A multicenter investigator-initiated Phase 2 trial of E7090 in patients with advanced or recurrent solid tumor with fibroblast growth factor receptor (FGFR) gene alteration: FORTUNE trial

Abstract

Background Aberrant fibroblast growth factor receptor (FGFR) signaling can substantially influence oncogenicity. Despite that FGFR gene abnormality is often detected by cancer genome profiling tests, there is no tumor-agnostic approval yet for these aberrations. E7090 (tasurgratinib) is an orally available selective tyrosine kinase inhibitor of FGFR1-3. Specific FGFR alterations were previously reported to be highly sensitive to E7090 based on a high-throughput functional evaluation method, called mixed-all-nominated-mutants-in-one (MANO) method, narrowing down the most promising targets. This trial was focused on the alterations identified by the MANO method and was performed under the nationwide large registry network for rare cancers in Japan (MASTER KEY Project). Methods/Design This single-arm Phase 2 trial was designed to evaluate the safety and efficacy of E7090 in patients with advanced or recurrent solid tumors harboring FGFR alterations. Three cohorts were set based on the type of FGFR alterations and the results of MANO method. A maximum of 45 patients will be enrolled from 5 institutions over 2.5 years. E7090 will be administered once daily as an oral single agent in 28-day cycles. The primary endpoint is the objective overall response rate; whereas, the secondary endpoints include progression-free survival, overall survival, disease control rate, safety, duration of response, and time to response. Ethics approval was granted by the National Cancer Center Hospital Certified Review Board. Patient enrollment began in June 2021. Discussion A unique investigator-initiated multicenter Phase 2 trial was designed based on the results of preclinical investigation aiming to acquire the approval of E7090 for solid tumors harboring FGFR gene alterations. The findings may serve as a novel model for the development of tumor-agnostic molecular targeted therapies against rare genetic abnormalities. Trial registration Japan Registry of Clinical Trial: jRCT2031210043 (registered April 20, 2021) ClinicalTrials.gov: NCT04962867 (registered July 15, 2021).

FGFR families: biological functions and therapeutic interventions in tumors

“…Common adverse effects include diarrhea, decreased appetite, fatigue, and asymptomatic lipase elevation 370,371 . E7090 selectively inhibits FGFR1–3 and has been found to be effective in patients with cholangiocarcinoma with FGFR2 gene fusions and in patients with gastric cancer with FGFR2 gene amplification or increased expression, but more information is needed for a larger sample size 372 . Debio 1347 is an ATP‐competitive, highly selective FGFR1–3 inhibitor, and it is mainly used to treat breast cancer and cholangiocarcinoma.…”

“… 370 , 371 E7090 selectively inhibits FGFR1–3 and has been found to be effective in patients with cholangiocarcinoma with FGFR2 gene fusions and in patients with gastric cancer with FGFR2 gene amplification or increased expression, but more information is needed for a larger sample size. 372 Debio 1347 is an ATP‐competitive, highly selective FGFR1–3 inhibitor, and it is mainly used to treat breast cancer and cholangiocarcinoma. The common adverse effects of debio 1347 include hyperphosphatemia, diarrhea, constipation, fatigue, loss of appetite, and dry mouth.…”