.9%) discontinued treatment (12 ongoing). Centrally reviewed ORR was 23.1% (95% CI 15.6–32.2) including 1 CR and 24 PRs; median DOR was 5.0 months (range 0.9–19.1 months). Among responders, 8 (32.0%) patients had a DOR of ≥6 months. Median PFS was 7.3 months (95% CI 5.6–7.6 months). Prespecified subgroup analysis: ORR was 34% (17/50) in the second-line setting and 13.8% (8/58) in the third-/later-line setting (3–8 prior treatments). Most common treatment-emergent adverse events (TEAEs, any grade) were hyperphosphatemia (76.9%), eye disorders (67.6%, excluding central serous retinopathy/retinal pigment epithelium detachment [CSR/RPED]), stomatitis (54.6%), and fatigue (39.8%). CSR/RPED occurred in 16.7% of patients (including 1 G3 event; 0 G4). Other common grade 3/4 TEAEs were stomatitis (14.8%; all G3), hyponatremia (13.0%; all G3), and hypophosphatemia (13.0%; 13 G3, 1 G4). Conclusions: Infigratinib is associated with promising anticancer activity and a manageable AE profile in patients with advanced, refractory CCA with an FGFR2 gene fusion or rearrangement. A phase III study of infigratinib versus gemcitabine/cisplatin is ongoing in the front-line setting (NCT03773302). Clinical trial information: NCT02150967.

Intrahepatic Cholangiocarcinoma: A Summative Review of Biomarkers and Targeted Therapies

“…In addition to these more well-known drugs, there are a number of other early phase studies examining drug safety and efficacy of inhibitors of mutant FGFR, as well as several upstream or downstream processes related to FGFR-based pathways [42,50]. Javle et al published results from a single-arm phase II study that examined efficacy and safety of infigratinib, a FGFR-selective tyrosine kinase inhibitor, in patients with previously treated advanced cholangiocarcinoma [49,51,54]. In a cohort of 108 patients with advanced or metastatic cholangiocarcinoma, the objective response rate was 23%, the median duration of response was 5.0 months, and the median progressionfree survival was 7.3 months (95% CI 5.6-7.6 months) [51,54,55].…”

“…Javle et al published results from a single-arm phase II study that examined efficacy and safety of infigratinib, a FGFR-selective tyrosine kinase inhibitor, in patients with previously treated advanced cholangiocarcinoma [49,51,54]. In a cohort of 108 patients with advanced or metastatic cholangiocarcinoma, the objective response rate was 23%, the median duration of response was 5.0 months, and the median progressionfree survival was 7.3 months (95% CI 5.6-7.6 months) [51,54,55]. The majority of patients experienced hyperphosphatemia despite taking a prophylactic phosphate binder (77%) and non-severe eye disorders (68%), while a minority of patients experienced serious eye disorders (16%, central serous retinopathy and retinal pigment epithelium detachment) [54,55].…”

Targetable Pathways in Advanced Bladder Cancer: FGFR Signaling

“…Infigratinib (BJG398) is an FGFR1–3-selective oral tyrosine kinase inhibitor [ 58 ] shown in a phase II study to reduce the size of tumors bearing FGFR3 alterations and stabilize disease in metastatic urothelial carcinoma patients [ 59 ]. Based on these findings, infigratinib was granted FDA approval [ 60 ]. A phase III clinical trial is testing this agent in the adjuvant setting following surgery in advanced bladder cancer with susceptible FGFR3 genetic alterations (ClinicalTrials.gov Identifier, NCT04197986).…”

Highlights from ASCO-GI 2021 from EORTC Gastrointestinal tract cancer group

“…Although the commonest fusion partner was BBICC1, 35% of patients had a novel fusion partner. Adverse events (mostly mechanism-based) were predominantly grade 1-2 and manageable [14].…”