Eli Lilly is sharpening its competitive edge in the crowded oral SERD arena as the FDA has approved a combination of its Inluriyo with its CDK4/6 inhibitor Verzenio.
The label expansion builds on Inluriyo’s existing monotherapy indication, approved nearly a year ago to treat ER-positive, HER2-negative breast cancer that carries ESR1 mutations in previously treated patients.
Given the longer progression-free survival (PFS), Jake Van Naarden, president of Lilly Oncology and head of corporate business development at Lilly, projected to Fierce that most patients will choose the combination over an oral SERD monotherapy.
In the phase 3 Ember-3 trial, Inluriyo-Verzenio helped patients with previously treated ESR1-mutated ER+/HER2- breast cancer achieve a median PFS of 11.1 months, versus 5.5 months for Inluriyo alone, translating into a 47% reduction in the risk of progression or death.
The PFS data were already made public in December 2024. But the FDA initially cleared only Inluriyo monotherapy because the combination cohort didn’t have mature enough overall survival data due to late enrollment, Van Naarden explained. Now, he said OS is “trending in the right direction.”
“Today’s full approval extends what Inluriyo in combination with Verzenio can do for patients, with a regimen that has confirmed benefit, is aligned to the clinically proven treatment paradigm of changing therapy at clinical progression, and doesn’t introduce burdensome monitoring requirements for patients or physicians,” Van Naarden said in a statement.
Those last two points represent a direct shot at AstraZeneca’s newly approved oral SERD rival, Etcamah. In a surprise accelerated approval earlier this month, the FDA greenlit Etcamah alongside a CDK4/6 inhibitor in a novel setting in which patients switch from their existing first-line aromatase inhibitor and CDK4/6 treatment upon detection of an ESR1 mutation, but before traditional radiographic disease progression. Under this approach, patients need to undergo blood-based testing to monitor for ESR1 mutations.
The FDA granted accelerated approval despite concerns raised by its own reviewers and a 6-3 advisory committee vote against finding that the approach had demonstrated a clinically meaningful benefit. Both the FDA’s external advisers and agency reviewers raised concerns that AZ’s phase 3 Serena-6 trial didn’t compare this brand-new first-line switch approach with the established practice of changing treatment after first-line progression.
As part of the accelerated approval, the FDA has required AZ to run a separate phase 3 trial to make that comparison.
Lilly’s Inluriyo-Verzenio regimen gives the company another argument in that debate. In Serena-6, median PFS was 16 months for AZ’s Etcamah combination versus 9.2 months for first-line patients who stayed on their existing therapy. Lilly’s Ember-3, meanwhile, showed a median PFS of 11.1 months for Inluriyo and Verzenio as second-line treatment. The results come from separate trials and patient populations and cannot be directly combined or compared, but Lilly argues that waiting until clinical progression before switching treatment can maximize the total time patients achieve disease control.
“I know that it sounds nice to intercept early, but the goal isn’t about treating with a new medicine early,” Van Naarden said. “The goal is about maximizing the total time of disease control using these two mechanisms and waiting for clinical progression [to give an oral SERD]. That is the evidence-based standard.”
Before Etcamah, the FDA-approved oral estrogen receptor degraders in this space had all been cleared for use after disease progression on at least one line of endocrine therapy.
“In less than a year since its approval, Inluriyo is the leading treatment option for people with ER+, HER2-, ESR1-mutated metastatic breast cancer, now reaching over half of all patients starting an oral SERD,” Van Naarden noted in a statement.
The field is now moving toward early-stage breast cancer after Etcamah and Roche’s giredestrant each missed the primary endpoint in phase 3 trials testing the drugs as upfront first-line treatments for advanced disease.
Giredestrant has already read out a positive phase 3 study as an adjuvant therapy, although questions remain about its design because it didn’t incorporate a CDK4/6 inhibitor. Lilly and AZ also have phase 3 trials underway in early-stage disease. Lilly’s Ember-4 is testing Inluriyo in patients who have already received two to five years of adjuvant endocrine therapy, with prior CDK4/6 inhibitor treatment allowed.
Adjuvant treatment remains the largest market opportunity for oral SERDs. Here, Van Naarden argued that tolerability could determine the final winner.
“That’s really important in the adjuvant setting where patients are going to be on these medicines for like five to 10 years,” he said. “You only get the benefit of the medicine if you take it.”