Behind the FDA Approval of Imlunestrant Plus Abemaciclib in ESR1-Mutated Breast Cancer

The FDA has approved imlunestrant (Inluriyo) in combination with abemaciclib (Verzenio) for adults with estrogen receptor (ER)–positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer, as detected by an FDA-authorized test, whose disease has progressed following at least 1 line of endocrine therapy.¹ The approval is supported by the phase 3 EMBER-3 trial (NCT04975308), in which median progression-free survival (PFS) among patients with ESR1-mutated tumors was 11.1 months (95% CI, 7.4-13.7) with the combination vs 5.5 months (95% CI, 3.8-7.2) with imlunestrant alone (HR, 0.53; 95% CI, 0.35-0.80).¹˒²

Targeted Oncology^TM spoke with Komal L. Jhaveri, MD, FACP, section head of the Endocrine Therapy Research Program and clinical director of the Early Drug Development Service at Memorial Sloan Kettering Cancer Center in New York, New York, and lead author of the EMBER-3 publication, about the unmet need the combination addresses, the EMBER-3 design and updated results, and what remains to be answered.

Targeted Oncology: What unmet needs does this most recent approval of imlunestrant and abemaciclib fill?

Komal Jhaveri, MD: While we have 3 drugs approved as monotherapy for ESR1-mutant tumors, about 40% of our patients don't respond to standard of care or to the new oral endocrine agents, such as oral [selective estrogen receptor degraders (SERDs)] or [proteolysis targeting chimerics (PROTACs)], as monotherapy, and about 60% will progress soon enough without a durable, long benefit. This is why getting a combination approved and available is so attractive. It was already NCCN endorsed, and now it is also FDA approved. We know the efficacy doubles from 5 months to 11 months in the ESR1-mutant population, and that makes it the most attractive option in a way.

The other very attractive thing is that the safety is still very good. The discontinuation rates for the doublet are very [low], and the [adverse] effects are what we already know about abemaciclib, so it's not a surprise for the community or for patients in terms of management. Just because we use 2 drugs does not mean it's going to be that much worse. Of course, there is more toxicity than with a single agent, but it's manageable. So that's the unmet need it fills: better durable benefit, more patients benefiting, and safety maintained.

Could you discuss the design of EMBER-3 and exactly what you were evaluating?

EMBER-3 enrolled 874 patients with ER-positive, HER2-negative metastatic breast cancer whose disease had progressed on an adjuvant aromatase inhibitor, or on first-line metastatic aromatase inhibitor therapy, with or without a CDK4/6 inhibitor. These endocrine-resistant patients were randomized to 1 of 3 arms. The first was imlunestrant monotherapy, given as a 400-mg oral dose. The second was standard-of-care endocrine therapy, which could be fulvestrant [Faslodex] or exemestane [Aromasin]. Six months into the study, a third arm was added: imlunestrant plus abemaciclib.

There were 3 primary end points: a monotherapy PFS comparison in patients with ESR1-mutant tumors, a monotherapy PFS comparison in all patients, and, if either of those was positive, a comparison of imlunestrant plus abemaciclib vs imlunestrant monotherapy in all concurrently randomized patients.

What we initially showed and published in The New England Journal of Medicine³ was that monotherapy was significant only in the ESR1-mutant population, with median PFS improving from 3.8 to 5.5 months. We now have an updated publication in Annals of Oncology,⁴ with 28.5 months of follow-up, and the PFS benefit was sustained, with a hazard ratio of 0.62. For the very first time with an oral SERD or novel endocrine agent in the metastatic setting, we also saw a very clinically meaningful numerical gain in overall survival with monotherapy. The difference was 11 months, 34.5 vs 23.1 months, which was very attractive.

We could not claim statistical significance for that, even though the P-value looks significant, because the PFS end points were 3: all patients, ESR1 mutant, and the doublet. Since the all-patient comparison was not statistically significant, very little alpha was passed along by the hierarchical design to the overall survival analyses, and so we could not claim significance. Regardless, I would say that was very meaningful clinically. The hazard ratio was 0.60.

In that analysis, we also saw a sustained benefit for the doublet compared with monotherapy. Doublet overall survival data still remain very immature, but the hazard ratio is now 0.82, so with longer follow-up it's favoring the right direction. The benefit was seen not only in the CDK-naive and CDK-pretreated groups together but also in the 65% majority subgroup that was CDK pretreated. So you're seeing patients who had a first-line CDK inhibitor and then were treated with imlunestrant plus abemaciclib, another CDK inhibitor, and they still benefit. That benefit is doubled in the ESR1-mutant population but also seen in ESR1 wild-type, and regardless of PI3K/AKT pathway mutations. We also saw a very interesting signal, in small groups of patients, among those who harbor both ESR1 and PI3K pathway mutations.

These data sets are very attractive for our community. The combination was NCCN endorsed in January and is now backed by the FDA. The FDA backing is for the ESR1-mutant population, but the NCCN endorsement is broader, so we certainly capitalize on these data and use them for our patients, because it's so well tolerated and the efficacy signal is very attractive.

What questions do you still have?

We would obviously love to see the final overall survival analysis for the monotherapy. We saw updated analyses and the benefit was sustained, which was really nice, but we'd love to see the final analysis. We'd also love to see longer follow-up for the doublet to see how that pans out. Statistical significance is never going to be possible there, because the alpha spending is not justified given the PFS, but I think it will still give us a better understanding.

Will that change what I do today? No. It still gives me a lot of excitement to use it, because PFS is a very meaningful end point for patients. We can't forget that. But it will be nice to see that overall survival signal.

What I'm really looking forward to is that this drug has now started its journey in the early-stage, curative setting. EMBER-4 [NCT05514054] is a phase 3 trial and one of the largest adjuvant trials with a novel oral SERD at this point. It has 8000 patients, and it asks this question: If patients have already had 2 to 5 years of their standard-of-care endocrine therapy, and are then randomized to imlunestrant alone or to continuing standard-of-care endocrine therapy, will the switch to imlunestrant prove superior, and should we be doing such a switch? I'm really looking forward to seeing results from EMBER-4, because I think it would be a game changer for our early-stage patients, where you could offer these oral SERDs after their initial 2 to 5 years of therapy.

Is there anything else you would want colleagues to know about this agent, this combination, or the research you're doing?

I'm sure my colleagues know most of this, but it would be nice for our patients to understand it as well. Being aware of your options in clinic is always a good thing to discuss with your clinician. There are so many options available now, which is great but can also make things complex and confusing. Understanding that you have an FDA label for the doublet in ESR1-mutant disease, an NCCN endorsement that may cover an even slightly broader population, and how to manage the toxicities is very relevant for our patients.

A unique thing I want my colleagues and patients to know is that because EMBER-3 allowed CDK4/6 inhibitor–naive patients—meaning you could have had an adjuvant progression and been treated in the first line, or had first-line progression and been treated in the second line—30% of the EMBER-3 population was treated in the first-line metastatic setting. An ESR1 mutation is a little less prevalent at baseline before first-line therapy, but it's still there, up to 8% and sometimes 10% depending on how much endocrine therapy they've had in the curative setting. Very rarely, you'll also have a patient who presents in the metastatic setting with brain metastases.

Interestingly, preclinically, we saw that imlunestrant can have activity in the brain. We already know abemaciclib has activity in the brain, and in the EMBER-3 data set we also showed, in a very small number of patients and in an exploratory analysis, a delay in [central nervous sytem (CNS)] progression, which kind of marries that preclinical story to the clinic. So if you have somebody with brain metastases—it's not very common, but I have seen it in my practice—or somebody with a baseline ESR1 mutation that you already know about from a [next-generation sequencing (NGS)] result, you can justify using this doublet even in the first line, especially because of the ESR1 mutation or the brain metastases. That's where I would use it in the first line. Otherwise, I would definitely consider it in the second line. That's something I would love to highlight to everybody.

REFERENCES

1. FDA approves imlunestrant in combination with abemaciclib for ER-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer. News release. FDA. September 2026. Accessed October 1, 2026. https://tinyurl.com/bdcz685w

2. FDA approves Inluriyo (imlunestrant) in combination with Verzenio (abemaciclib) for adults with ER+, HER2-, ESR1-mutated advanced or metastatic breast cancer. News release. Eli Lilly and Company. September 2026. Accessed October 1, 2026. https://tinyurl.com/5ep3m9v2

3. Jhaveri KL, Neven P, Casalnuovo ML, et al. Imlunestrant with or without abemaciclib in advanced breast cancer. N Engl J Med. 2025;392(12):1189-1202. doi:10.1056/NEJMoa2410858

4. Jhaveri KL, Neven P, Casalnuovo ML, et al. Imlunestrant with or without abemaciclib in advanced breast cancer: updated efficacy results from the phase III EMBER-3 trial. Ann Oncol. 2026;37(4):532-543. doi:10.1016/j.annonc.2025.11.018