The Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has recommended that Inluriyo ( imlunestrant, Eli Lilly Nederland B.V.) be given marketing authorization for the treatment of adults with locally advanced or metastatic breast cancer with an activating estrogen receptor 1 (ESR1) mutation.

Breast cancer is the most common female cancer in the EU, responsible for almost a third (29.4%) of all cancers in women and the leading cause of cancer deaths in women (16.7% of all female cancer deaths). Although mortality has reduced from around 18 per 100,000 in 2002 to about 15 per 100,000 in 2022, there remains a significant gap between Eastern and Western EU countries: Incidence is higher in the West, but the East has higher death rates.

Between 5% and 10% of all breast cancers are metastatic at diagnosis, and 20%-30% of patients diagnosed with early-stage breast cancer eventually progress to the metastatic stage. The most common type of metastatic tumor is estrogen receptor-positive (ER+) and human epidermal growth factor receptor 2-negative (HER2-), representing 68% of metastatic tumors. Median survival in metastatic breast cancer is just under 3 years.

Mutations Associated With Treatment Resistance

ESR1 mutations are associated with resistance to endocrine therapy, the key treatment mode for metastatic hormone receptor-positive breast cancers. They are relatively rare in primary tumors, occurring in only around 1 in 100 cases, but may be found in between 10% and 50% of metastatic endocrine therapy-resistant tumors, suggesting that they play a key role in acquired treatment resistance and disease progression. 

ESR1 mutations may affect tumor sensitivity to various therapies, both established and new treatments, hampering development of effective treatments. They have been associated with shorter progression-free survival and shorter distant recurrence-free survival.

European Society for Medical Oncology (ESMO) guidelines recommend hormone therapy as first-line treatment for ER+ metastatic breast cancer but acknowledge that up to 50% of patients develop resistance due to ESR1 mutations. In patients with metastatic ER+/HER2- breast cancer who show progression or recurrence during hormone therapy — with or without a CDK4/6 inhibitor — ESMO advocates routine testing to detect acquired ESR1 mutations, for example through liquid biopsy, to guide subsequent targeted therapy decisions.

New Drug Improves Survival

The CHMP has recommended Inluriyo as monotherapy for the treatment of adult patients with ER+/HER2-, locally advanced or metastatic breast cancer with an activating ESR1-mutation, who have disease progression following treatment with an endocrine based regimen. In pre- or perimenopausal women and in men, Inluriyo should be combined with a luteinizing hormone-releasing hormone agonist.

The drug’s active ingredient, imlunestrant, is an estrogen endocrine agonist that antagonizes and degrades wild-type and mutant estrogen receptor alpha, leading to inhibition of estrogen receptor-dependent gene transcription and cellular proliferation in ER+ breast cancer cells.

A phase 3, randomized, open-label study showed that imlunestrant as monotherapy improved progression-free survival compared with fulvestrant or exemestane in adults with ER +/ HER2 ‑ locally advanced or metastatic breast cancer with an activating ESR1-mutation when they had disease progression following treatment with an endocrine-based regimen.

Inluriyo is an oral treatment available as 200 mg film-coated tablets. The most common side effects include increased liver enzymes, fatigue, diarrhea, nausea, and vomiting. 

Treatment with the drug should be initiated and supervised by physicians experienced in the use of cancer treatments.

Detailed recommendations for the use of Inluriyo will be described in the summary of product characteristics, which will be published on the EMA website in all official European Union languages after the marketing authorization has been granted by the European Commission.