Eli Lilly will not seek a broad FDA approval for a combination of the company’s oral SERD med Inluriyo and CDK4/6 inhibitor Verzenio despite seemingly promising phase 3 results.
Instead, the Indianapolis pharma will only pursue a label for the combo covering patients with ER-positive, HER2-negative advanced breast cancer who carry ESR1 gene mutations, the same limited indication that Inluriyo monotherapy recently obtained from the FDA, Jake Van Naarden, president of Lilly Oncology, told Fierce Pharma.
“I don’t think there’s a path to an [intent-to-treat] indication. It’s just not been where the conversation has been,” Van Naarden said in an interview with Fierce about Lilly’s interactions with the FDA, later adding that “we’re not going to fight with them on that.” The intent-to-treat description refers to all participants randomized in a clinical trial, rather than specific subgroups.
The revelation comes as a disappointment, because, while Inluriyo itself previously failed to show a progression-free survival benefit against endocrine therapy in patients without ESR1 mutations in the company’s phase 3 Ember-3 trial, the Inluriyo-Verzenio combo yielded better results in that patient subgroup. For the Inluriyo-Verzenio combo, the trial assessed outcomes against Inluriyo monotherapy.
When Inluriyo was initially cleared by the FDA in September, Lilly said it would share a more mature analysis of the combo with the FDA.
The 2nd-line fight
An updated analysis from the Ember-3 trial shows the two-drug combo reduced the risk of progression or death by 41% compared with Inluriyo alone in a group of previously treated patients regardless of their ESR1 status, according to results presented at the 2025 San Antonio Breast Cancer Symposium (SABCS).
Patients with and those without ESR1 mutations appeared to have benefited from the combo. The ESR1-mutant group logged a progression-free survival improvement of 51%, while the effect size was smaller, at 36%, in patients without the biomarker.
None of those numbers bear statistical significance because the study had already met the statistical bar during the primary analysis, which recorded a 43% PFS benefit for the combo in all patients. But, while the combo’s performance in the ESR1 subgroup improved from 47% at the primary analysis, its results deteriorated from 41% in the nonmutant population.
At the current second interim analysis with 14 months of additional follow-up from the first, the trial didn’t achieve a high prespecified threshold for significance on overall survival. At 33% data maturity, Inluriyo and Verzenio showed a favorable trend toward an 18% OS improvement in the overall population, with the duo’s advantage over single-agent Inluriyo starting to show after two years. No breakdown of OS data by patients' ESR1 status was offered.
But, as Van Naarden hinted when commenting about common FDA practice, “when the effect size is enriched in a subpopulation that’s identifiable, that’s where the agency wants to go.”
Lilly’s acknowledgement of defeat in an all-comers second-line population could hand rival Roche a win. But Van Naarden doesn’t think so.
Similar to Ember-3’s combo arm, Roche’s evERA trial recently found that the Swiss pharma’s oral SERD candidate giredestrant, used alongside everolimus (Novartis’ Afinitor), significantly lowered the risk of progression or death by 44% versus everolimus alone in patients with second-line ER-positive, HER2-negative breast cancer. Based on the results, Roche is pushing for an all-comers label.
But the regimen’s benefit similarly appeared to be mostly driven by the ESR1-mutant group, which logged a 62% PFS improvement. The ESR1 wild-type patients who received the Roche combo only saw a minor 16% difference on PFS, according to an exploratory analysis. An immature OS analysis produced a 21% trend in favor of the combo in the wild-type group, which Roche argued was clinically meaningful.
“We’ve seen this exact movie before. It’s not going to end differently,” Van Naarden said, suggesting that Roche will end up with an ESR1-mutant label, too. He was referring to how Menarini’s first-in-class oral SERD, Orserdu, also only secured an ESR1-mutant label even though its pivotal study, Emerald, showed a benefit in an all-comers population. An exploratory analysis found a weak 14% advantage on PFS in patients without ESR1 mutations.
The fight beyond 2nd line
With these data, Van Naarden argued that the second-line setting is “done and dusted” for oral SERDs to be simply ESR1-mutant drugs.
Meanwhile, Roche has a first-line trial, pionERA, which is pitting giredestrant against AstraZeneca’s injectable SERD Faslodex, both combined with a CDK4/6 inhibitor, in patients who developed resistance to prior endocrine therapy as adjuvant treatment for early-stage breast cancer.
Van Naarden, calling the future outcome of that first-line study “a big unknown,” instead highlighted efforts in the adjuvant setting, which he said the entire oral SERD class was really meant for.
There, Roche is currently one step ahead. At SABCS, the Swiss drugmaker reported that, in the phase 3 lidERA trial, giredestrant led to a 30% reduction in the risk of invasive disease recurrence or death versus endocrine therapy when used as an adjuvant therapy after surgery for early-stage breast cancer.
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To counter Roche’s offering, Lilly is running the Ember-4 trial, which is different from lidERA in that it’s being conducted in patients who have previously received two to five years of adjuvant endocrine therapy. More importantly, participants are allowed to have received a CDK4/6 inhibitor. With that design, Ember-4 is effectively testing Inluriyo in a post-CDK4/6 setting, as adjuvant Verzenio is given for up to two years alongside endocrine therapy, and Novartis’ Kisqali is dosed for three years.
In lidERA, only a short course of up to 12 weeks of CDK4/6 inhibitor therapy prior to randomization is allowed.
With target enrollment of 8,000 patients, Ember-4 will be Lilly’s largest oncology trial in the company’s history, according to Van Naarden. Following all the positive oral SERD readouts, Van Naarden said he now has increased confidence that the study will be successful.
“I think that study will work, and I think it will be a lot more relevant clinically than the Roche study that is reading out now,” Van Naarden said. “In second line, I think the medicine can help people. But I think we can all agree that, if you have the opportunity to increase the cure fraction of an early-stage disease setting, that is more important than prolonging survival in a late-stage setting.”