Preoperative window-of-opportunity studies can provide key information on molecular drug response, pharmacodynamic (PD) effects, and downstream effects of medications, such as endocrine therapy (ET), in early breast cancer, as well as potentially predicting impact in advanced breast cancer. Data from the Phase I EMBER trial showed the favorable safety and preliminary efficacy of imlunestrant, a next-generation, oral, selective estrogen receptor degrader (SERD), in patients with estrogen receptor-positive (ER+) advanced breast cancer who had progressed on previous ET, regardless of ESR1 mutation status. The safety, PD, and pharmacokinetic (PK) effects of imlunestrant 400mg and 800mg were analyzed in the Phase I EMBER-2 trial, with a 200mg cohort added later for analysis. In this study, Neven et al1 evaluated data from the EMBER-2 trial. Their findings are summarized below.
The international, open-label, noncontrolled, Phase I EMBER-2 trial included treatment-naïve, postmenopausal patients with Stage I to III ER+, human epidermal growth factor receptor 2-negative (HER2–) early breast cancer. Patients were scheduled to receive surgery with curative intent or repeat biopsy in cases where neoadjuvant therapy was planned. Further eligibility criteria included having a tumor with a largest diameter of 1cm or greater by ultrasound, Eastern Cooperative Oncology Group (ECOG) score of 0 or 1, and adequate organ function. Ineligibility criteria included diagnosis of bilateral invasive, metastatic, or inflammatory breast cancer; prior receipt of breast cancer treatment; and presence of serious concomitant systemic or cardiac conditions.
Patients were randomized to 400mg and 800mg cohorts. The 200mg cohort, to which patients were nonrandomly assigned, was added after completion of the randomized portion of the trial. Patients received daily imlunestrant for about two weeks before surgery or biopsy. A total of 87 patients were enrolled in the trial, 59 in the randomized portion and 28 in the nonrandomized portion. Eighty-three patients completed study therapy, with 75 and 79 patients having adequate samples for PD and PK evaluation, respectively.
Among all patients, median age was 64 years, and 95 percent of patients had Stage I to II breast cancer. Sixty-seven and 30 percent of patients had invasive ductal carcinoma (IDC) and invasive lobular carcinoma (ILC), respectively. Most patients had progesterone receptor-positive (PR+) disease. Fifty-one percent of patients evaluable for Ki-67 had a baseline Ki-67 index above 19 percent, followed by a baseline of 5 to 19 percent (43%) and less than five percent (6%). Baseline characteristics did not significantly differ across treatment arms.
In the overall PD evaluable population (n=75), median treatment duration was 16 days. PD endpoints were evaluated in 27 patients in the 400mg arm, 26 patients in the 800mg arm, and 22 patients in the 200mg arm. Overall, there was an 81-percent reduction in geometric mean for ER and PR from baseline to Week 2. Additionally, immunohistochemistry showed notable reductions in ER and PR expression in most tumors. Gene expression analysis of samples from the 400mg and 800mg arms showed that imlunestrant affected the expression of 11 ER-regulated genes. ER degradation and downstream effects of imlunestrant did not differ based on histological subtype (IDC vs. ILC).
Overall, the Ki-67 geometric mean decreased by 70 percent (200mg arm: 69%; 400mg arm: 71%; 800mg arm: 72%). The complete cell cycle arrest (CCCA) rate was measured in patients with a Ki-67 index of 5 percent or greater (n=59). The 200mg cohort had the lowest CCCA rate, at 15 percent (n=3/20), followed by the 400mg (n=5/22, 23%) and 800mg (n=6/17, 35%) cohorts.
Similar to the EMBER trial, PK analyses showed that steady-state plasma imlunestrant concentrations increased with dose from 200mg to 800mg. Data from 10 patients showed an approximately 15-fold increase in steady-state tumor imlunestrant concentrations on Day 15, compared to predose plasma concentrations.
Across all treatment arms, 57 patients (66%) reported at least one treatment-emergent adverse event (TEAE). Most TEAEs were mild in nature, with only three patients (1 in each treatment arm) experiencing a Grade 3 or greater TEAE. Diarrhea (17%) and fatigue (14%) were the most frequently reported TEAEs overall. The rates of diarrhea and nausea were 32 and 14 percent, respectively, in the 800mg cohort, which was higher than in the 200mg (diarrhea: 11%, nausea: 11%) and 400mg (diarrhea: 10%, nausea: 3%) cohorts.
A total of 28 patients (32.6%) reported at least one treatment-related AE (TRAE), none of which were Grade 3 or greater. Fatigue was the most frequently reported TRAE (9%). The rate of treatment-related diarrhea was increased in the 800mg arm, compared to the 200mg and 400mg arms (18% vs. 7% and 0%, respectively). Additionally, the rate of treatment-related nausea was zero percent in the 400mg cohort, compared to 11 percent in both the 200mg and 800mg cohorts.
Combined with results from the EMBER trial, the findings from the EMBER-2 trial determined that 400mg once per day is the optimal dose of imlunestrant, as it showed similar biologic effects as the 800mg dose with fewer gastrointestinal AEs.
Reference
- Neven P, Stahl N, Vidal M, et al. A preoperative window-of-opportunity study of oral SERD, imlunestrant, in newly diagnosed ER-positive, HER2-negative early breast cancer: results from EMBER-2 Study. Clin Cancer Res. 2024. Epub ahead of print.