Abstract PO5-05-03: Phase 1/2 Dose Expansion Study Evaluating First-In-Class eIF4A Inhibitor Zotatifin in Patients with ER+ Metastatic Breast Cancer
Authors: Rosen Ezra Y. , Sharma Manish , Berz David , Caswell-Jin Jennifer , Fulgar Georgina , Densel Mark , Chiang Gary , Sperry Samuel , Warner Douglas , Meric-Bernstam Funda 
Published: May 2024

Background

Zotatifin (eFT226) is a first-in-class, potent and sequence selective inhibitor of RNA helicase eIF4A that promotes a stable mRNA:eIF4A:drug ternary complex at specific polypurine motifs present within the 5’-UTR of select transcripts, thereby blocking production of the encoded proteins. In preclinical models zotatifin treatment simultaneously down-regulated translation of numerous oncogenes including CDK4, ERα, ERBB2, KRAS, and CCND1. Previous clinical research has demonstrated the activity of zotatifin in combination with other agents in ER+ metastatic breast cancer (MBC).

Methods

Part 1 is a 3+3 dose escalation portion of the protocol followed by Part 2 as a Simon’s two-stage design in patients with ER+ MBC enrolled at the recommended phase 2 dose (RP2D) of zotatifin (0.07 mg/kg IV two weeks on/one week off) in combination with fulvestrant (ful) and abemaciclib (abema) (Z+F+A). Part 1a and Part 1b are 3+3 dose escalation portions evaluating zotatifin in combination with ful (Z+F) at QW IV and Q2W IV dosing schedules, respectively. Key eligibility criteria included at least one line of therapy for advanced/metastatic disease, progression on hormone therapy, and in addition, the Z+F cohorts required prior CDK 4/6 inhibitor (CDKi). Primary endpoint of Part 1a/1b was determination of RP2D and primary endpoint of part 2 was objective response rate (ORR) per RECIST v1.1. Additional endpoints included safety, progression-free survival (PFS) and other efficacy analyses, and characterization of pharmacodynamic (PD) markers and pharmacokinetics.

Results

As of a data cut-off of July 6, 2023, 20 pts were enrolled in the Z+F+A cohort and had a median of four prior metastatic lines of therapy. In 19 evaluable pts in Z+F+A cohort, there were four confirmed partial responses (PR), one unconfirmed PR, and 10 pts with best overall response (OR) of stable disease (SD). All pts with PR/unconfirmed PR received prior CDKI, ful, and chemotherapy for MBC. Confirmed PRs were observed in patients with and without mutations in ESR1 and PIK3CA. mPFS, while not yet mature, exceeds 20 weeks. In Z+F+A the most common adverse events (AEs) were diarrhea (80%, all grades (Gr)) and nausea (75%, all Gr 1/2) and the most common Gr 3/4 AE was diarrhea (15%). In Z+F cohorts of 0.07 mg/kg QW (n=3), 0.1 mg/kg Q2W (n=3), and 0.14 Q2W (n= 2) there were no dose-limiting toxicities or Gr 5 adverse events (AEs). There was one confirmed PR and one SD in 0.1 and 0.14 mg/kg Q2W cohorts, respectively, and no PR or SD in the 0.07 mg/kg QW cohort. In Z+F+A, 9 pts had paired pre- and on-treatment ctDNA analyzed by Guardant assay. Of the remaining 11 pts, 4 came off study prior to scheduled collection of the on-treatment sample and 5 had unavailable samples. Of the 9 patients with paired samples, 8 had ctDNA decreases of &gt;50%, all of whom had SD or PR. In the Z+F Q2W cohort, 2 of 3 patients had ctDNA decreases &gt;50%, one of whom had a PR. Reduction below the limit of detection was seen for mutant alleles in ESR1, PIK3CA and other genes with potential to confer resistance to endocrine therapy.

Conclusion

Z+F+A showed encouraging efficacy in heavily pretreated ER+ MBC patients, with results that compare favorably to other treatment options available after progression on CDKi plus endocrine treatment. Efficacy was seen independent of ESR1 or PIK3CA mutations, suggesting the potential to treat a broad, unrestricted patient population. Initial results with Z+F Q2W dosing are encouraging and support continued dose escalation of this regimen.

Citation Format: Ezra Y. Rosen, Manish Sharma, David Berz, Jennifer Caswell-Jin, Georgina Fulgar, Mark Densel, Gary Chiang, Samuel Sperry, Douglas Warner, Funda Meric-Bernstam. Phase 1/2 Dose Expansion Study Evaluating First-In-Class eIF4A Inhibitor Zotatifin in Patients with ER+ Metastatic Breast Cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-05-03.