Decreases in ctDNA VAF Tied to Improved CBR With Imlunestrant in Pretreated ER+/HER2– Advanced Breast Cancer

Substantial decreases in circulating tumor DNA (ctDNA) variant allele frequency (VAF) at the start of cycle 2 or 3 of treatment with imlunestrant (LY3484356) were associated with improved efficacy for the oral selective estrogen receptor degrader in patients with pretreated, estrogen receptor (ER)–positive, HER2-negative advanced breast cancer, according to data from an exploratory analysis of the phase 1 EMBER trial (NCT04188548).¹

Findings presented at the 2024 ESMO Breast Cancer Congress showed that patients who achieved a molecular response (MR; n = 33), defined as a VAF decrease of at least 50% from baseline at day 1 of cycle 2 or 3, experienced a median progression-free survival (PFS) of 8.2 months (95% CI, 5.4-13.8) compared with 1.9 months (95% CI, 1.8-4.8) for patients who did not have a MR (n = 56; log-rank P = .003).

“Higher mean VAF percentage changes cycle 2 day 1, or cycle 3 day 1, were associated with clinical benefit and response,” lead study author Karthik V. Giridhar, MD, and colleagues, wrote in a presentation of the data. Giridhar is an oncologist in the Department of Medical Oncology at Mayo Clinic Comprehensive Cancer Center in Rochester, Minnesota.

EMBER is a first-in-human, global, open-label, dose-escalation and -expansion study evaluating imlunestrant in patients with advanced or metastatic breast cancer or endometrial cancer.^2,3

Previous data presented at the 2023 ESMO Congress showed that patients with ER-positive, HER2-negative advanced breast cancer treated with imlunestrant monotherapy (n = 114) experienced a median PFS of 4.3 months (95% CI, 3.6-7.1). Those given single-agent imlunestrant in the second line following a CDK4/6 inhibitor–containing regimen (n = 48) achieved a median PFS of 6.5 months (95% CI, 3.7-8.3). Findings also showed that patients treated with imlunestrant plus everolimus (Afinitor; n = 42) had a median PFS of 15.9 months (95% CI, 11.3-19.1), and those given imlunestrant plus alpelisib (Vijoice; n = 21) had a median PFS of 9.2 months (95% CI, 3.7-11.1).²

The objective response rate in patients with measurable disease was 8% for imlunestrant alone (n = 6 of 76), 21% for imlunestrant plus everolimus (n = 6 of 28), and 58% for imlunestrant plus alpelisib (n = 7 of 12). The respective clinical benefit rates (CBRs) were 42% (n = 48 of 114), 62% (n = 26 of 42), and 62% (n = 13 of 21).

In the monotherapy arm, the rates of any-grade and grade 3 or higher treatment-emergent adverse effects (TEAEs) were 93% and 21%, respectively. Those respective rates were 100% and 43% for imlunestrant plus everolimus and 100% and 81% for imlunestrant plus alpelisib. TEAEs did not lead to treatment discontinuation for any patients in the monotherapy arm. The rates of discontinuation due to TEAEs were 7% for imlunestrant plus everolimus and 34% for imlunestrant plus alpelisib.

To be included in the trial, patients with ER-positive, HER2-negative advanced breast cancer needed to have endocrine-sensitive or untreated de novo disease. In phase 1a, no more than 3 prior therapies for advanced breast cancer were permitted. In phase 1b, patients were not allowed to have more than 2 prior lines of therapy that included a CDK4/6 inhibitor. For patients treated with imlunestrant plus alpelisib, a PIK3CA mutation was required per local testing.

In phase 1a, patients received oral imlunestrant monotherapy at 1 of 5 dose levels ranging from 200 mg to 1200 mg per day. Patients enrolled in phase 1b were given imlunestrant alone, imlunestrant plus everolimus at 10 mg per day, or imlunestrant plus alpelisib at 300 mg per day, per physician decision.

Determining the recommended phase 2 dose of imlunestrant was the trial’s primary end point. Secondary end points included safety, pharmacokinetics, and antitumor activity.

In the exploratory analysis, investigators examined the association between ctDNA at baseline and during treatment with CBR.¹ Serial plasma samples were collected from patients and analyzed for ctDNA using the Guardant360 assay. Efficacy end points assessed for the exploratory analysis included CBR—defined as a complete response, partial response (PR), or stable disease for at least 24 weeks—and PFS, both per RECIST 1.1 criteria.

In the monotherapy cohort, the median age was 63 years (range, 32-95), and 66.7% of patients had measurable disease. The median number of prior lines of therapy in any setting was 3 (range, 0-9), and the median number of prior lines of therapy in the advanced breast cancer setting was 2 (range, 0-8). Notably, 98.2% of patients received prior endocrine therapy, including 57.9% in the neoadjuvant/adjuvant setting and 95.6% in the locally advanced/metastatic setting. In the neoadjuvant/adjuvant setting, prior endocrine therapies included an aromatase inhibitor (AI; 32.5%) and tamoxifen (42.1%). In the advanced setting, prior endocrine therapies consisted of an AI (78.1%), fulvestrant (Faslodex; 51.8%), and tamoxifen (13.2%).

Prior chemotherapy was given to 65.8% of patients, including 50.9% in the neoadjuvant/adjuvant setting and 25.4% in the advanced setting. Ninety-three percent of patients received a prior CDK4/6 inhibitor, which was given exclusively in the advanced setting.

At baseline, 90% of evaluable patients (n = 98 of 109) had detectable ctDNA. ESR1, PIK3CA, and TP53 mutations were the most common alterations observed. Notably, in the 11 patients with undetectable ctDNA at baseline, the CBR was 63.6%, which included 1 patient who achieved a PR.

Additional data from a genomic subgroup analysis showed that significant differences in CBR were not observed based on mutation status, including in patients with PIK3CA mutations with or without an ESR1 co-mutation. However, a numerically lower CBR was reported in patients harboring detectable RB1, PTEN, BRCA2, or ATM mutations.

The ongoing phase 3 EMBER-3 trial (NCT04975308) is further evaluating imlunestrant alone and in combination with abemaciclib (Kisqali) vs investigator’s choice of endocrine therapy in patients with ER-positive, HER2-negative advanced breast cancer.⁴

References

1. Giridhar KV, Ma CX, Bidard F-C, et al. ctDNA analyses in patients with ER-positive (ER+), HER2- negative (HER2-) advanced breast cancer (ABC) treated with imlunestrant in the EMBER phase I study. Ann Oncol. 2024;9(suppl 4):1-34. doi:10.1016/esmoop/esmoop103010
2. Jhaveri K, Jeselsohn R, Ma CX, et al. Imlunestrant with or without everolimus or alpelisib, in ER+, HER2- advanced breast cancer (aBC): Results from the phase Ia/b EMBER study. Ann Oncol. 2023;34(suppl 2):S338-S339. doi:10.1016/j.annonc.2023.09.560
3. A study of LY3484356 in participants with advanced or metastatic breast cancer or endometrial cancer (EMBER). ClinicalTrials.gov. Updated May 30, 2024. Accessed June 11, 2024. https://clinicaltrials.gov/study/NCT04188548
4. A study of imlunestrant, investigator's choice of endocrine therapy, and imlunestrant plus abemaciclib in participants with ER+, HER2- advanced breast cancer (EMBER-3). ClinicalTrials.gov. Updated April 18, 2024. Accessed June 11, 2024. https://clinicaltrials.gov/study/NCT04975308