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Dose-Expansion Portion of Phase 1 Study of E7090 in Patients with CCA

2020 Year in Review: Cholangiocarcinoma — December 19, 2020

Interim analysis of the part 2 dose-expansion portion of an ongoing 2-part phase 1 Japanese study shows that the FGFR1 tyrosine kinase inhibitor E7090 was active with a manageable safety profile in CCA patients with FGFR2 gene fusion.

Fibroblast growth factor receptor (FGFR) genetic alterations, including gene fusion, mutation, and amplification, have been implicated in several cancers, including cholangiocarcinoma (CCA). E7090 is a selective tyrosine kinase inhibitor (TKI) directed against FGFR1 that has shown promising preclinical activity in models harboring genetic alterations.1 An ongoing 2-part, first-in-human, phase 1 study is being conducted in Japan to evaluate the tolerability and safety of E7090 in patients with advanced solid tumors. In the part 1 portion of this study, which evaluated the toxicity, pharmacokinetic (PK), and pharmacodynamic (PD) profiles of E7090, no dose-limiting toxicities were identified and the recommended phase 2 dose was determined to be 140 mg daily. Interim analysis of the part 2 dose-expansion portion of this study in patients who harbored FGFR2 gene alterations were reported at the American Society of Clinical Oncology (ASCO) 2020 Gastrointestinal Cancers Symposium.

In the part 2 dose-expansion portion of the study, eligibility criteria included patients with CCA harboring FGFR2 gene fusion and gastric cancer harboring FGFR2 gene amplification or FGFR2 protein high expression, and failure of standard therapies or for whom no appropriate treatment is available. Eligible patients received E7090 until disease progression or unacceptable toxicity.

At the time of data cutoff (July 31, 2019), 16 patients were enrolled in part 2, including 6 patients in the CCA cohort and 10 patients in the gastric cancer cohort. In the CCA study population, median age was 53.7 years, 16.7% were female, and 50% of patients had Eastern Cooperative Oncology Group (ECOG) performance status of 1. Five (83%) patients had received ≥2 previous treatments, and 3 (50%) had undergone surgery.

In terms of tumor response per investigator assessment, 5 (83%) patients achieved partial response as the best overall response; 1 patient achieved stable disease for a disease control rate of 100%. In Kaplan-Meier plots, median progression-free survival (PFS) was 8.26 months, and median overall survival (OS) was not estimable. Two patients remain on treatment.

In the total population (CCA and gastric cancer cohorts), grade 3/4 treatment-emergent adverse events (AEs) occurred in 11 (69%) patients and grade 3/4 treatment-related AEs in 12.5%. Treatment-emergent serious AEs occurred in 5 (31%) patients; none of which were treatment-related. Dose reductions due to treatment-emergent AEs occurred in 5 (31%) patients. The most common treatment-related AEs (≥30%) included hyperphosphatemia (100%), palmar-plantar erythrodysesthesia syndrome (56%), paronychia (50%), dysgeusia (31%), stomatitis (31%), diarrhea (25%), increased aspartate aminotransferase (12.5%), and blood creatinine increased (19%).

Based on the results of the part 2 dose-expansion portion of the phase 1 study, the investigators concluded that E7090 was associated with promising clinical activity and a manageable safety profile in CCA patients with FGFR2 gene fusion; for these reasons, a phase 2 study has been initiated in patients with CCA harboring FGFR2 gene fusion.

Source: Morizane C, et al. J Clin Oncol. 2020;38(4_suppl). Abstract 538.

Reference

  1. Miyano SW, Yamamoto Y, Kodama K, et al. E7090, a novel selective inhibitor of fibroblast growth factor receptors, displays potent antitumor activity and prolongs survival in preclinical models. Mol Cancer Ther. 2016;15:2630-2639.

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