367P - Phase I/II dose escalation study evaluating first-in-class eIF4A inhibitor zotatifin in ER+ metastatic breast cancer

Background

Zotatifin (zota) is a first-in-class, sequence selective inhibitor of RNA helicase eIF4A that blocks translation of key oncogenes including CCND1, CDK4, ERα, ERBB2, FGFR1, and KRAS. Prior clinical research of zota combined with abemaciclib (abema) and fulvestrant (ful) in heavily pretreated ER+ metastatic breast cancer (MBC) showed a progression-free survival of 7.4 months and an objective response rate (ORR) of 26%. Based on dose response decreases in circulating tumor DNA and a well-tolerated safety profile, dose escalation was reinitiated at a Q2W dosing schedule.

Methods

Part 1b of the study is a 3+3 dose escalation of zota IV Q2W in combination with ful. Key eligibility criteria included at least one line of therapy for MBC, progression on hormone therapy, and prior CDK 4/6 inhibitor. Primary endpoint of part 1b is determination of the recommended phase 2 dose (RP2D) and the primary endpoint of part 2 (combination of zota + ful + abema) is ORR. Additional endpoints included safety, other efficacy analyses, and pharmacodynamic (PD) markers and pharmacokinetics (PK).

Results

As of a data cut-off of April 22, 2024, 15 patients (pts) were enrolled in the dose escalation cohort and had a median of 4 prior lines of therapy in the metastatic setting. In zota Q2W cohorts of 0.1 mg/kg (n=3), 0.14 mg/kg (n= 3), and 0.2 mg/kg (n=6) there were no dose-limiting toxicities (DLTs) or serious adverse events (SAEs). The best overall response in these cohorts were 1 partial response, 2 stable disease (SD), and 3 SD, respectively. At 0.28 mg/kg Q2W (n=3), one pt had DLTs of grade (Gr) 3 mucositis and Gr 4 thrombocytopenia, and one pt had DLTs Gr 3 fatigue and Gr 3 pulmonary embolism. A third pt had a Gr 5 lung infection considered unrelated to study drug. Part 2 of the study is now evaluating the combination of zota Q2W + ful + abema. PD and PK will be reported.

Conclusions

In dose escalation cohorts of heavily pre-treated ER+ MBC pts, eIF4A inhibitor zotatifin achieved the RP2D of 0.2 mg/kg Q2W and showed evidence of anti-tumor activity in combination with ful. The combination of Q2W zotatifin is currently being evaluated in part 2 of the study in combination with abemaciclib and fulvestrant in late line ER+ MBC.

Clinical trial identification

NCT04092673, September 13, 2019.

Editorial acknowledgement

Legal entity responsible for the study

eFFECTOR Therapeutics, Inc.

Funding

eFFECTOR Therapeutics, Inc.

Disclosure

E. Rosen: Financial Interests, Institutional, Advisory Board: eFFECTOR Therapeutics. J. Caswell-Jin: Financial Interests, Institutional, Funding: eFFECTOR Therapeutics, Novartis; Financial Interests, Personal, Advisory Board: eFFECTOR Therapeutics. G. Fulgar: Financial Interests, Personal, Stocks/Shares: eFFECTOR Therapeutics; Financial Interests, Personal, Full or part-time Employment: eFFECTOR Therapeutics. M. Densel: Financial Interests, Personal, Full or part-time Employment: eFFECTOR Therapeutics; Financial Interests, Personal, Stocks/Shares: eFFECTOR Therapeutics. G. Chiang: Financial Interests, Personal, Full or part-time Employment: eFFECTOR Therapeutics; Financial Interests, Personal, Stocks/Shares: eFFECTOR Therapeutics. S. Sperry: Financial Interests, Personal, Full or part-time Employment: eFFECTOR Therapeutics; Financial Interests, Personal, Stocks/Shares: eFFECTOR Therapeutics. D. Warner: Financial Interests, Personal, Full or part-time Employment: eFFECTOR Therapeutics; Financial Interests, Personal, Stocks/Shares: eFFECTOR Therapeutics. F. Meric-Bernstam: Financial Interests, Personal, Other, Consultant: AstraZeneca, OnCusp Therapeutics, Zymeworks; Financial Interests, Personal, Other, Consulting: Calibr, Ecor1, Exelixis, GT Aperion, Infinity Pharmaceuticals, LOXO-Oncology, LegoChem Bio, Lengo Therapeutics, Tallac Therapeutics, Becton Dickinson, eFFECTOR Therapeutics, Jazz Pharmaceuticals; Financial Interests, Personal, Advisory Board: Daichii Sankyo, Incyte, Karyopharm, Protai, TheraTechnologies, Zentalis, FogPharma, Harbinger Health, Mersana Therapeutics, Sanofi Pharmaceuticals; Financial Interests, Personal, Other, Consutling: Menarini Group; Financial Interests, Personal, Advisory Board, Advisory Board/Consultant: Seagen; Financial Interests, Personal, Invited Speaker: Dava Oncology; Financial Interests, Institutional, Other, Local PI / Research Grant: Aileron Therapeutics, Bayer Healthcare, CytomX Therapeutics Inc., Daiichi Sankyo Co. Ltd., eFFECTOR Therapeutics, Taiho Pharmaceutical Co.; Financial Interests, Institutional, Other, Local PI / Research Grant / Coordinating PI: AstraZeneca; Financial Interests, Institutional, Local PI: Calithera Biosciences, Curis Inc., Debiopharm International, Guardant Health Inc., Klus Pharma, Novartis, Jazz Pharmaceuticals, Zymeworks; Financial Interests, Institutional, Other, Local PI / Steering Committee Member: Genentech Inc.; Financial Interests, Institutional, Research Grant: Takeda Pharmaceutical Co., Puma Biotechnology Inc., Repare; Other, Travel support: European Organisation for Research and Treatment of Cancer (EORTC), European Society for Medical Oncology (ESMO); Other, Travel Support: Cholangiocarcinoma Foundation, Dava Oncology. All other authors have declared no conflicts of interest.