FDA Grants Full Approval to Lilly's Inluriyo Plus Verzenio in ESR1-Mutated Advanced Breast Cancer
核心洞察
The FDA granted full approval to imlunestrant (Inluriyo (搜索)) plus abemaciclib (Verzenio) for adults with ER-positive, HER2-negative, ESR1 (搜索)-mutated advanced or metastatic breast cancer (搜索) after at least one prior endocrine therapy line.
In the Phase 3 EMBER-3 trial, the all-oral combination doubled median progression-free survival to 11.1 months versus 5.5 months with imlunestrant alone (HR=0.53; 95% CI, 0.35-0.80).
Most adverse events with the combination were Grade 1 or 2, with permanent discontinuation of imlunestrant in 1% of patients and of abemaciclib in 3.4% of patients.
Eli Lilly and Company has received full FDA approval for Inluriyo (搜索) (imlunestrant), an oral estrogen receptor (搜索) antagonist, in combination with Verzenio (abemaciclib), a CDK4/6 (搜索) inhibitor, for adults with estrogen receptor-positive (ER+), HER2-negative (HER2-), ESR1 (搜索)-mutated locally advanced or metastatic breast cancer (搜索) (MBC) as detected by an FDA-authorized test, with disease progression following at least one line of endocrine therapy. The company announced the approval on Sept. 18, 2026, and said the combination is now available in the United States.
The decision is based on results from the Phase 3 EMBER-3 trial, which evaluated switching both endocrine therapy and CDK4/6 (搜索) inhibitor at clinical progression. In patients with ESR1 (搜索)-mutated MBC, the combination doubled median progression-free survival (PFS) compared with Inluriyo (搜索) alone, at 11.1 months versus 5.5 months (HR=0.53 [95% CI, 0.35-0.80]).
EMBER-3 Design and Endpoints
EMBER-3 (NCT04975308) was a Phase 3, randomized, open-label study of Inluriyo (搜索), investigator's choice of endocrine therapy, and Inluriyo plus abemaciclib in patients with ER+, HER2- locally advanced or metastatic breast cancer (搜索) whose disease had recurred or progressed during or following an aromatase inhibitor (AI) with or without a CDK4/6 (搜索) inhibitor.
In the trial, 874 patients with previously treated, ER-positive, HER2-negative advanced breast cancer (搜索) were randomly assigned to imlunestrant monotherapy (n=331), imlunestrant plus abemaciclib (n=213), or investigator's choice of standard-of-care endocrine therapy with exemestane or fulvestrant (n=330). Imlunestrant was given at 400 mg orally once daily and abemaciclib at 150 mg orally twice daily, with treatment cycles across 28 days.
The approval analysis focused on patients whose tumors harbor an ESR1 (搜索) mutation (n=159). Patients received Inluriyo (搜索) (n=92) or Inluriyo plus Verzenio (n=67) after an AI, with or without a CDK4/6 (搜索) inhibitor, in either the adjuvant or metastatic setting. The trial's primary endpoints were PFS per investigator assessment for single-agent imlunestrant versus standard of care in all patients and in patients with ESR1 mutations, as well as PFS for imlunestrant plus abemaciclib versus imlunestrant in all patients. Overall survival was a key secondary endpoint.
Targeting Two Drivers of Tumor Growth
Inluriyo (搜索) is an oral estrogen receptor (搜索) antagonist, also described as an oral selective estrogen receptor degrader (SERD), designed to bind ER, switch off signals that drive cancer cell growth, and trigger ER breakdown. Verzenio targets proteins that control how quickly cancer cells divide. The all-oral combination therefore addresses two distinct drivers of tumor growth, one degrading mutated estrogen receptors and the other targeting CDK4/6 (搜索) proteins.
In about half of patients with ER+, HER2- MBC, tumors develop an ESR1 (搜索) mutation during or after treatment with AIs, a common class of hormone-blocking medicines. These mutations can cause estrogen receptors to become overactive, fueling cancer growth. Up to 50% of people with ER+, HER2- metastatic breast cancer (搜索) previously treated with endocrine therapy may develop an ESR1 mutation that is difficult to treat with other endocrine therapies.
"We have an urgent need for effective and safe treatment options for patients with disease progression on adjuvant or first-line therapy. Combining therapies that work on two distinct drivers of tumor growth, the estrogen receptor (搜索) and CDK4/6 (搜索), is an important strategy to help address treatment resistance," said Komal Jhaveri, MD, FACP, FASCO, associate attending in Breast Medicine and Early Drug Development Services and section head of the Endocrine Therapy Research Program at Memorial Sloan Kettering Cancer Center, and principal investigator for the EMBER-3 and EMBER-4 trials. "In EMBER-3, switching both the endocrine therapy and CDK 4/6 inhibitor, for the majority of patients, to imlunestrant plus abemaciclib at disease progression achieved a median progression-free survival of 11.1 months and a safety profile consistent with that of each medicine individually, establishing a meaningful new treatment option."
Safety Profile
In EMBER-3, the majority of adverse events (AEs) with Inluriyo (搜索) plus Verzenio were Grade 1-2. The most common (at least 10%) adverse reactions, including laboratory abnormalities, were decreased neutrophils, diarrhea, decreased hemoglobin, decreased lymphocytes, nausea, decreased platelets, fatigue, increased triglycerides, infections, increased AST, increased creatinine, increased ALT, vomiting, musculoskeletal pain, abdominal pain, decreased appetite, increased cholesterol, rash, cough, headache, and decreased weight.
Permanent discontinuation of Inluriyo (搜索) alone due to adverse reactions in the combination arm occurred in 1% of patients, and permanent discontinuation of Verzenio alone in the combination arm occurred in 3.4% of patients. Serious adverse reactions occurred in 21% of patients who received the combination, with pneumonia (2.4%), abdominal pain, and renal failure (each 1.4%) reported in more than 1% of patients. Fatal adverse reactions occurred in 3.8% of patients receiving the combination, including pneumonia (1.4%), myocardial infarction, interstitial lung disease, and sepsis (0.5% each).
Specific warnings in the combination setting included diarrhea, which occurred in 86% of patients who received Inluriyo (搜索) plus Verzenio, with Grade 3 or 4 diarrhea in 9%; decreased neutrophil count in 86%, with Grade 3 or 4 decreases in 21%; ILD or pneumonitis in 2.9%; ALT increase in 33% for all grades (Grade 3 or 4: 5%) and AST increase in 36% for all grades (Grade 3 or 4: 2.5%); venous thromboembolic events in 4.8%; and creatinine increase in 36% for all grades (Grade 3 or 4: 1.1%). The Inluriyo label carries a warning and precaution for embryo-fetal toxicity. The Verzenio label carries warnings and precautions for severe diarrhea, neutropenia, interstitial lung disease/pneumonitis, hepatotoxicity, venous thromboembolism, embryo-fetal toxicity, and increased serum creatinine without affecting renal function. Neither agent has a boxed warning.
Inluriyo (搜索) is dosed as 200 mg tablets taken as a once-daily dose of 400 mg on an empty stomach, at least 2 hours before food or 1 hour after food. Verzenio is an oral tablet taken twice daily and is available in 50 mg, 100 mg, 150 mg, and 200 mg strengths.
Second Approval in Under a Year
The combination approval marks the second FDA authorization for Inluriyo (搜索) in less than a year, following its September 2025 approval as monotherapy for adults with ER+, HER2-, ESR1 (搜索)-mutated MBC whose disease progressed after at least one line of endocrine therapy. In the monotherapy setting, serious adverse reactions occurred in 10% of patients, with pleural effusion (1.2%) reported in more than 1%; fatal adverse reactions occurred in 1.8%, including cardiac arrest, acute myocardial infarction, right ventricular failure, hypovolemic shock, and upper gastrointestinal hemorrhage (each 0.3%).
Jacob Van Naarden, executive vice president and president of Lilly Oncology, said Inluriyo (搜索) has become the leading treatment option for people with ER+, HER2-, ESR1 (搜索)-mutated metastatic breast cancer (搜索), now reaching over half of all patients starting an oral SERD. "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," he said. "In fact, all available evidence suggests that switching endocrine therapy and CDK4/6 (搜索) inhibitor at clinical progression improves patient outcomes more than switching therapy earlier."
The FDA granted full approval rather than accelerated approval, meaning the decision is not contingent on confirmatory trial results. Verzenio, discovered and developed by Lilly researchers, was first approved in 2017 and is authorized in more than 90 countries. It is the first CDK4/6 (搜索) inhibitor approved to treat node-positive, high-risk early breast cancer (搜索), and has demonstrated statistically significant overall survival in the Phase 3 MONARCH 2 study in metastatic breast cancer.
Adjuvant Study Readout Expected in 2027
Inluriyo (搜索) is also being studied in the Phase 3 EMBER-4 trial (NCT05514054) in the adjuvant setting for people with ER+, HER2- early-stage breast cancer (搜索) at increased risk of recurrence following standard-of-care endocrine therapy, including CDK4/6 (搜索) inhibitors. EMBER-4 is the largest adjuvant oral SERD clinical trial, with more than 8,000 patients enrolled worldwide across more than 650 sites in more than 30 countries. Initial results are anticipated in 2027.
EMBER-4 was designed as a sequential trial, with patients enrolled following initial standard adjuvant endocrine therapy, including patients with or without prior CDK4/6 (搜索) inhibitor treatment. The design mirrors how patients are treated in practice and asks whether Inluriyo (搜索) can provide additional protection for patients who have already received initial standard-of-care hormone therapy when risk of recurrence increases.
Breast cancer (搜索) is the second most commonly diagnosed cancer worldwide, according to GLOBOCAN, with an estimated 2.3 million new cases in 2022 and approximately 666,000 deaths that year. Approximately 70% of breast cancers express the estrogen receptor (搜索). In the United States, more than 310,000 new breast cancer cases were estimated for 2024. Of all high-risk early-stage breast cancer cases diagnosed in the U.S., approximately 30% will become metastatic, and an estimated 6% to 10% are metastatic at diagnosis. Estimated five-year survival rates are 99% for localized disease, 86% for regional or locally advanced disease, and 30% for metastatic or advanced disease.