Elacestrant Plus Abemaciclib Shows Efficacy in ER+/HER2– Advanced or Metastatic Breast Cancer

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The combination of elacestrant (Orserdu) and abemaciclib (Verzenio) provided clinical benefit with acceptable safety in patients with estrogen receptor (ER)–positive/HER2-negative advance or metastatic breast cancer with prior exposure to endocrine therapy and CDK4/6 inhibitors, irrespective of ESR1 mutational status, according to data from a pooled analysis of the phase 1b portion of the ELECTRA (NCT05386108) and arm C of the phase 2 ELEVATE (NCT05563220) studies.¹

The pooled data of cohort 3 from ELECTRA and arm C of ELEVATE, which were presented during the 2024 San Antonio Breast Cancer Symposium, showed that when elacestrant was given at a daily dose of 345 mg plus abemaciclib at 150 mg twice daily (n = 38), the regimen induced an objective response rate (ORR) of 18%, which included a complete response (CR) rate of 5% and a partial response (PR) rate of 13%; the stable disease (SD) rate was 66% and 16% of patients experienced disease progression. The clinical benefit rate (CBR) was 84%.

With a median follow-up of 7.5 months at data cutoff, efficacy-evaluable patients from the phase 1b portion of ELECTRA who received the doublet (n = 27) experienced a median progression-free survival (PFS) was 8.7 months (95% CI, 6.1-16.6). When broken down further, those who previously received endocrine therapy and CDK4/6 inhibitors (n = 24) experienced a median PFS of 8.7 (95% CI, 6.1-16.6), those with ESR1 mutations (n = 11) had a median PFS of 8.7 months (95% CI, 2.0-not calculable [NC]), and those without those mutations (n = 12) had a median PFS of 7.2 months (95% CI, 1.9-NC). Those who received prior endocrine therapy plus CDK4/6 inhibition for 12 months or longer (n = 16) experienced a median PFS of 16.6 months (95% CI, 7.5-NC).

Of note, evaluable patients from arm C of the ELEVATE study (n = 26/30) had a median observational time for PFS of 4.6 months at data cutoff, and thus, median PFS could not be assessed.

“Elacestrant could become an endocrine therapy backbone in combination with abemaciclib in patients with ER-positive/HER2-negative metastatic breast cancer due to its potential to extend PFS, enable an all-oral treatment option, and delay chemotherapy or antibody-drug conjugate–based regimens,” Hope S. Rugo, MD, FASCO, of the University of California San Francisco Helen Diller Family Comprehensive Cancer Center, in San Francisco, California, and colleagues, wrote in a poster of the data.

Patients with ER-positive/HER2-negative metastatic breast cancer who receive endocrine therapy in the frontline setting are known to have disease that becomes resistant to intrinsic alterations in the cell cycle or PI3K/AKT/mTOR pathways, or to acquired ESR1 mutations, resulting in progressive disease. Investigators hypothesized that elacestrant plus abemaciclib would offer an all-oral option that is able over overcoming some of these resistance mechanisms.

Taking a Closer Look at ELECTRA and ELEVATE

Both studies enrolled patients with ER-positive/HER2-negative advanced or metastatic breast cancer who were at least 18 years of age, had previously received endocrine therapy and CDK4/6 inhibitors in the metastatic setting except for abemaciclib, and an ECOG performance status of 0 or 1.

For ELECTRA specifically, patients must have received at least 1 line of endocrine therapy with or without CDK4/6 inhibition excluding abemaciclib in the advanced setting. They were allowed to have received up to 2 prior lines of chemotherapy in the advanced or metastatic setting, and they did not need to have brain metastases to be included.

A total of 27 patients were included in the phase 1b portion of the study and they received elacestrant at once-daily doses ranging from 258 mg to 345 mg plus abemaciclib at twice-daily doses ranging from 100 mg to 150 mg.

To be eligible for arm C of ELEVATE, patients must have received 1 to 2 prior lines of endocrine therapy plus CDK4/6 inhibition excluding abemaciclib in the advanced setting and they could not have previously received chemotherapy in the advanced or metastatic setting.

A total of 30 patients were included in the phase 2 portion of the research and they were administered elacestrant at a once-daily dose of 345 mg plus abemaciclib at a twice-daily dose of 150 mg.

Breaking Down Baseline Characteristics in the Pooled Population

Those included in the pooled analysis (n = 42) had a median age of 60 years (range, 29-84) and all were female. Regarding ECOG performance status, 64% had a status of 0 and 36% had a status of 1. Metastatic sites included visceral (71%), liver (41%), lung (26%), and bone (48%). Moreover, 53% of patients had ESR1 mutations and 28% had PIK3CA mutations. Twelve percent of patients had primary endocrine resistance.

Patients had received a median of 1 prior therapy for advanced or metastatic disease, with a range of 1 to 6. All patients had prior CDK4/6 inhibitor exposure, with 55% of patients having received palbociclib (Ibrance), 40% having received ribociclib (Kisqali), and 5% having received both agents. Most patients (71%) received 1 prior line of endocrine therapy for advanced or metastatic disease; 26% and 2% of patients received 2 or 3 prior lines, respectively. Types of endocrine therapy included fulvestrant (Faslodex; 52%), aromatase inhibitor (AI; 71%), tamoxifen (7%), and tamoxifen and an AI (5%). Moreover, 14% of patients had 1 prior line of chemotherapy and 2% had 2 prior lines.

The following clinical characteristics of patients included in ELECTRA were of note: 74% had visceral metastases, 70% had prior exposure to fulvestrant, 52% had 2 or more lines of endocrine therapy for advanced or metastatic disease, 26% had primary endocrine resistance, 46% had ESR1-mutated tumors, and 25% had PIK3CA-mutated disease. In arm C of ELEVATE, it was noted that 73% of patients had visceral metastases, 43% previously received fulvestrant, 17% had 2 prior lines of endocrine therapy for advanced or metastatic disease, 7% had primary endocrine resistance, half had ESR1-mutated disease, and 32% had PIK3CA-mutated tumors.

Additional Efficacy Insights

In cohort 1 of ELECTRA (n = 7), patients received elacestrant at a once-daily dose of 258 mg plus abemaciclib at a twice-daily dose of 100 mg and experienced an ORR of 29%, all of which were PRs; the SD rate was 29% and 43% of patients experienced disease progression. The CBR was 57% and the 24-week CBR was also 57%. In cohort 2 of the study (n = 7), patients were given elacestrant at a once-daily dose of 345 mg plus abemaciclib at a twice-daily dose of 100 mg and experienced an ORR of 29%, all of which were PRs; the SD rate was 43% and 29% of patients had progressive disease. In this group, the CBR was 71%, and the 24-week CBR was 57%. Lastly, in cohort 3 of the study (n = 12), patients received the recommended phase 2 dose (RP2D) of the combination, which was 345 mg of elacestrant once daily paired with 150 mg of abemaciclib twice daily. These patients experienced an ORR of 25%, which included a CR rate of 8% and a PR rate of 17%; the SD rate was 58% and 17% of patients experienced disease progression.

Median PFS was also evaluated by dose level in the full ELECTRA cohort. In evaluable patients who received the combination at the RP2D (n = 12), the median PFS was 8.7 months (95% CI, 7.2-NC). In those who received elacestrant at a once-daily dose of 345 mg with abemaciclib at a twice-daily dose of 100 mg (n = 7), the median PFS was 7.5 months (95% CI, 1.9-NC). Finally, in those who received elacestrant at a once-daily dose of 258 mg with abemaciclib at a twice-daily dose of 100 mg (n = 8), the median PFS was 8.4 months (95% CI, 1.7-17.3).

In arm C of ELEVATE (n = 26), patients received elacestrant at a once-daily dose of 345 mg plus abemaciclib at a twice-daily dose of 150 mg and experienced an ORR of 15%. The CR, PR, and SD rates were 4%, 12%, and 69%, respectively; 15% of patients experienced disease progression. In this cohort, the CBR was 85%. In this arm, the average observation time was not reached at 24 weeks.

Pooled Safety Findings

Data from the pooled analysis (n = 24), showed that the most common treatment-emergent adverse effects (AEs) experienced by 20% or more of patients who received the regimen at the RP2D were diarrhea (all grade, 83%; grade 3, 5%), nausea (64%; 5%), vomiting (41%; 2%), fatigue (36%; 5%), decreased neutrophil count or neutropenia (33%; 26%), anemia (24%; 7%), constipation (21%; 0%), and reduced appetite (21%; 0%). Notably, no grade 4 AEs were observed during the treatment period.

Looking Ahead

The phase 2 portion of the research examining elacestrant at a once-daily dose of 345 mg with abemaciclib at a twice-daily dose of 150 mg is ongoing.

Disclosures: There were no disclosures published with this abstract.

References

1. Rugo HS, Tolaney SM, Chan N, et al. Elacestrant plus abemaciclib (abema) combination in patients (pts) with estrogen receptor-positive (ER+), HER2-negative (HER2-) advanced or metastatic breast cancer (mBC). Presented at: 2024 San Antonio Breast Cancer Symposium; December 10-13, 2024; San Antonio, TX. Poster PS7-07.
2. Ibrahim NK, Hamilton EP, Kim S-B, et al. Elacestrant in combination with abemaciclib in patients (pts) with brain metastasis from estrogen receptor-positive (ER+), HER2-negative (HER2-) breast cancer: Preliminary data from ELECTRA, an open-label, multicenter, phase 1b/2 study. J Clin Oncol. 2024;42(suppl 16):1064. doi:10.1200/JCO.2024.42.16_suppl.1064