Zotatifin Triplet May Improve Outcomes Post–CDK4/6 Inhibition in ER+ Breast Cancer


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Ezra Rosen, MD, PhD, highlights the early-phase investigation of zotatifin in estrogen receptor-positive metastatic breast cancer, explains the agent’s unique mechanism of action as well as its efficacy and safety in a heavily pretreated population, and underscores the need for improved sequencing of the myriad of treatment options in the post–CDK4/6 inhibitor space.

Despite the ever-growing landscape of therapeutics for patients with estrogen receptor (ER)–positive metastatic breast cancer beyond the first line, there is still a substantial need for effective options for those who develop resistance to standard endocrine therapies through multiple mechanisms. Due to its unique mechanism of action, adding the selective eIF4A inhibitor zotatifin (eFT226) to standard agents may prove more effective than the use of these agents alone in heavily pretreated populations, according to Ezra Rosen, MD, PhD.

Data from 2 expansion cohorts of a phase 1/2 study (NCT04092673) presented at the 2023 ASCO Annual Meeting showed that the triplet combination of zotatifin, abemaciclib (Verzenio), and fulvestrant (Faslodex; n = 19) elicited a confirmed objective response rate (ORR) of 21%, which included 4 partial responses (PR) and 1 unconfirmed PR.1 Additionally, those treated with the doublet of zotatifin and fulvestrant (n = 17) experienced a confirmed ORR of 5.9%, which consisted of 1 PR. In the triplet and the doublet arms, stable disease was achieved by 47% and 35% of patients, respectively.

“There’s been a huge unmet need for [effective therapies] in the post–endocrine therapy space. We’re trying to fill that by targeting ER [proteins] and other essential proteins involved in metastatic breast cancer using this novel strategy,” said Rosen, a breast oncologist, early drug development specialist, and assistant attending physician at Memorial Sloan Kettering Cancer Center in New York, New York.

In an interview with OncLive®, Rosen highlighted the early-phase investigation of zotatifin in ER-positive metastatic breast cancer, explained the agent’s unique mechanism of action as well as its efficacy and safety in a heavily pretreated population, and underscored the need for improved sequencing of the myriad of treatment options in the post–CDK4/6 inhibitor space.

OncLive: Please describe the rationale for evaluating zotatifin with abemaciclib and/or fulvestrant in patients with heavily pretreated, ER-positive metastatic breast cancer.

Rosen: In ER-positive metastatic breast cancers, we now have an array of treatments that can work very well. Patients can do quite well on those for many months and even years. However, once patients progress on those standard-of-care [SOC] treatments, which typically involve anti-estrogen treatment along with CDK4/6 inhibition [or] specific targeted therapies, we often have to move to other targeted therapies [or] cytotoxic chemotherapies.

What is unique about zotatifin’s mechanism of action?

[Zotatifin] is an eIF4A inhibitor. The eIF4A protein is an essential component of the eIF4 complex; this is necessary for translation, which is an essential cellular process. We know that the manufacturing of ERs is dependent on this complex. We think of this inhibitor as a way to decrease ER [levels] and target the endocrine underpinnings of metastatic breast cancer, which is ER positive. This drug is targeting other oncogenes as well [as ER]. Given the polygenic nature of some patients who are coming in [after receiving] multiple other therapies, we think that this treatment may be optimal [in the post–CDK4/6 inhibitor setting].

Could you describe the patient population included in the 2 breast cancer expansion cohorts of this phase 1/2 study?

These are heavily pretreated patients who unfortunately are sick when they’re coming onto this study. All these patients received at least 1 line of endocrine therapy, and nearly all had received a prior CDK4/6 inhibitor. These patients have likely received 4 to 7 lines of treatment or more before coming on the study.

What efficacy findings from the study were presented at this year’s ASCO Meeting?

We have 2 separate expansion cohorts of patients on this study: a zotatifin-plus-fulvestrant [cohort], with fulvestrant being a SOC estrogen therapy, and a triplet drug combination [cohort] of fulvestrant, abemaciclib, and [zotatifin]. The most striking results come from the triplet therapy arm, [which] showed 5 PRs; that translated to a [21% confirmed] ORR.

What should be taken away from the analysis with regard to the safety profile of zotatifin?

We were quite concerned about how patients would feel on this therapy coming onto this study, given that we’re targeting translation, which is an essential cellular process. [However,] this drug is impressively well tolerated. Nausea or fatigue were the most common adverse effects [AEs], but typical chemotherapy AEs like diarrhea, skin rash, or fever [were] essentially not seen on this study. The fatigue is usually seen in the first 24 hours after infusion [of] the drug, after which [this effect] essentially resolves. Nausea is well controlled with SOC antiemetics.

Are any next steps planned for this research?

We’re excited to see signs of efficacy and activity [with zotatifin] in this heavily pretreated metastatic breast cancer population. We’re trying to drive this project forward on multiple fronts. First, [we are] enrolling additional patients to home in on the efficacy and toxicity profile [of zotatifin]. Second, we have [collected] pre-treatment and on-treatment biospecimens from patients on the study. These biopsies are essential to figuring out [which] patients are responding and why they are responding. If we can figure out what these biomarkers of response are, we may be able to further [identify] who would get the most clinical benefit from a drug like this.

The other thing that we’re contemplating—and this is in the works right now—is combining zotatifin with other agents.

What is your main message for colleagues regarding this research?

[Zotatifin] works by a completely novel mechanism and is showing signs of activity in [patients with] ER-positive metastatic breast cancer who are heavily pretreated. I hope this [agent will have a role] post-CDK4/6 inhibition, [which] we all know is a SOC first-line treatment for metastatic breast cancer. It’s a bit of a crowded space [after] the first line in metastatic breast cancer, and we’re trying to figure out where [zotatifin] might be optimally used.

What other research in the breast cancer space were you excited to see presented at the 2023 ASCO Annual Meeting?

The positive read-out of the [phase 3] NATALEE trial [NCT03701334] study is the thing I’m most excited about for my patients. [The study provides] a different option in the adjuvant setting for patients who have higher risk, ER-positive breast cancer.

Disclosures: Dr Rosen had no relationships to disclose.

Clinicians referring a patient to MSK can do so by visiting msk.org/refer, emailing referapatient@mskcc.org, or by calling 833-315-2722.


Rosen E, Sharma M, Berz D, et al. Phase 1/2 dose expansion study evaluating first-in-class eIF4A inhibitor zotatifin in patients with ER+ metastatic breast cancer. J Clin Oncol. 2023;41(suppl 16):1080. doi:10.1200/JCO.2023.41.16_suppl.1080

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