NEW YORK – After patients with estrogen receptor (ER)-positive advanced breast cancer develop resistance to frontline hormone therapy due to ESR1 mutations, treatment with Eli Lilly's imlunestrant appears to stave off their cancer progression longer than standard endocrine therapy, researchers reported at the San Antonio Breast Cancer Symposium on Wednesday.
However, data from the same Phase III EMBER-3 trial also showed that when the investigational next-generation selective estrogen receptor degrader (SERD) was given as a second-line treatment with Lilly's CDK 4/6 inhibitor Verzenio (abemaciclib), the combination benefited ER-positive breast cancer patients not only if they had ESR1-driven endocrine resistance but also if they'd developed resistance through other mechanisms.
"With combinations, we think there may be more comprehensive ER blockade," Komal Jhaveri, clinical director of the early drug development service at Memorial Sloan Kettering Cancer Center, said during a presentation of the EMBER-3 data, addressing why benefit with imlunestrant monotherapy was seen only in ESR1-mutated tumors, while the efficacy of imlunestrant-Verzenio was broader. "Potentially, [with the combination] we think we are overcoming the resistance mechanisms beyond ESR1."
The EMBER-3 data were published simultaneously in the New England Journal of Medicine.
Currently, the first-line treatment for patients with ER-positive HER2-negative advanced breast cancer is endocrine therapy plus a CDK 4/6 inhibitor. But patients eventually develop resistance. The data from the Lilly-sponsored EMBER-3 trial suggest single-agent imlunestrant might be a new option for the up to 50 percent of advanced breast cancer patients who develop resistance to standard endocrine therapy due to ESR1 mutations. Menarini Group's SERD Orserdu (elacestrant) is already available in this setting in the ESR1-mutated subset.
The data on imlunestrant-Verzenio, meanwhile, suggest the potential for the SERD to be a new backbone treatment in second-line ER-positive advanced breast cancer that is easier to administer and has broad activity across subpopulations. "This is the first time we've really begun to see oral SERDs break out from the ESR1-mutation box … perhaps reflecting the idea that a more active endocrine agent in combination with effective targeting using cross-talk pathways in tumors that are fundamentally ER-dependent can really transform the natural history of the disease," said Harold Burstein, an oncologist at Dana-Farber Cancer Institute's Breast Oncology Center, in reviewing the data from EMBER-3 at the meeting.
Lilly is planning to submit these data with regulatory bodies. "EMBER-3 is the first Phase III trial to show benefit of combining an oral SERD with a CDK4/6 inhibitor for a patient population where an all-oral regimen would represent a meaningful advance," Lilly Chief Medical Officer David Hyman said in a statement. "We're highly encouraged by these data for both imlunestrant as monotherapy and in combination with Verzenio, as well as the safety and tolerability profile, which demonstrate the potential for imlunestrant to be a meaningful new oral endocrine therapy option for patients. We look forward to … completing regulatory submissions to global health authorities."
Imlunestrant's activity
In the trial, researchers enrolled more than 870 patients with ER-positive HER2-negative breast cancer who had recurred or progressed after receiving an aromatase inhibitor or an aromatase inhibitor plus a CDK4/6 inhibitor. Patients were randomized to one of three arms: imlunestrant monotherapy; physician's choice of standard endocrine (fulvestrant or exemestane); or imlunestrant plus Verzenio. Researchers tracked progression-free survival on imlunestrant compared against standard endocrine therapy in all patients with ER-positive HER2-negative breast cancer, as well as in the subset of patients with ESR1 mutations. Then, they tracked patients' progression-free survival in the imlunestrant monotherapy arm versus imlunestrant-Verzenio in all randomized patients.
In the subset of patients with ESR1 mutations, imlunestrant monotherapy reduced the risk of progression or death by 38 percent compared to standard endocrine therapy. The median progression-free survival was 5.5 months on imlunestrant versus 3.8 months on standard endocrine therapy. Looking across all patients regardless of ESR1 mutation status, median progression-free survival was 5.6 months versus 5.5 months, respectively, which is not a statistically significant difference. Focusing on those without ESR1 mutations, there was also no difference in median progression-free survival between the two arms.
In the second portion of the trial, when researchers compared imlunestrant-Verzenio against imlunestrant monotherapy across all randomized patients, the median progression-free survival was 9.4 months and 5.5 months, respectively. The SERD-CDK4/6 inhibitor combination reduced the risk of progression or death by 43 percent compared to treatment with just imlunestrant.
In those with ESR1 mutations, median progression-free survival was 11.1 months on imlunestrant-Verzenio versus 5.5 months on imlunestrant. In those without ESR1 mutations, median progression-free survival was 9.1 months and 5.5 months, respectively. In patients with PI3K pathway mutations and those who had prior CDK4/6 inhibitors, the median progression-free survival was 7.6 months and 9.1 months, respectively, on imlunestrant-Verzenio. On just imlunestrant, patients lived without progression for 3.8 months and 3.7 months, respectively, in these subgroups.
"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 noted in a statement, calling the data practice-changing.
In EMBER-3, 37 percent of patients had an ESR1 mutation and 40 percent had a mutation in a gene in the PI3K pathway, including in PI3K, AKT, or PTEN. Researchers used a centralized ctDNA assay to gauge patients' mutations.
Overall survival data were not mature at the time of analysis, but there was a trend favoring single-agent imlunestrant over standard endocrine therapy. With imlunestrant-Verzenio, Dana-Farber's Burstein noted that at 15 percent data maturity, there are more deaths in the combination arm currently than with imlunestrant. "It's unlikely that you'd get regulatory approval, unless [researchers] follow this for a longer period of time, and we're assured of the safety of the combination," Burstein said.
Furthermore, in comparing imlunestrant-Verzenio to imlunestrant, Lilly did not compare the combination to standard treatment. "We don't know how this [combination] would have compared to, say, fulvestrant with [Verzenio], fulvestrant with alpelisib [Novartis' PI3K inhibitor Piqray], or fulvestrant with capivasertib [AstraZeneca's AKT inhibitor Truqap]," Burstein added.
More options for patients
In the second-line endocrine-resistant ER-positive advanced breast cancer setting, "we as a breast cancer community certainly have options, whether it's aromatase inhibitors, we have three of those; whether it's CDK4/6 inhibitors, we have three of those; whether it's agents targeting the PI3/AKT/mTOR pathway, we have those," Jhaveri said. "Now, it seems we have an option with imlunestrant as monotherapy in [tumors with] ESR1 mutations, the way we have approval for elacestrant for ESR1 mutations."
If single-agent imlunestrant reaches the market based on this data, it will compete with Menarini's Orserdu. Last year, the US Food and Drug Administration approved Orserdu as a second-line treatment for patients with ESR1-mutated ER-positive HER2-negative advanced breast cancer after progression on endocrine therapy. The agency approved Guardant Health's Guardant360 CDx as a blood-based assay for identifying patients with ESR1 mutations who are eligible for treatment.
Menarini is also exploring the potential of its SERD Orserdu in combination with Verzenio in second-line ER-positive advanced breast cancer. At this meeting, researchers led by Hope Rugo, director of breast oncology clinical trials at the University of California, San Francisco, shared a pooled analysis from two Phase Ib/II trials, ELECTRA and ELEVATE, of Orserdu plus Verzenio and reported that the combination appears to have activity in patients regardless of their ESR1 mutations status. The median progression-free survival in all efficacy-evaluable patients and in those with ESR1 mutations was 8.7 months and 7.2 months in those without detected ESR1 mutations.
In patients who received prior endocrine therapy and a CDK4/6 inhibitor for at least a year, Orserdu-Verzenio staved off progression for a median 16.6 months. Orserdu "could become an endocrine therapy backbone in combination with [Verzenio] in patients with ER-positive HER2-negative metastatic breast cancer due to its potential to extend progression-free survival, enable an all-oral treatment option, and delay chemotherapy or antibody-drug conjugate-based regimens," the authors said in a poster presented at the meeting.
Similarly, Jhaveri concluded that the EMBER-3 data, taken together, are encouraging for patients with ER-positive, HER2-negative advanced breast cancer and show that imlunestrant, as monotherapy or combined with Verzenio, could provide an all-oral targeted therapy option after they progress on endocrine therapy.
She acknowledged that researchers are exploring other endocrine therapies and CDK4/6 combinations in this setting, but also pointed out that, currently, only imlunestrant-Verzenio has prospective Phase III data supporting its broader efficacy. "This is the only Phase III prospective dataset that we currently have today where we would be able to say that this combination of a novel endocrine agent with a CDK4/6 inhibitor … would be active and be offered in patients despite prior CDK4/6 inhibitor therapy and regardless of ESR1 mutations and PI3K pathway mutations," she said.
Certainly, combining two oral medications like imlunestrant-Verzenio or Orserdu-Verzenio would preclude patients from needing monthly intramuscular injections as is the case with existing SERDs like fulvestrant. In EMBER-3, for example, 72 percent of patients receiving fulvestrant in the standard treatment arm reported injection site pain, swelling, or redness.
Jhaveri highlighted that unlike fulvestrant, imlunestrant can also penetrate the blood-brain barrier, which suggests the drug could potentially be efficacious in breast cancer patients with central nervous system metastases. In EMBER-3, at one year, only 2 percent of patients with ESR1-mutated breast cancer had CNS progression on imlunestrant compared to 7 percent on standard endocrine therapy. The rate of CNS progression in all patients was 2 percent on imlunestrant and 3 percent in the standard treatment arm.
Imlunestrant had a manageable safety profile and didn't cause any ocular or cardiac safety signals as seen with other SERDs. The rate of treatment discontinuation was low, Jhaveri reported, at around 6 percent in the imlunestrant-Verzenio arm.
The data from EMBER-3 on the broader activity of imlunestrant-Verzenio is encouraging for patients without ESR1 mutations who have developed endocrine resistance, agreed Kate Lathrop, associate professor and program director of the medical oncology and hematology fellowship program at University of Texas Health Science Center at San Antonio. "There are certain reasons why drugs, whether it's toxicity, cost, sequencing, might be better for an individual patient," said Lathrop, reflecting on the EMBER-3 data, at the meeting. "Having more options is always better."