Imlunestrant, an investigational next-generation selective estrogen receptor degrader (SERD), improved progression-free survival in sufferers with endocrine therapy-pretreated, ER-positive, HER2-negative superior breast cancer-;as monotherapy in sufferers with ESR1 mutations and as mixture remedy with abemaciclib (Verzenio) in all sufferers, no matter ESR1 mutation status-;in accordance with outcomes from the part III EMBER-3 medical trial introduced on the San Antonio Breast Most cancers Symposium (SABCS), held December 10-13, 2024.
The outcomes of this examine have been concurrently revealed within the New England Journal of Drugs.
The principle goal of this EMBER-3 trial was to judge the function of imlunestrant, a brain-penetrant oral SERD, as monotherapy or together with the CDK4/6 inhibitor, abemaciclib, in sufferers with ER-positive, HER2-negative superior breast most cancers whose illness had recurred or progressed throughout or after an aromatase inhibitor alone or with a CDK4/6 inhibitor.”
Komal Jhaveri, MD, the Patricia and James Cayne Chair for Junior School, part head of the Endocrine Remedy Analysis Program, and medical director of the Early Drug Growth Service at Memorial Sloan Kettering Most cancers Middle, and presenter of the examine
“CDK4/6 inhibitors have been a essential addition to plain endocrine remedy with aromatase inhibitors, and if development happens, combining a SERD with a CDK4/6 inhibitor will be useful. Nonetheless, given the constraints of present SERDs like fulvestrant, together with lack of oral bioavailability and want for month-to-month intramuscular injection, together with restricted efficacy in sufferers who develop ESR1-mutations, novel SERDs similar to imlunestrant are being developed with the objective of enhancing each efficacy and affected person expertise by way of ease of administration,” mentioned Jhaveri, noting that ESR1 mutations are seen in 40%-50% of sufferers progressing on endocrine remedy.
In contrast to fulvestrant, imlunestrant will be taken orally and may penetrate the blood-brain barrier, providing the potential for concentrating on central nervous system metastases, defined Jhaveri, who can also be an affiliate professor at Weill Cornell Medical Faculty.
Within the multicenter examine, 874 sufferers with ER-positive, HER2-negative superior breast most cancers have been randomly assigned (1:1:1) to obtain both imlunestrant alone, commonplace endocrine remedy (fulvestrant or exemestane) alone, or imlunestrant plus abemaciclib.
In comparison with commonplace endocrine remedy, imlunestrant considerably improved progression-free survival in sufferers with ESR1 mutations however not within the general inhabitants. Within the sufferers harboring ESR1 mutations, imlunestrant lowered the chance of development or demise by 38%.
“These promising outcomes imply that imlunestrant is probably one other single-agent possibility for the numerous sufferers whose recurrent breast cancers harbor ESR1 mutations,” mentioned Jhaveri.
Moreover, in comparison with imlunestrant alone, imlunestrant and abemaciclib collectively have been related to a 43% discount in danger of development or demise, leading to median progression-free survival of 9.4 months and 5.5 months respectively, for the mixture and monotherapy teams. The good thing about combining these two therapies, each of which will be taken orally, have been noticed in all sufferers, together with these with and with out ESR1 mutations or PI3K-pathway mutations and together with these beforehand handled with a CDK4/6 inhibitor.
“The consistency of those outcomes throughout clinically related subgroups is reassuring given most sufferers eligible for second-line remedy have acquired a CDK4/6 inhibitor beforehand and plenty of at present accessible second-line therapies require biomarker choice,” famous Jhaveri, who known as the info observe altering.
Imlunestrant was nicely tolerated, each as monotherapy and together, Jhaveri mentioned. Imlunestrant confirmed favorable security profile, with typically low-grade and manageable hostile occasions, and with out the oral SERD-specific security indicators of ocular or cardiac points. The protection profile of the mixture was in keeping with the recognized fulvestrant-abemaciclib profile with a comparatively low discontinuation price of 6.3% that compares favorably to accessible mixture regimens. Moreover in patient-reported outcomes information from the examine, 72% of sufferers receiving fulvestrant reported injection web site ache, swelling, or redness.
“Taken collectively, these information are encouraging for sufferers and present that imlunestrant, as monotherapy or mixed with abemaciclib, may present an all-oral focused remedy possibility after development on endocrine remedy for sufferers with ER-positive, HER2-negative superior breast most cancers.”
One limitation of the examine is that not like the part III postMONARCH and EMERALD trials, EMBER-3 didn’t require prior remedy with a CDK4/6 inhibitor. Nonetheless, most sufferers (65%) within the mixture remedy comparability in EMBER-3 have been CDK4/6 inhibitor pretreated and the remedy impact of imlunestrant-abemaciclib in these sufferers was in keeping with the general inhabitants.
This examine was supported by Eli Lilly and Firm. Jhaveri has consulting or advisory roles with Novartis, Pfizer, Taiho Oncology, Genentech, AbbVie, Eisai, AstraZeneca, Blueprint Medicines, Daiichi Sankyo, Solar Pharma Superior Analysis Firm Ltd., Menarini/Stemline Therapeutics, Gilead, Scorpion Therapeutics, Olema Prescription drugs, Bicycle Therapeutics, Lilly/Loxo Oncology, and Zymeworks. Jhaveri additionally has analysis funding assist to her establishment from Novartis, Genentech, AstraZeneca, Pfizer, Lilly/Loxo Oncology, Zymeworks, Immunomedics/Gilead, Puma Biotechnology, Merck Prescription drugs, Context Therapeutics, Scorpion Therapeutics, Eisai, RayzeBio, and Blueprint Medicines.