Endocrine therapy (ET) is the standard of care for patients with estrogen receptor-positive (ER+) advanced breast cancer (ABC), but efficacy and patient experiences can be improved upon. Preclinical data has shown that the next-generation oral selective estrogen receptor degrader (SERD) imlunestrant has favorable pharmacokinetic (PK) properties, is effective in both ESR1-mutant and ESR1-wildtype disease, and improves efficacy when administered in combination with targeted therapy. Jhaveri et al1 evaluated the PKs, safety, and preliminary efficacy of imlunestrant as monotherapy and in combination with targeted therapy in patients with ER+, human epidermal growth factor receptor 2-negative (HER2–) ABC enrolled in the Phase Ia/Ib EMBER clinical trial. Their findings are summarized below.
The EMBER trial was a global, open-label, dose-escalation (Phase Ia)/dose-expansion (Phase Ib) study. The i3+3 design was implemented for Phase Ia, with five dose levels ranging from 200 to 1,200mg once daily. During Phase Ib, imlunestrant monotherapy and combination therapy were assessed. Patients in Part A received imlunestrant plus (+) abemaciclib with or without (±) aromatase inhibitor (AI), and those in Part B received imlunestrant or imlunestrant+everolimus/alpelisib.
Eligibility criteria included prior sensitivity to ET or untreated de novo ABC. Part A patients were cyclin-dependent kinase 4 or 6 (CDK4/6) inhibitor-naïve and had up to one previous line of therapy. Part B patients could have up to two prior therapies, and all patients were previously treated with a CDK4/6 inhibitor. Patients treated with alpelisib had PIK3CA-mutated disease. Exclusion criteria included symptomatic central nervous system metastasis, inflammatory breast cancer, concurrent systemic disorders, and visceral crisis.
In Phases Ia and Ib, 74 and 188 patients with ER+, HER2– ABC, respectively, were treated. Fifty-one of 114 patients treated with imlunestrant monotherapy received the recommended Phase II dose (RP2D) of 400mg once daily. A total of 148 patients received imlunestrant in combination with targeted therapy (+abemaciclib±AI, n=85; +everolimus, n=42; +alpelisib, n=21). In the imlunestrant+abemaciclib±AI cohort, 69.4 percent of patients did not undergo prior ABC treatment. All patients in the imlunestrant+everolimus/alpelisib cohort received prior therapy. Fifty-six and 47.6/47.4 percent of patients who received imlunestrant RP2D and imlunestrant+everolimus/alpelisib, respectively, harbored an ESR1 mutation.
No dose-limiting toxicities were observed among patients who underwent imlunestrant monotherapy. Maximum tolerated dose was not reached. Grade 1 to 2 nausea (39.2%), fatigue (39.2%), and diarrhea (29.4%) were the most frequent treatment-emergent adverse events (TEAEs) for the RP2D group. Only 9.8 percent of patients experienced Grade 3 or greater treatment-related AEs. There were no discontinuations due to toxicity.
In all combination therapy groups, diarrhea was the most common TEAE. Other common TEAEs included nausea and fatigue (imlunestrant+abemaciclib±AI) , fatigue and aspartate aminotransferase increase (imlunestrant+everolimus), and rash and hyperglycemia (imlunestrant+alpelisib) cohort. Grade 3 toxicity was highest with combination alpelisib treatment.
PK analyses supported once daily dosing of 400mg or greater. Abemaciclib, AI, everolimus, and alpelisib did not affect the PKs of imlunestrant, and drug-drug interactions were not observed.
Clinical benefit rate (CBR) among patients who received imlunestrant monotherapy was 42.1 percent. Median progression-free survival (PFS) was 4.3 months overall; fulvestrant- and CDK4/6 inhibitor-pretreated patients had a median PFS of 3.8 and 6.5 months, respectively. Patients who received the RP2D had a CBR of 54.9 percent and median PFS of 7.2 months. Overall response rate (ORR) was 7.9 percent for the overall monotherapy group and 11.8 percent for the RP2D subgroup.
In the imlunestrant+abemaciclib cohort, CBR was 79.1 percent with AI and 71.4 percent without AI. ORR was greater (61.8% vs. 32.1%) and median PFS was longer (not reached vs. 19.2 months) among those who received an AI, compared to those who did not. CBR, ORR, and median PFS were 61.9 percent, 21.4 percent, and 15.9 months, respectively, for patients treated with imlunestrant+everolimus. In the imlunestrant+alpelisib cohort, CBR, ORR, and median PFS were 61.9 percent, 58.3 percent, and 9.2 months, respectively.
Patients with ESR1 mutations experienced longer median PFS than those without ESR1 mutations who received imlunestrant monotherapy (5.4 vs. 3.7 months) and RP2D (7.1 vs. 5.6 months). Similarly, patients with ESR1 mutations who received imlunestrant+everolimus/alpelisib had a median PFS of 16.8/10.7 months, compared to 13.7/7.8 months for those without ESR1 mutations.
This study demonstrated the preliminary efficacy of imlunestrant in this patient population, but longer follow-up is necessary to determine long-term safety and impact on patient outcomes.
The results showed that imlunestrant 400mg once daily had a manageable safety profile, favorable PKs, and preliminary efficacy as monotherapy and in combination with targeted therapy in the treatment of ER+, HER2– ABC.
Reference
- Jhaveri KL, Lim E, Jeselsohn R, et al. Imlunestrant, an oral selective estrogen receptor degrader, as monotherapy and in combination with targeted therapy in estrogen receptor–positive, human epidermal growth factor receptor 2–negative ABC: Phase Ia/Ib EMBER study. J Clin Oncol. 2024;JCO2302733. Epub ahead of print.