Imlunestrant is currently being investigated as monotherapy or in combination with other anticancer therapies for patients with estrogen receptor positive, locally advanced or metastatic breast cancer and endometrial cancer.
Imlunestrant is an oral selective estrogen receptor disruptor (SERD) currently under investigation as monotherapy or in combination with other anticancer therapies for patients with estrogen receptor positive (ER+) locally advanced or metastatic breast cancer and endometrial cancer. Researchers launched the phase 1a/b dose-escalation study of immunosuppression in December 2019 and published the first interim data at the American Society of Cancer Oncology annual meeting in 2021.1
On April 7, 2021, 65 patients entered the study, including 58 with ER+ advanced breast cancer and 7 with ER+ endometrial endometrioid cancer (EEG). The patients with advanced breast cancer had received a median of 2 prior lines of therapy, including fulvestrant (60% of patients), a CDK4/6 inhibitor (83%) and chemotherapy (26%).
Of the 54 patients with ctDNA data (circulating tumor DNA), 37% had ESR1 mutations. Enrolled patients received imlunestrant at doses of 200 mg once daily (QD) to 1200 mg QD.1
Based on the study design, patients were considered evaluable for efficacy for objective response rate (ORR) if they had measurable disease according to the Response Evaluation Criteria in Solid Tumors (RECIST v1.1) at baseline and at least 1 tumor assessment after baseline or discontinuation of treatment prior to their first post-baseline assessment.
At the data limit, the efficacy of 35 patients with ER+ advanced breast cancer was evaluable. Two of the 35 had a partial response at 24 weeks at the 400 mg daily dose.
One had prior treatment with fulvestrant, CDK4/6, and chemotherapy-refractory disease. The other patient had 3 lines of prior endocrine therapy, including an mTOR inhibitor.
The clinical benefit rate (CBR) was 48% (13/27) of all dose levels. In EEG patients, the researchers observed no objective responses in 6 patients who could measure efficacy and the CBR was 50% (2/4).
Plasma ctDNA analysis indicated that 86% (18/21) had early decreases (cycle 2 day 1) in total ctDNA, including patients with mutated ESR1. The magnitude of the decrease was greater in patients who experienced clinical benefit than in patients who did not. At data cut-off, 35 patients remained on treatment, including both those with confirmed partial response and 79% (31/39) of those with stable disease or partial response.1
The pharmacokinetic analysis showed dose-proportional increases across all doses evaluated. In preclinical studies, the steady-state of imlunestrant in patient plasma at all doses evaluated exceeded the EC80 range associated with efficacy. The concentration was above the steady state peak serum concentration of fulvestrant.1
In October 2021, the sponsor initiated a randomized, open-label, phase 3 study in patients with ER+, human epidermal growth factor receptor 2 negative, locally advanced or metastatic breast cancer previously treated with endocrine therapy. Patients will be randomized to receive imlunestrant monotherapy, the investigator’s choice of endocrine monotherapy (fulvestrant or exemestane), or a combination of imlunestrant and abemaciclib. The trial is expected to complete its primary endpoint in June 2023 and fully complete by 2026.2.3
No dose-limiting toxicities were observed from the published phase 1 data and no maximum tolerated dose was established. Treatment-emergent adverse reactions (TEAEs) were mostly Grade 1-2, including nausea (19 [29%]), diarrhea (11 [17%]), and fatigue (8 [12%]†1
Grade 3 TEAEs occurred in 6 (9%) patients, including 2 (3%) patients with TEAEs: diarrhea (n=1) and decreased neutrophil count (n=1). Three patients (5%) experienced serious adverse events, of which only 1 (grade 3 diarrhoea) was treatment-related.
No cardiac safety signals occurred. The investigators performed dose reductions for 2 patients (3%) due to adverse events, including the 1 with treatment-related Grade 3 diarrhea. None of the patients discontinued due to an AE.
About the author
Marlene Wang, MSis a researcher in the pharmaceutical industry.
- Lilly announces new clinical data from Verzenio and Oral SRD programs at the American Society of Clinical Oncology annual meeting. Eli Lilly and Company. https://investor.lilly.com/news-releases/news-release-details/lilly-announces-new-clinical-data-verzenio-and-oral-serd. Accessed May 10, 2022.
- A study on immunoassay, investigator’s choice of endocrine therapy and immunotherapy plus abemaciclib in participants with ER+, HER2-advanced breast cancer (EMBER-3). https://clinicaltrials.gov/ct2/show/study/NCT04975308. Accessed May 10, 2022.
- A phase 3, randomized, open-label trial of immunostrogen, investigator’s choice of endocrine therapy and immunostrogen plus abemaciclib in patients with estrogen receptor positive, HER2-negative locally advanced or metastatic breast cancer previously treated with endocrine therapy. Eli Lilly and Company. https://www.lillyloxooncologypipeline.com/molecule/selective-er-degrader/clinical-trial/NCT04975308. Accessed May 10, 2022.