In an interview with _Pharmacy Times®,_ Komal Jhaveri MD, FACP, Breast Medical Oncologist and Early Drug Development Specialist at Memorial Sloan Kettering Cancer Center, discussed results from the EMBER-3 trial, which evaluated the efficacy and safety of the novel oral Selective Estrogen Receptor Degrader (SERD) imlunestrant, both as monotherapy and in combination with the CDK4/6 inhibitor abemaciclib, in patients with ER +, HER2- metastatic breast cancer. Jhaveri shared that imlunestrant monotherapy demonstrated improved progression-free survival compared to standard endocrine therapy, particularly in patients with ESR-1 mutations. The combination of imlunestrant plus abemaciclib further enhanced progression-free survival, with consistent benefits seen across key patient subgroups. Importantly, both the monotherapy and combination regimens exhibited favorable safety profiles, suggesting these may be attractive treatment options for this patient population.
**Pharmacy Times**
What are the key findings from the EMBER-3 trial regarding the safety and efficacy of imlunestrant as monotherapy and in combination with abemaciclib?
**Komal Jhaveri MD, FACP**
EMBER-3 really is a global open label phase 3 trial that enrolled men and women, regardless of their menopausal status. If they had progression or recurrence on or within 12 months of their adjuvant therapy, which could have been an aromatase inhibitor, with or without a CDK4/6 inhibitor, or progression on their first line metastatic therapy. Again, with an aromatase inhibitor, with or without a CDK4/6 inhibitor, with no other therapy for advanced disease. A total of 874 patients were randomized — one is to one is to one, using 3 stratification factors of visceral metastases, prior CDK4/6 inhibitor therapy and region to 1 of the 3 treatment arms. Arm A being imlunestrant alone; arm B was standard of care, endocrine therapy; and arm C was imlunestrant plus abemaciclib. The trial has 3 primary endpoints. This is investigator assessed PFS, evaluating imlunestrant versus standard of care endocrine therapy in ESR immune patients and in all patients. Then looking at investigator assessed PFS for imlunestrant plus abemaciclib versus imlunestrant if one of the monotherapy comparison endpoints was significant.
Now, when we look at the patient population that was enrolled here, approximately 37% had ESL-1 mutations; 38% had PI3K pathway mutations — which means mutation in the PI3K gene, AKT gene, or P10 alteration. About a third of these patients had recurrence on or within 12 months of adjuvant therapy, and the remaining two thirds had recurrence on their first line therapy. 60% overall had received prior CDK4/6 inhibitor therapy, majority of which were palbociclib and ribociclib.
Now moving on to results, for the first primary endpoint imlunestrant statistically significantly improved investigator assessed PFS compared to standard of care endocrine therapy with median PFS of 5.5 months versus 3.8 months, with a hazard ratio of 0.62. For the second endpoint, which is, investigator assessed PFS for imlunestrant versus standard of care endocrine therapy, PFS difference did not reach statistical significance. The hazard ratio is 0.87. It's notable, however, that majority of the patients without any ESR1 mutation did not have a difference in PFS. The hazard ratio here is 1. For the third primary endpoint imlunestrant plus abemaciclib significantly improved investigator assessed PSF compared to imlunestrant alone. This was patients, regardless of ESR-1 mutation status and the median PFS here was 9.4 months versus 5.5 months. The hazard ratio is 0.57.
Now when we looked at the key subgroups, consistent benefits for monotherapy were seen regardless of prior visceral metastases, absence or presence, prior CDK4/6 inhibitor therapy or ESR-1 mutation status. Similarly, when we looked at the combination versus imlunestrant, consistent benefits were seen across these subgroups. In fact, we specifically looked at whether there was benefit with or without ESR-1 mutations, there was consistent benefit. When we looked at key subgroups, such as prior CDK4/6 inhibitor pretreated patients, 65% of the patients had a CDK4/6 inhibitor before they were enrolled to the combination of imlunestrant and abemaciclib.
We also looked at another key subgroup, which is looking at PI3K pathway mutation status, because both are important and have implications for our current clinical practice. When we looked at both, consistent benefit was seen with imlunestrant. In patients with prior CDK4/6 pretreated patients, we did see that the median PFS is 9.1 months, which is consistent to the overall patient population. Again, hazard ratio was consistent there as well with overall patient population. When we looked at PI3K mutation status, median PFS was 7.6 months versus 4.8 months. Again, consistent with what we've seen in terms of hazard ratio with overall patient population.
Now let's move on to safety from the EMBER-3 trial. I think it was very reassuring to see the safety data as well. The most common toxicities that were reported for monotherapy were diarrhea, fatigue and nausea. These were predominantly grade 1 toxicities and mainly single episodes. The frequencies that we see were less than equal to 10% increase compared to standard of care endocrine therapy. When we looked at grade 3 or 4 higher events in imlunestrant arm, it was 17% — it was 21% in standard of care endocrine therapy arm. Discontinuation rates were very, very low and importantly, no concerning signal of cardiac or ocular toxicity, which has been a class concern. Now, while patients in the fulvestrant arm, 9% reported adverse reactions to that. It was very interesting to see that patient reported data collected on a survey, 72% of these patients reported an injection site swelling, discomfort or redness. Really suggesting that, from a patient perspective, again, an oral option is appealing. Now, when we looked at the doublet — the combination of imlunestrant plus abemaciclib, one would think that, because there was diarrhea and nausea seen with imlunestrant alone, and we know that abemaciclib has a diarrhea signal as well, that we would see a lot more diarrhea. In fact, while diarrhea was the most common toxicity reported for the combination, again, these were predominantly grade 1, and the safety profile was very consistent with what we already know with abemaciclib. This has already been shown — in fact, the discontinuation rates for imlunestrant plus abemaciclib in EMBER-3 was very low, at 6%.
Overall, just to summarize, I think these were attractive data. Imlunestrant alone showed statistically significant improvement in investigators assessed PFS compared to standard of care, endocrine therapy in ESR-1 mutant patients. Statistical significance was not reached in overall population with monotherapy. Consistent benefit was seen for key subgroups, and imlunestrant demonstrated a very favorable safety profile with no concerning signals of cardiac or ocular toxicity. The combination of imlunestrant plus abemaciclib was efficacious and showed a significant improvement in investigator assessed PFS compared to imlunestrant alone, regardless of ESR-1 mutation, with a median PFS of 9.4 months versus 5.5 months. And consistent benefit was seen across key subgroups, including prior CDK4/6 inhibitor or PI3K pathway mutation status. The safety profile was very reassuring, with no new safety signals. The safety profile was like what we already know with the abemaciclib, and the combination had a low discontinuation rate of 6%.
So as such, imlunestrant really as monotherapy, and in combination with abemaciclib is an all-oral targeted option for patients who've had progression with prior endocrine therapy and have ER+ or HER2- metastatic breast cancer.
**Pharmacy Times**
How does the unique mechanism of action of SERDs differ from traditional endocrine therapies?
**Jhaveri**
So, when we think about traditional endocrine therapies, we have tamoxifen, which is a serum estrogen receptor modulator. We have aromatase inhibitors, which inhibit the enzyme aromatase and prevent the conversion from testosterone to estrogen. And then we have fulvestrant that was approved initially, which is an intramuscular injection. Now, what we have seen is that these 3 agents have been effective. Fulvestrant was effective after progression and prior endocrine therapies, and we currently still utilize tamoxifen and aromatase inhibitors, but we face limitations with these therapies. What are these limitations? These limitations include toxicity concerns, both with tamoxifen and aromatase inhibitors. We have injection site issues with fulvestrant. They also include resistance issues. For instance, we think about tamoxifen as a weak ER suppressor. This has tissue specific, agonistic and antagonistic properties for breast cancer, it is different, and it is different for other tissues in the body. When we think about aromatase inhibitors, under the selective pressure of aromatase inhibitors, there is emergence of ESR-1 mutations, which can be as prevalent as 40% to 50% in the second- or third-line metastatic setting. These are ligand independent, ER dependent pathway activations for patients. Last but not the least, while fulvestrant is effective despite prior endocrine therapy. It has no oral bioavailability. It has those dependent efficacies we cannot go beyond the 500-milligram dosing and limited activity in ESR-1 mutations. So, we are very excited with this newer class of novel endocrine agents, because these agents are being developed with the idea of overcoming these toxicity issues and overcoming these issues with pharmacokinetic liabilities, and address the resistance mechanism, specifically the ESR-1 mutation resistant mechanism that has really been prevalent in the metastatic setting. So imlunestrant is such an oral cert. Additionally, I think I'd add that immunostran also has brain penetration. CNS penetration was seen pre clinically, and in fact, because of that, we have also planned within EMBER-3 a post hoc exploratory analysis looking at the cumulative incidence of CNS progression. We did see that it favored the trend, favored imlunestrant in the EMBER-3 trial. However, the hazard ratio estimates here must be really interpreted with caution, given the low event rate. But I think it's one additional feature that is probably attractive, especially because we know abemaciclib also has some CNS penetration, now imlunestrant has CNS penetration, and the combination is so effective that we would hope that this can also be helpful for patients with ER+ disease and brain metastases.
**Jhaveri**
Last, but not the least, I would add that the safety profile, which really allows us not only to do combinations in the metastatic setting, and we saw low discontinuation rates for the combination of abemaciclib and imlunestrant. But monotherapy safety data is also very important, as these agents are now being evaluated for early-stage patients. So, we already have an ongoing EMBER-4 study, which is being evaluated for early-stage patients. The challenge in early stages is nonadherence. Approximately 50% of our patients are non-adherent to their 5-year duration of endocrine therapy because of toxicity challenges. And so, we have optimal endocrine therapy agents — agents that are better than these currently approved agents and are safe and tolerable. We hope that patients can stay on these therapies beyond the 5 years to the extended duration that we're now utilizing for our patients as well, and this will have an impact on their outcome. So really looking forward to seeing what these agents might do in early stage in these ongoing efforts, eventually, when they read out.
**Pharmacy Times**
Is there anything you would like to add?
**Jhaveri**
The implication of the data for imlunestrant and abemaciclib, which was seen in this second line setting, regardless of prior CDK4/6 inhibitor, regardless of ESR-1 mutations, and regardless of the pathway mutation, perhaps could mean that maybe even without knowing the biomarker status, which is what we currently do to assigned treatments, we might be able to consider this as a potential treatment option, given that the PFS that we see with this doublet is 9.4 months. Something which is very attractive looking at the other contemporary phase 3 trial results that we have, and importantly, with very low discontinuation rates and a good safety profile for the combination — the discontinuation rate being 6%. So, I do think that they have implications for what we currently think about and do with the clinic for our patients in the second line setting.