The combination of zotatifin plus fulvestrant and abemaciclib demonstrated promising activity in a cohort of heavily pretreated patients with ER-positive metastatic breast cancer, according to study results presented during the 2023 San Antonio Breast Cancer Symposium.
Efficacy was observed regardless of the presence of ESR1 or PIK3CA mutations, which suggests the potential for widespread application of the treatment platform across populations of patients with metastatic breast cancer. Zotatifin is a first-in-class, investigational selective translation regulator inhibitor. Preclinical research showed that zotatifin was effective in downregulating the translation of oncogenes such as CDK4, ERα, ERBB2, KRAS, and CCND1.
Ezra Y. Rosen, MD, PhD, breast oncologist at Memorial Sloan Kettering Cancer Center, and colleagues enrolled patients in a phase 1/2 dose-expansion study. Patients were eligible for inclusion if they had received at least one therapy line in the advanced or metastatic state and had experienced progression on hormone therapy.
Zotatifin was given intravenously at a dose of 0.07 mg/kg (2 weeks on/1 week off), in combination with fulvestrant and abemaciclib. In addition, a dose-escalation cohort was assigned to zotatifin plus fulvestrant at treatment schedules of every week and every 2 weeks.
Rosen and colleagues reported data from 20 patients treated with the triplet combination (median prior therapy lines, n = 4). Among 19 evaluable patients, they observed 4 confirmed partial responses and 1 unconfirmed partial response. In addition, 10 patients achieved stable disease as their best overall response.
The researchers noted that all patients achieving a confirmed or unconfirmed partial response had previous exposure to CDK4/6 inhibitors, fulvestrant, and chemotherapy in the metastatic state. Some patients with confirmed partial responses harbored ESR1 and PIK3CA mutations, while others did not. Although the median progression-free survival was not mature at the time of reporting, Rosen stated that it exceeded 20 weeks.
The zotatifin plus fulvestrant cohorts included data from 8 patients treated at doses of 0.07 mg/kg every week (n = 3), 0.1 mg/kg every 2 weeks (n = 3), and 0.14 mg/kg every 2 weeks (n = 2). The most common any-grade adverse events were diarrhea (80%) and nausea (75%), with diarrhea the most common grade 3 or grade 4 adverse event (15%). The researchers observed no dose-limiting toxicities or grade 5 adverse events at any treatment level.
Rosen and colleagues observed one partial response in a patient treated at 0.1 mg/kg level. One additional patient treated at the 0.14 mg/kg level achieved stable disease. They observed no partial response or stable disease in the 0.07 mg/kg cohort.
Nine patients in the triplet cohort and 3 patients in the zotatifin/fulvestrant cohorts had available circulating tumor DNA samples. Eight patients treated with the triplet had decreases in circulating tumor DNA greater than 50%. All of these patients achieved partial responses or stable disease.
In addition, 2 patients in the zotatifin plus fulvestrant cohort had circulating tumor DNA decreases greater than 50%, including 1 patient with a partial response. The researchers also observed reductions in ESR1, PIK3CA, and other genes associated with endocrine resistance to levels below detection.
The manufacturer of zotatifin announced in a press release that the FDA granted Fast Track designation to the combination of zotatifin plus fulvestrant and abemaciclib as a second- or third-line treatment for metastatic breast cancer in patients with disease progression after endocrine therapy and exposure to a CDK4/6 inhibitor.
“We are grateful to receive this Fast Track designation from the FDA, which is a meaningful milestone for the development of zotatifin and reflects the demonstrated potential for zotatifin in combination with fulvestrant and abemaciclib to address unmet needs in ER-positive, HER2-negative breast cancer,” said Steve Worland, PhD, CEO of eFFECTOR Therapeutics.
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Disclosures: Authors declared financial ties to drugmakers. See full study for details. Worland is an employee of eFFECTOR Therapeutics.
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