Komal Jhaveri, MD, FACP on The Phase III EMBER Trial

Speaker 1: At the San Antonio Breast Cancer meeting this year, I had the opportunity to present the results from the Phase III EMBER-3 trial. Now, we know that the estrogen receptor and the CDK4/6 pathways are critical oncogenic pathways and essential therapeutic targets, and even beyond progression, we know that these are very important therapeutic strategies. We certainly have data for Abemaciclib, not only in CDK4/6 naive, but also in CDK4/6 pre-treated patients. And while we have Fulvestrant, which is broadly approved, both as monotherapy and in combinations, we know that it's limited activity in ESR-I mutants. And we also know that because of the requirement of intramuscular injections, this can be painful and burdensome for patients. Recently, we did have approval for oral SERD such as Elacestrant, which is an ER agonist and antagonist, and this was approved as monotherapy in ESR-I mutants. Imlunestrant is a brain-penetrate oral SERD, which is a pure ER antagonist that delivers durable ER inhibition. And frequently we've seen its activity both as monotherapy and in combination with Abemaciclib. And in fact, the combination had a safe tolerable safety profile. So EMBER-3 was designed as a Phase III open-label global study where patients could be men or women regardless of menopausal status with ER-positive HER2-negative breast cancer who've had recurrence on or within 12 months of their adjuvant therapy or have progressed on their first-line metastatic therapy in both settings with an aromatase inhibitor with or without a CDK4/6 inhibitor and no other therapy for advanced disease were then randomized to one of the three arms. In fact, 874 patients were randomized to either Imlunestrant alone, which is given at 400 milligrams orally daily versus standard of care endocrine therapy versus the combination of Imlunestrant plus Abemaciclib. Now the third combination arm was added as a study amendment early in study accrual. The trial has three primary endpoints, and this included investigator-assessed PFS looking at the comparison of Imlunestrant versus standard of care endocrine therapy in ESR-I mutant and in all patients. And then if one of the two endpoints were significant, it would then look at the comparison of Imlunestrant versus Abemaciclib versus Imlunestrant in the concurrently randomized patients. Overall survival was to be tested if PFS was significant for that endpoint. So this was a graphical testing approach where the doublet versus monotherapy would be only tested if the monotherapy comparison endpoints were significant and OS only to be tested if PFS correspondingly was significant. And so when it came to the results for the first primary endpoint, Imlunestrant significantly improved progression pre-survival compared to standard of care endocrine therapy in ESR one mutants, improvement from 3.8 months in the control arm to 5.5 months in PFS. The hazard ratio here is 0.62. And when we looked at the overall patient population, it did not reach statistical significance. The hazard ratio was 0.87. Notably, the majority of patients that did not have ESR I mutations, there was no PFS difference. And the hazard ratio here was one. Now for the third primary endpoint, which is looking at PFS in all patients comparing Imlunestrant strength plus Abemaciclib versus Imlunestrant alone, again, there was a significant improvement in PFS. PFS was 9.4 months for the doublet versus 5.5 months. The hazard ratio is 0.57. Now, the stratification factors for these randomizations that were utilized were prior CDK4/6 inhibitor therapy, visceral metastases presence or absence, and region. And when we looked at subgroup analyses, whether it was for the modern therapy comparison in ESR I mutant patients, or whether it was for the combination versus Imlunestrant alone, consistent benefit was seen regardless of presence or absence of visceral metastasis, regardless of prior CDK4/6 inhibitor therapy. And regardless of PIK3CA pathway mutation status. To clarify more, overall, approximately 37% had ESR I mutations and overall approximately 40% had PI-TK pathway mutation, which could have included a mutation in PI-TK, AKT, or P-10G. And these mutations were really tested after randomization prior to study treatment start using a centralized ctDNA assay. Now, key subgroup analysis that I'd like to highlight were that when we compared the combination regimen with Imlunestrant alone and focused by ESR I mutation status, again, a consistent benefit was seen regardless of ESR I mutations. PFS was 11.1 months versus 5.5 in those patients with ESR I mutations and it was 9.1 months in patients without ESR I mutations who received the doublet. Similarly, if we look at our clinic patients in the second line metastatic setting, majority would've received a CDK4/6 inhibitor therapy. And when we think about treatment selection, we usually base it based on a biomarker. So it was important to focus on these two key subgroups and look at the benefit of Imlunestrant vs Abemaciclib, and again, in both these key clinical subgroups, there was a consistent benefit specifically in patients with prior CDK4/6 inhibitor, which comprised of 65% of the patients who were then randomized to the doublet of Imlunestrant Abemaciclib benefit was seen and this was 9.1 versus 5.5. Again, the hazard ratio here is 0.59. Similarly, consistent benefit was also seen in patients with PI-TK pathway mutation status. Here, the PFS was 7.6 versus 3.8 months. Now moving on quickly to safety, Imlunestrant monotherapy was very well tolerated. The most common toxicities were diarrhea, fatigue, and nausea, which were predominantly grade one. And importantly, single episodes. Grade three or higher toxicity was 17% compared to 21% in the standard of care endocrine therapy arm. There were no concerning signals of cardiac or ocular toxicity. And when we looked at injection site reactions as an adverse event in the Fulvestrant arm, that was reported 9%. However, patient reported injection site discomfort, swelling, or redness was 72% based on a PROCTCA survey. With the doublet again, as expected there were higher toxicities with the two drugs. However, reassuringly, diarrhea being the most common, but more importantly, it was predominantly grade one. And the safety profile was consistent with what we already know about with Abemaciclib and what has already been reported and published with the combination of Fulvestrant plus Abemaciclib with no new added safety signal. The discontinuation rates were very low for monotherapy at 4% and even for the combination were reassuringly low at 6%. So in summary, Imlunestrant versus standard of endocrine therapy improved progression-free survival and that was in ESR I mutant patients. There was no statistical significance in the overall patient population. There was consistent benefit in all key subgroups. The overall survival analyses were immature and are currently ongoing. The monotherapy was very well tolerated with very low grade toxicities, very low discontinuation rates, and no oral SERD related safety signals of ocular or cardiac toxicities. The combination was also very well tolerated with very low discontinuation rates at 6%. And the side effect profile was similar to what we have known for Fulvestrant plus Abemaciclib. The combination improved progression free survival compared to Imlunestrant significantly, and it was statistically significant with a substantial PFS benefit at 9.4 months regardless of ESR I mutation status and with consistent benefit in all key subgroups including prior CDK4/6 inhibitor therapy and PIK3 pathway mutation status. And as such, Imlunestrant alone or in combination with Abemaciclib is an all oral targeted option after progression on endocrine therapy in ER-positive, HER2 negative advanced breast cancer. And these results are now available in the New England Journal of Medicine, which was a simultaneous publication on December 11th as well.