Oncology Overview: Investigational Imlunestrant for Breast Cancer, Endometrial Cancer

Imlunestrant is an orally selective estrogen receptor degrader (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 imlunestrant’s phase 1a/b dose escalation study in December 2019 and published its first interim data at the 2021 American Society of Cancer Oncology annual meeting.¹

As of April 7, 2021, the study enrolled 65 patients, including 58 with ER+ advanced breast cancer and 7 with ER+ endometrial endometrioid cancer (EEC). The advanced breast cancer patients had received a median of 2 prior lines of therapy, including fulvestrant (60% of patients), a CDK4/6 inhibitor (83%), and chemotherapy (26%).

Among the 54 patients with ctDNA (circulating tumor DNA) data available, 37% had ESR1 mutations. Enrolled patients received imlunestrant at doses from 200 mg once daily (QD) to 1200 mg QD.¹

Based on the study design, patients were considered efficacy-evaluable for objective response rate (ORR) if they had measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST v 1.1) at baseline and at least 1 post-baseline tumor assessment or discontinued treatment prior to their first post-baseline assessment.

At the data cutoff, 35 patients with ER+ advanced breast cancer were efficacy evaluable. Two of 35 had partial response after 24 weeks at the 400 mg daily dose.

One had prior fulvestrant treatment, 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) from all dose levels. In EEC patients, the researchers observed no objective responses in 6 efficacy-measurable patients and CBR was 50% (2/4).

Plasma ctDNA analysis indicated 86% (18/21) had early declines (cycle 2 day 1) in overall ctDNA, including patients with mutant ESR1. The magnitude of decrease was greater in patients who experienced clinical benefit than those who did not. At data cutoff, 35 patients remained on treatment, including both patients with confirmed partial responses, and 79% (31/39) of those with stable disease or partial responses.¹

The pharmacokinetic analysis demonstrated dose-proportional increases across all evaluated doses. The steady state of imlunestrant in patient plasma exceeded the EC80 range associated with efficacy in preclinical studies in all evaluated doses. The concentration was higher than the steady state of fulvestrant peak serum concentration.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 are being randomized to receive monotherapy with imlunestrant, 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 in 2026.^2,3

Adverse Events

From the published phase 1 data, no dose-limiting toxicities were observed and no maximum tolerated dose was established. Treatment-emergent adverse events (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 AEs, only 1 of which (grade 3 diarrhea) was treatment-related.

No cardiac safety signals occurred. The researchers executed dose reductions for 2 patients (3%) due to AEs, including the 1 with treatment-related grade 3 diarrhea. No patients discontinued due to an AE.

About the Author

Marlene Wang, MS, is a research scientist in the pharmaceutical industry.

References

1. Lilly Announces New Clinical Data from Verzenio and Oral SERD 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.
2. A Study of Imlunestrant, Investigator's Choice of Endocrine Therapy, and Imlunestrant Plus Abemaciclib in Participants With ER+, HER2- Advanced Breast Cancer (EMBER-3).https://clinicaltrials.gov/ct2/show/study/NCT04975308. Accessed May 10. 2022.
3. A Phase 3, Randomized, Open-Label Study of Imlunestrant, Investigator's Choice of Endocrine Therapy, and Imlunestrant 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.