SABCS 2024 – Ember-3 dims hopes for Lilly’s SERD

So far oral SERDs have worked best in breast cancer patients with ESR1 mutations, and Lilly’s imlunestrant is no exception. In the phase 3 Ember-3 second-line trial presented at SABCS on Wednesday, imlunestrant monotherapy only showed a progression-free survival benefit over standard of care among this genetic subgroup, and not in all-comers.

However, a combination of imlunestrant and Lilly’s CDK4/6 inhibitor Verzenio did improve PFS versus imlunestrant alone in the entire trial population – and showed a benefit regardless of ESR1 mutation status.

One question is why the trial compared the combo versus imlunestrant, rather than standard of care. Another is whether Lilly will file mono or combo therapy, and in which populations of ER-positive, HER2-negative breast cancer. The company would only say that discussions with regulators were ongoing.

A spokesperson added: “The combination arm of the study was added as a protocol amendment after the study began so those data are less mature. We will need to see whether regulators prefer to wait for more mature data for the combo or will assess both together.”

One worry about the combo could be toxicity: adverse events were higher with imlunestrant plus Verzenio than in the monotherapy group, and there was one death, from an unknown cause, attributed to the doublet.

Still, the authors of the trial, which was published simultaneously in the NEJM, noted that imlunestrant plus Verzenio looked less toxic than other combo regimens, including those incorporating AstraZeneca’s injectable SERD Faslodex.

Picking through the Embers

So far, Menarini’s Orserdu is the only oral SERD approved, but only in ESR1m disease. While Orserdu’s Emerald trial enriched for this genetic subtype, Ember-3 didn’t appear to. Still, 32-42% of patients had an ESR1 mutation.

Also unlike Emerald, Ember-3 didn’t require patients to have previously received a CDK4/6 inhibitor, though around 60% of patients had.

Ember-3 first compared imlunestrant versus Faslodex or exemestane on its primary endpoint of progression-free survival, assessed separately in ESR1m and all-comers. PFS with the combo, versus imlunestrant monotherapy, was to be tested only if imlunestrant monotherapy prevailed on one of the PFS outcomes.

In ESR1m, imlunestrant reduced the risk of progression or death by 38% versus standard of care; but no benefit was seen in all-comers. Meanwhile, in all-comers, the combo reduced this risk by 43% over monotherapy.

Ember-3 data in second-line, ER-positive, HER2-negative breast cancer

Source: SABCS & NEJM.

There was a trend towards an overall survival benefit with imlunestrant monotherapy versus standard of care in ESR1m patients, with a 45% reduction in the risk of death, but the p value of 0.008 didn’t meet the bar for statistical significance.

Meanwhile, the OS analysis of imlunestrant monotherapy vs imlunestrant-Verzenio was immature.

One encouraging point for Lilly is that imlunestrant-Verzenio showed a benefit regardless of ESR1m status, something that looks less clear for Arvinas and Pfizer’s rival SERD vepdegestrant.

The Tactive-U study, combining vepdegestrant with Verzenio and also presented this week at SABCS (the San Antonio Breast Cancer Symposium), found an ORR of 27% among 15 patients overall, but this was driven by ESR1m (38% ORR, with only a 14% ORR in ESR1 wild type). In Tactive-U all patients had received a prior CDK4/6 inhibitor.

Readout of vepdegestrant’s pivotal second-line Veritac-2 trial was recently delayed to early 2025 – and Arvinas has already cautioned about making cross-trial comparisons with Ember-3, not least because vepdegestrant’s trial requires prior CDK4/6 inhibitor therapy.