It looks like Eli Lilly’s oral selective estrogen receptor degrader (SERD) imlunestrant may need some extra help to reach a broad patient population with ER-positive, HER2-negative breast cancer.
While treatment with imlunestrant led to a statistically significant 38% reduction in the risk of disease progression or death versus standard endocrine therapy in patients with ESR1-mutated ER+/HER2- breast cancer following progression on a prior aromatase inhibitor, it failed to mount a statistically significant progression-free survival (PFS) showing in all patients. The result came from the phase 3 EMBER-3 trial.
In patients without ESR1 mutations, imlunestrant and the control group showed no difference in PFS. This group’s result reduced the Lilly med’s PFS benefit in the overall population to a nonsignificant 13%.
Patient survival data remained immature, reaching 31% maturity in the ESR1 subgroup and 23% in all patients. But the survival results are trending in favor of imlunestrant over control.
Presented at the 2024 San Antonio Breast Cancer Symposium (SABCS), the data support past observations that SERDs tend to perform better in ESR1-mutated tumors than in wild-type cases. Menarini’s Orserdu, the first oral SERD approved by the FDA, is also limited by ESR1 as an exploratory analysis found its PFS improvement in the overall population was primarily driven by patients with this genetic subtype.
Luckily for Lilly, a few months after launching EMBER-3 in 2021, at the risk of complicating the statistical design, the company added a third arm to the study. This last cohort combined imlunestrant with Lilly’s own CDK4/6 inhibitor Verzenio.
The study may be a bit complicated, but it was essentially trying to answer two questions, Lilly’s chief medical officer, David Hyman, M.D., explained in an interview: “Where do we use imlunestrant, and should we be using alone or in combination with a CDK4/6 inhibitor?”
Lilly’s bet appears to have paid off. Compared with imlunestrant alone, the drug’s combination with Verzenio led to a 43% reduction in the risk of progression or death in all patients. The combo stretched the median PFS to 9.4 months versus 5.5 months for single-agent imlunestrant.
The benefit was shared among key subgroups. The magnitude of improvement was 47% In those with ESR1 mutations or 41% in those without the biomarker. Among ESR1-mutated patients, the median PFS was 11.1 months for the combo and 5.5 months for imlunestrant monotherapy.
Among those without the mutations, the median PFS numbers were 9.1 months and 5.5 months, respectively.
Data on patients’ life expectancy were immature for the combo comparison. At just 15% maturity, overall survival data favored imlunestrant over Verzenio-imlunestrant in all patients.
Questions from an 'unprecedented' showing
But the EMBER-3 trial design raises two important sticking points.
First, since imlunestrant failed by itself in the overall population, is it the appropriate comparator for the imlunestrant-Verzenio combo? Second, without a Verzenio monotherapy arm, there’s no direct evidence whether the CDK4/6 inhibitor even needs to be paired up with imlunestrant.
On the first point, Lilly's Hyman said oral SERDs like imlunestrant have some efficacy in non-ESR1-mutated cases but that they are not superior to existing endocrine therapies.
As to the second question, Lilly’s postMONARCH trial could offer an indirect comparison. In that phase 3 study, the combination of Verzenio and AstraZeneca’s intramuscular SERD drug Faslodex reduced the risk of progression or death by 27% versus Faslodex alone in CDK4/6-pretreated ER+/HER2- breast cancer. The median PFS for the Verzenio-Faslodex arm was six months.
That makes the Verzenio-imlunestrant combo’s 9.4-month median PFS “unprecedented” for any endocrine-based combination therapy in second-line ER+/HER2- breast cancer, Hyman noted.
However, to complicate that indirect comparison, the current EMBER-3 trial allowed patients with or without prior exposure to a CDK4/6 inhibitor to enroll. Among patients who had previously tried a CDK4/6 inhibitor irrespective of ESR1 status, the Verzenio-imlunestrant combo’s PFS benefit reached 49% versus imlunestrant alone. The median PFS length was 9.1 months and 3.7 months, respectively, in this comparison.
The EMBER-3 situation also makes a cross-trial comparison with Menarini’s EMERALD trial for Orserdu difficult because prior CDK4/6 use was mandatory in that latter study. There, Orserdu monotherapy reduced the risk of progression or death by 45% versus standard endocrine therapy in ESR1-mutated cases, as the drug doubled median PFS to 3.8 months.
Lilly’s EMBER-3 trial population mirrors U.S. prescribing practices for second-line breast cancer, Hyman said. Despite the advancement of CDK4/6 inhibitors, about 40% of U.S. patients still don’t get these drugs in the first line, he noted.
Hyman also touted imlunestrant’s tolerability profile, which he said bodes well for future studies that explore the oral SERD in earlier treatment settings. In EMBER-3, discontinuations due to adverse events were recorded in four (1.2%) patients in the imlunestrant arm and six (2.9%) in the combo arm.
“With some of the other SERD in this space, we start to see either GI toxicity or other things like ocular eye toxicity, cardiac toxicity that starts to give people pause about what they’re actually accomplishing,” Hyman said. “We have a really clean profile here, which was exciting for us, not only for metastatic disease, but our adjuvant program.”
Meanwhile, Lilly has launched the phase 3 EMBER-4 trial pitting imlunestrant against physicians’ choice of adjuvant endocrine therapy among ER+/HER2- breast cancer patients who have received two to five years of standard adjuvant endocrine therapy after surgery but who are at an increased risk of recurrence.
Long line of competition
The oral SERD space had its fair share of setbacks but remains highly active, built on the belief that these drugs could become the future endocrine backbone therapy in breast cancer.
Sanofi scrapped amcenestrant in 2022 after a second trial flop. The same year, Roche’s giredestrant chalked up a midphase failure in second- or third-line breast cancer.
Roche is still betting heavily on giredestrant, with two phase 3 trials, persevERA and evERA, expected to read out next year, plus three more in progress or being planned, including the lidERA adjuvant trial.
AstraZeneca also has multiple phase 3 trials for its camizestrant, with the first readout, from SERENA-6, expected in the second half of 2025.
The first phase 3 data for Pfizer and Arvinas’ PROTAC protein degrader vepdegestrant could read out from the VERITAC-2 trial “in the coming months,” Pfizer CEO Albert Bourla, Ph.D., said on a call in October.
Also at the SABCS meeting, Olema Oncology provided an update of its palazestrant in combination with Novartis’ CDK4/6 inhibitor Kisqali from an ongoing phase 1b/2 study that enrolled both first- and later-line patients. The six-month PFS rate was 70% among 43 patients with wild-type ESR1, 81% among 17 patients with ESR1 mutations and 67% among 46 CDK4/6-pretreated patients.
Palazestrant monotherapy is under evaluation in the OPERA-01 trial in second- or third-line treatment. And Olema is plotting OPERA-02 to test the palazestrant-Kisqali combo in the first line.