Zotatifin Triplet Shows Promising Activity, Low Toxicity in Heavily Pretreated ER+ Breast Cancer

Ezra Rosen, MD, PhD

The triplet combination of zotatifin (eFT226), abemaciclib (Verzenio), and fulvestrant (Faslodex) demonstrated a confirmed overall response rate (ORR) of 21% in heavily pretreated patients with estrogen receptor (ER)–positive metastatic breast cancer, according to findings from 2 expansion cohorts of a phase 1/2 study (NCT04092673) presented at the 2023 ASCO Annual Meeting.

In the dose-expansion study, zotatifin was examined as a doublet with fulvestrant and as a triplet with fulvestrant and abemaciclib. ORR with the triplet regimen consisted entirely of partial responses. An additional patient met the criteria for partial response on a single scan, which had not yet been confirmed at the time of the data cutoff, making the unconfirmed ORR with the triplet 26%. The confirmed ORR with the doublet was 5.9%. Most adverse events (AEs) were mild to moderate, and many were associated with the other drugs in the regimen. No dose-limiting toxicity was observed and there were no serious adverse events.

“What we have strikingly seen is, number one, these drugs are very well tolerated, and number 2, even in the heavily pretreated metastatic breast cancer population we've seen partial responses,” said lead author, Ezra Rosen, MD, PhD, a breast oncologist and early drug development specialist, assistant attending physician,from the Memorial Sloan Kettering Cancer Center.

Zotatifin is a selective inhibitor of eukaryotic translation initiation factor 4A (elF4A), which is required for protein translation initiation and is involved in the overproduction of proteins that lead to tumorigenesis. It is an RNA helicase that is activated through the PI3K/RAS pathway and plays a role in regulating genes associated with cancers, including CDK4/6.

“This drug can possibly target estrogen receptor where other standard-of-care drugs do not hit estrogen receptor,” said Rosen. “The unique mechanism of zotatifin points to the fact that it may also be targeting other oncogenes as well. In a patient with resistance by multiple mechanism, this drug may show some signs of utility where other drugs don't work.”

The open-label study included several cohorts, with the cohorts presented at ASCO enrolling 38 participants with metastatic or locoregionally recurrent ER-positive breast cancer. From other cohorts of the study across solid tumors, 0.07 mg/kg on days 1 and 8 of a 21-day cycle was established as the recommended phase 2 dose (RP2D), which was administered to most patients. In the doublet cohort, additional dose escalation was completed, with intravenous zotatifin administered at 0.10 mg/kg every 2 weeks (n = 3), 0.07 mg/kg every week (n = 2), and 0.14 mg/kg every 2 weeks (n = 1). Abemaciclib and fulvestrant were administered at FDA-approved doses.

In the doublet group (n = 18), the median age of patients was 56 years (range, 40-72), 89% of patients had visceral metastases, and the ECOG performance status was 0 (22%) and 1 (78%). The median number of prior therapies was 5 (range, 1-11) and 78% of patients had received 2 or more prior endocrine therapies for metastatic disease. All patients had received a prior CDK4/6 inhibitor, 89% had received prior fulvestrant, and 83% had received prior chemotherapy.

In the triplet group (n = 20), the median age of patients was 57 years (range, 38-82), 75% had visceral metastases, and the ECOG performance status was 0 (50%) or 1 (50%). The median number of prior regimens received by patients was 4 (range, 1-11) and 50% of patients had received 2 or more regimens for metastatic disease. At baseline, 60% of patients had received 2 or more prior endocrine therapies, 95% had received a CDK4/6 inhibitor, 65% had received fulvestrant, and 75% had received prior chemotherapy.

In addition to ORR, 35% of patients experienced stable disease with the zotatifin doublet and 47% had stable disease with the triplet. The disease control rate with the doublet was 41% and it was 74% with the zotatifin triplet. In the doublet, the 1 PR was seen at the 0.10 mg/kg every 2 weeks dose of zotatifin, suggesting activity even at a lower dose level than the RP2D.

Of those evaluable (n = 9), an interim analysis revealed a decline of 50% or more in circulating tumor DNA (ctDNA) for 89% of patients, which correlated to response. In one patient, a 100% decrease in ctDNA was observed along with a 75% reduction in tumor size, which remained ongoing at week 40. Another patient with stable disease experienced an 83% reduction in ctDNA.

In the doublet arm, the 1 PR was seen in a patient previously treated with 2 CDK4/6 inhibitors, fulvestrant, and chemotherapy. This patient had alterations in ESR1 and CCND1 amplification. In the triplet cohort, responses were observed in patients treated with multiple prior CDK4/6 inhibitors, including in 1 patient with prior abemaciclib exposure. Moreover, all responses were in patients who had previously received fulvestrant, chemotherapy, and alpelisib (Piqray). These responses were seen in patients with PIK3CA and ESR1 mutations.

The most common treatment-emergent adverse events (TEAEs) of any grade with the zotatifin triplet were diarrhea (80%), nausea (75%), vomiting (55%), fatigue (55%), dysgeusia (40%), dry mouth (35%), abdominal pain (30%), anemia (30%), dyspnea (30%), and peripheral neuropathy (30%). Grade 3 or higher TEAEs were rare, with the most common being diarrhea (15%) and anemia (10%).

“On the triplet therapy, most patients are tolerating this drug very well. Nausea and fatigue are the 2 most commonly experienced adverse events in this trial arm,” said Rosen. “Loose stool and diarrhea are also commonly seen, as is typically seen with abemaciclib.”

For the zotatifin doublet, the most common TEAEs of any grade were nausea (50%), constipation (28%), vomiting (28%), fatigue (28%), headache (22%), abdominal pain (22%), anemia (22%), and diarrhea (22%). There were 3 cases of grade 3 or higher TEAEs in this group, specifically headache, anemia, and diarrhea.

“Because these drugs were actually so well tolerated at the RP2D, we're actually currently redose escalating in an attempt to get more efficacy,” said Rosen. “In addition to this, we're expanding the number of patients to try to learn more about the specific genomic context in which we're seeing patient responses in study. We also have before treatment and on treatment biopsies and we're examining RNA and protein from patients on this study in an attempt to figure out who is responding and why to better figure out who to treat here.”

Reference

1. 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