Zotatifin With Fulvestrant and Abemaciclib Shows Favorable Activity in ER+ Breast Cancer

In a cohort of 7 patients with ER+ breast cancer, treatment with zotatifin in combination with fulvestrant and abemaciclib led to 2 partial responses and and additional patient with stable disease continuing beyond 24 weeks.

Treatment with zotatifin (eFT226) continues to elicit a favorable activity profile and tolerability among 7 heavily pretreated patients with ER-positive breast cancer who received the agent in combination with fulvestrant and abemaciclib, according to eFFECTOR Therapeutics.1

In the open-label, sequential-group, dose-escalation and cohort-expansion, phase 1/2 study, a cohort of 7 patients were administered zotatifin, fulvestrant and abemaciclib. Among those enrolled to this cohort, confirmed partial responses (PRs) were observed in 2 patients. A third patient had stable disease continuing beyond 24 weeks for an objective response rate (ORR) of 29% (n = 2) and a clinical benefit rate (CBR) of 43% (n = 3).

Data regarding the overall response rate (ORR) and clinical benefit rate (CBR) for the remaining 11 patients in the trial are expected to be released in the first half of 2023.

“We are making steady headway across all our clinical programs and look forward to a number of key data milestones in 2023 for both the zotatifin and tomivosertib [eFT-508] programs,” remarked Steve Worland, PhD, president, and chief executive officer of eFFECTOR, in the press release. “With zotatifin, we continue to see activity across both ER+ BC expansion cohorts, and the drug continues to be generally well-tolerated. The safety results to date have led us to believe that we may be able to increase the dose of zotatifin, which may achieve greater anti-tumor activity. Therefore, we have resumed dose escalation and plan to wait for dose escalation data as well as data from the ongoing ECBF+A cohort before pursuing additional expansion cohorts. We have also completed enrollment in the third and final cohort in our phase 1b study with zotatifin in COVID-19 and anticipate providing top-line data from this trial in the first half of 2023.”

The study is evaluating the safety, pharmacokinetics (PK), pharmacodynamics, and antitumor activity of zotatifin in patients with KRAS-mutated non–small cell lung cancer (NSCLC) and ER-positive breast cancer.2

Part 1 of the trial was the dose-escalation portion to determine the recommended phase 2 dose (RP2D) and maximum tolerated dose. Parts 1a and 1b are dose-escalation portions which will enroll patients with advanced breast cancer who are refractory or intolerant to standard of care (SOC) therapy. In part 2, the expansion cohort, the safety, pharmacology, and clinical activity of zotatifin administered as a monotherapy will be observed.

The primary end points of part 1 of the trial are to evaluate the safety and tolerability of zotatifin monotherapy in patients with defined, advanced solid tumors, determine the RP2D, and evaluate the PK profile. In part 2 of the trial, the primary end point is to evaluate the preliminary antitumor activity of zotatifin as both a monotherapy and in combination for patients with advanced solid tumors.

In the cohort of 18 patients receiving zotatifin and fulvestrant, 1 patient experienced a confirmed PR and 1 reported stable disease continuing beyond 24 weeks. As a part of this doublet, zotatifin was generally safe and well-tolerated.

As a part of the triplet combination of zotatifin, fulvestrant, and abemaciclib, 2 of 7 patients experienced confirmed PRs, while another patient had stable disease continuing beyond 24 weeks. This led to an ORR of 29% and CBR of 43%. Regarding safety, zotatifin was also generally safe and well-tolerated when used in this triplet combination.1

Due to the dose-dependent target engagement observed by 2 independent methods, without signs of target saturation, the company has resumed to dose-escalation in the trial. Topline data are anticipated in the second half of 2023.

Additionally, initiation of the Cyclin D1 amplified cohort of patients with ER-positive breast cancer has been deferred and enrollment in the KRAS G12C NSCLC cohort has been paused until completion of dose-escalation portion of the trial.

eFFECTOR Therapeutics provides positive clinical data update for zotatifin and general corporate update. News release. eFFECTOR Therapeutics, Inc. January 5, 2023. Accessed January 11, 2023. https://yhoo.it/3QA0VX2
Study of eFT226 in subjects with selected advanced solid tumor malignancies (Zotatifin). ClinicalTrials.gov. Updated November 18, 2022. Accessed January 11, 2023. https://clinicaltrials.gov/ct2/show/NCT04092673