Evaluation of BGJ398, a Fibroblast Growth Factor Receptor 1-3 Kinase Inhibitor, in Patients With Advanced Solid Tumors Harboring Genetic Alterations in Fibroblast Growth Factor Receptors: Results of a Global Phase I, Dose-Escalation and Dose-Expansion Study

Abstract

Purpose This two-part, first-in-human study was initiated in patients with advanced solid tumors harboring genetic alterations in fibroblast growth factor receptors (FGFRs) to determine the maximum tolerated dose (MTD), the recommended phase II dose (RP2D), and the schedule, safety, pharmacokinetics, pharmacodynamics, and antitumor activity of oral BGJ398, a selective FGFR1-3 tyrosine kinase inhibitor. Patients and Methods Adult patients were treated with escalating dosages of BGJ398 5 to 150 mg once daily or 50 mg twice daily continuously in 28-day cycles. During expansion at the MTD, patients with FGFR1-amplified squamous cell non-small-cell lung cancer (sqNSCLC; arm 1) or other solid tumors with FGFR genetic alterations (mutations/amplifications/fusions) received BGJ398 daily on a continuous schedule (arm 2), or on a 3-weeks-on/1-week-off schedule (arm 3). Results Data in 132 patients from the escalation and expansion arms are reported (May 15, 2015, cutoff). The MTD, 125 mg daily, was determined on the basis of dose-limiting toxicities in four patients (100 mg, grade 3 aminotransferase elevations [n = 1]; 125 mg, hyperphosphatemia [n = 1]; 150 mg, grade 1 corneal toxicity [n = 1] and grade 3 aminotransferase elevations [n = 1]). Common adverse events in patients treated at the MTD (n = 57) included hyperphosphatemia (82.5%), constipation (50.9%), decreased appetite (45.6%), and stomatitis (45.6%). A similar safety profile was observed using the 3-weeks-on/1-week-off schedule (RP2D). However, adverse event-related dose adjustments/interruptions were less frequent with the 3-weeks-on/1-week-off (50.0%) versus the continuous (73.7%) schedule. Antitumor activity (seven partial responses [six confirmed]) was demonstrated with BGJ398 doses ≥ 100 mg in patients with FGFR1-amplified sqNSCLC and FGFR3-mutant bladder/urothelial cancer. Conclusion BGJ398 at the MTD/RP2D had a tolerable and manageable safety profile and showed antitumor activity in several tumor types, including FGFR1-amplified sqNSCLC and FGFR3-mutant bladder/urothelial cancers.

Mechanisms of Primary Drug Resistance in FGFR1-Amplified Lung Cancer

“…In a phase I clinical trial, 11% of patients with FGFR1-amplified SQLC treated with a highly selective and potent FGFR inhibitor, BGJ398, experienced a partial response (9). Additional clinical trials using the FGFR inhibitors, AZD4547 or JNJ-42756493 to treat solid tumors bearing FGFR1, 2, or 3 alterations yielded similar results.…”

“…Of note, additional patients exhibited tumor shrinkage, but less than required for a partial response, thus suggesting insufficient tumor cell killing by FGFR inhibition alone (9,11,12). We therefore sought to identify mechanisms that underlie primary drug resistance in FGFR1-amplified lung cancer.…”

Acquired Resistance to FGFR Inhibitor in Diffuse-Type Gastric Cancer through an AKT-Independent PKC-Mediated Phosphorylation of GSK3β

“…Targeting FGFR2 is an attractive therapeutic option for DGC, as FGFR2 amplification is found in approximately 10% of all gastric tumors, and high FGFR2 expression has been correlated with tumor progression and poor survival in DGC (37). A recent clinical trial has demonstrated that gastric cancers with high-level FGFR2 amplification have a high response rate to AZD4547 (15), and several clinical and preclinical studies have also shown that FGFR amplification predicts sensitivity to FGFR inhibitors such as BGJ398 and AZD4547 (38)(39)(40).…”

FGFR a promising druggable target in cancer: Molecular biology and new drugs

“…BGJ398 appeared to be superior in FGFRinhibiting potency . In a phase I clinical trial in patients with advanced solid tumors harboring genetic FGFR alterations, BGJ398 proved antitumor activity, good tolerability and manageable safety profile (Nogova et al, 2016). This compound is being tested in several clinical trials in patients with solid tumors (NCT02160041; NCT01004224; NCT01928459), cholangiocarcinoma (NCT02150967) and glioblastoma (NCT01975701).…”