Abstract B160: First-in-human phase 1 study of E7090, a novel selective inhibitor of FGFRs, in patients with advanced solid tumors
Authors: Koyama Takafumi , Shimizu Toshio , Iwasa Satoru , Fujiwara Yutaka , Kondo Shunsuke , Kitano Shigehisa , Yonemori Kan , Shimomura Akihiko , Iizumi Sakura , Sasaki Tatsuya , Furuse Junji , Yamamoto Noboru 
Published: August 2018

Background: FGFR genetic alterations, such as gene fusion, mutation, and amplification, have been implicated in several types of cancer. E7090 is an orally available and selective inhibitor of the tyrosine kinase activities of FGFR1, -2, and -3 that showed antitumor activity in some preclinical models harboring FGFR genetic alterations. Method: This first-in-human phase I study (NCT02275910) was initiated to evaluate the safety and tolerability, pharmacokinetic (PK) and pharmacodynamic (PD) properties, and preliminary antitumor activity of E7090. It consists of dose escalation part in patients (pts) with advanced solid tumors unselected for FGFR alteration and expansion cohort restricted to pts with tumors harboring FGFR alteration. Modified toxicity probability interval design was employed for dose escalation based on a dose-limiting toxicity (DLT). E7090 was administered orally on a once-daily (QD) continuous schedule in 28-day cycles. In cycle 0, pts received a single oral dose of E7090 on Day 1 followed by 7 days interruption for PK analysis. Serum PD biomarkers for FGFR inhibition (FGF23 and Vitamin D) were measured. Results: As of 28 March 2017, 24 pts with advanced solid tumors were treated in the dose escalation part at dose ranges of 1-180 mg QD. One patient experienced DLT (Grade 3 AST/ALT increased) at 180 mg QD. Maximum tolerated dose was not defined and the recommended dose for expansion cohort was determined to be 140 mg QD based on PK, PD and safety data. Treatment-related treatment emergent adverse events (TEAEs) (≥20% of pts) were hyperphosphatemia (38%), creatinine increased (33%), ALT increased (25%), diarrhea (25%), lipase increased (21%), and nausea (21%). Grade 3 treatment-related TEAEs were ALT increased (8%), AST increased (4%), decreased appetite (4%), lymphocyte count decreased (4%), neutrophil count decreased (4%), and vomiting (4%). No Grade 4 TEAEs were observed. There were no TEAEs leading to death or withdrawal from the study treatment. Cmax and AUC increased with increasing dose with median tmax of 2-5 hr and mean t1/2 of 15.1-26.4 hr. One partial response was observed at 180 mg QD in patient with FGFR2 amplified gastric cancer who had received three lines of prior chemotherapy. E7090 treatment induced dose-dependent increases in serum FGF23 and Vitamin D, and these increases reached maximum at approximately 100 mg QD. Conclusions: E7090 has a tolerable and manageable safety profile and demonstrated PD biomarker changes with encouraging antitumor activity in FGFR2 amplified gastric cancer. These findings will be further evaluated in expansion cohort.

Citation Format: Takafumi Koyama, Toshio Shimizu, Satoru Iwasa, Yutaka Fujiwara, Shunsuke Kondo, Shigehisa Kitano, Kan Yonemori, Akihiko Shimomura, Sakura Iizumi, Tatsuya Sasaki, Junji Furuse, Noboru Yamamoto. First-in-human phase 1 study of E7090, a novel selective inhibitor of FGFRs, in patients with advanced solid tumors [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B160.