Imlunestrant alone, with abemaciclib delays progression of advanced breast cancer
Click Here to Manage Email Alerts
Key takeaways:
- Imlunestrant monotherapy delayed progression among patients with ESR1 mutations.
- The imlunestrant-abemaciclib combination delayed progression regardless of ESR1 mutation status.
SAN ANTONIO — Imlunestrant alone or as part of combination therapy extended PFS for certain patients with advanced breast cancer resistant to hormone therapy, according to study results presented at San Antonio Breast Cancer Symposium.
The randomized phase 3 EMBER-3 trial included patients with ER-positive, HER2-negative advanced disease who had received endocrine therapy alone or with a cyclin-dependent kinase (CDK) 4/6 inhibitor.
Imlunestrant (Eli Lilly & Co.) — a next-generation selective estrogen receptor degrader (SERD) — conferred benefit as monotherapy for patients with ESR1 mutations. The combination of imlunestrant and the CDK 4/6 inhibitor abemaciclib (Verzenio, Eli Lilly) significantly extended PFS for all patients regardless of ESR1 mutation status.
The results support the role of all-oral targeted therapy for this patient population, according to researcher Komal Jhaveri, MD, clinical director of the early drug development service and section head of the endocrine therapy research program at Memorial Sloan Kettering Cancer Center.
“We want our patients to have options, and we want to move the bar of efficacy beyond what we have been able to achieve in the second-line metastatic setting,” Jhaveri said during a press conference. “In the post-CDK 4/6 inhibitor space, we’re currently achieving median PFS of about 6 months. With this doublet, we’re seeing a substantial PFS benefit, and importantly the safety profile should be very reassuring.”
Up to half of patients who progress on endocrine therapy develop ESR1 mutations, according to study background.
“CDK4/6 inhibitors have been a critical addition to standard endocrine therapy with aromatase inhibitors and, if progression occurs, combining a SERD with a CDK4/6 inhibitor can be beneficial,” Jhaveri said in a press release. “However, given the limitations of existing SERDs like fulvestrant — including lack of oral bioavailability and need for monthly intramuscular injection — along with limited efficacy [among] patients who develop ESR1 mutations, novel SERDs such as imlunestrant are being developed with the goal of improving both efficacy and patient experience through ease of administration.”
Imlunestrant — unlike fulvestrant — can be administered orally and can penetrate the blood-brain barrier. This provides the potential to target central nervous system metastases, Jhaveri said.
The multicenter EMBER-3 trial included 874 patients with ER-positive, HER2-negative advanced breast cancer.
Researchers randomly assigned them 1:1:1 to 400 mg daily imlunestrant; standard endocrine therapy with fulvestrant or exemestane alone; or 400 mg daily imlunestrant plus abemaciclib. Baseline characteristics appeared balanced between groups, Jhaveri said.
Primary endpoints included investigator-assessed PFS for imlunestrant monotherapy vs. standard endocrine therapy among patients with ESR1 mutations, imlunestrant monotherapy vs. standard endocrine therapy for all patients, and the imlunestrant-abemaciclib combination vs. imlunestrant alone.
OS, PFS by blinded independent central review, overall response rate and safety served as secondary endpoints.
The findings, published in The New England Journal of Medicine, showed imlunestrant monotherapy did not confer a PFS benefit in the overall study population (median, 5.6 months vs. 5.5 months; HR = 0.87; 95% CI, 0.72-1.04).
However, among patients who had ESR1 mutations, imlunestrant alone reduced risk for progression or death by 38% (median, 5.5 months vs. 3.8 months; HR = 0.62; 95% CI, 0.46-0.82) compared with standard endocrine therapy.
“These promising results mean that imlunestrant is potentially another single-agent option for the many patients whose recurrent breast cancers harbor ESR1 mutations,” Jhaveri said.
The combination of imlunestrant and abemaciclib reduced risk for progression or death by 43% (median, 9.4 months vs. 5.5 months; HR = 0.57; 95% CI, 0.44-0.73) compared with imlunestrant alone.
Researchers observed the PFS benefit among patients with ESR1 mutations (median, 11.1 months vs. 5.5 months; HR = 0.53; 95% CI, 0.35-0.8) or without (median, 9.1 months vs. 5.5 months; HR = 0.59; 95% CI, 0.43-0.81)
The benefit also persisted among patients with PI3K pathway mutations (median, 7.6 months vs. 3.8 months; HR = 0.61; 95% CI, 0.42-0.87) and among those who received prior CDK 4/6 inhibitor therapy (median, 9.1 months vs. 3.7 months; HR = 0.51; 95% CI, 0.38-0.68).
“The consistency of these results across clinically relevant subgroups is reassuring given most patients eligible for second-line therapy have received a CDK4/6 inhibitor previously and many currently available second-line therapies require biomarker selection,” Jhaveri said.
Interim OS analyses showed trends toward longer survival with imlunestrant monotherapy vs. standard endocrine therapy among all patients (23% maturity; HR = 0.69; 95% CI, 0.5-0.96) and among those with ESR1 mutations (31% maturity; HR = 0.55; 95% CI, 0.35-0.86).
With 15% maturity, OS results showed no statistically significant benefit with the combination vs. imlunestrant alone (HR = 1.34; 95% CI, 0.81-2.21).
Jhaveri characterized imlunestrant as well tolerated.
A comparable percentage of patients assigned imlunestrant monotherapy vs. standard endocrine therapy experienced any-grade treatment-emergent adverse events (83% vs. 84%) or grade 3 or higher treatment-emergent adverse events (17% vs. 21%). A higher percentage of those assigned imlunestrant experienced any-grade fatigue (23% vs. 13%) or diarrhea (21% vs. 12%).
The most common treatment-emergent adverse events among those assigned imlunestrant-abemaciclib included diarrhea (86%), nausea (49%), neutropenia (48%), anemia (44%) and fatigue (39%). About half (49%) developed grade 3 or higher treatment-emergent adverse events, the most common of which were neutropenia (20%), diarrhea (8%) and fatigue (5%).
Researchers did not observe the cardiac or ocular issues previously observed with oral SERD therapy.
Among those who received the imlunestrant-abemaciclib combination, 6.3% discontinued therapy. This compares favorably to other combination regimens, Jhaveri said.
A majority (72%) of patients who received fulvestrant reported injection site swelling, redness or pain.
“Taken together, these data are encouraging for patients and show that imlunestrant — as monotherapy or combined with abemaciclib — could provide an all-oral targeted therapy option after progression on endocrine therapy for patients with ER-positive, HER2-negative advanced breast cancer,” Jhaveri said.
Researchers acknowledged study limitations, including the fact EMBER-3 — unlike the phase 3 postMONARCH and EMERALD trials — did not make treatment with a CDK 4/6 inhibitor an eligibility requirement.
However, Jhaveri and colleagues noted about two-thirds (65%) of patients who received the imlunestrant-abemaciclib combination had received CDK 4/6 inhibitor therapy and emphasized the treatment benefit observed with the combination appeared consistent across the entire trial population.
Perspective
Back to TopKate Lathrop, MD
Having more than one drug option is always a benefit for our patients. Even though there may be slight differences with how these drugs get approved by the FDA or other regulatory institutions that we don’t control, there are certain reasons — whether related to toxicity, cost or sequencing — might be better for an individual patient. Having more than one option is always better.
Decisions specific to imlunestrant will depend on if the regulatory agencies approve it, what they think of the data and what spaces they approve it in. For patients who do not have ESR1 mutations who are almost primary endocrine resistant — these are patients who recur very soon after starting on hormonal therapy — if you’re going to put them on a CDK 4/6 inhibitor, I think these data are very encouraging that we can have prolonged PFS in this patient population. The ESR1 mutation is probably acting as a marker of other mechanisms of resistance that we’re hitting with these combinations, so I think this will add value to the clinic and to patients.
Collapse
Jhaveri K, et al. Abstract GS1-01. Presented at: San Antonio Breast Cancer Symposium; Dec. 10-13, 2024; San Antonio.
Click Here to Manage Email Alerts