Sanofi's Oral SERD Amcenestrant Shows Strong Efficacy in Combination with Ibrance for ER+/HER2- Metastatic Breast Cancer

May 22, 2021 /BioonBIOON/ -- Sanofi recently announced results evaluating the oral selective estrogen receptor degrader (SERD) amcenestrant for the treatment ofBreast CancerData from the open-label Phase 1 AMEERA-1 study. In a pooled analysis, amcenestrant in combination with the targeted anticancer CDK4/6 inhibitor Ibrance® (generic name: palbociclib) demonstrated encouraging antitumor activity in postmenopausal women with estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (MBC).# TumorActivity:The objective response rate (ORR) was 34% and the clinical benefit rate (CBR) was 74%, with a favorable overall safety profile.。

Amcenestrant is an oral SERD that antagonizes and degrades the estrogen receptor (ER), thereby inhibiting the ER signaling pathway.Currently, amcenestrant is being developed: as a monotherapy for second- or third-line treatment of ER+/HER2- MBC, in combination with palbociclib for first-line treatment of ER+/HER2- MBC, as adjuvant therapy for early breast cancer, and in combination with palbociclib for first-line treatment of ER+ MBC.

Metastatic breast cancer (MBC) refers to breast cancer that has spread from the breast to another part of the body, such as the liver, brain, bones, or lungs. MBC is also known as Stage IV, the most advanced stage of breast cancer. Approximately two out of every three breast cancer cases are hormone receptor-positive (HR+), meaning the cancer is driven by estrogen or progesterone. HR+ breast cancer can be classified as estrogen receptor-positive (ER+) and/or progesterone receptor-positive (PR+).

ER-positive breast cancer accounts for approximately 75% of all breast cancers, and is currentlyDiagnosis# The Most Common Type of Breast Cancer. The 5-year relative survival rate for women with distant metastatic breast cancer is 28.1%. Endocrine therapy is one of the initial treatment options for HR+ MBC and is considered the standard of care for first-line treatment. However, new treatment options remain necessary, as resistance frequently develops over time, limiting the efficacy of endocrine therapy in patients with metastatic disease.

Dr. John Reed, Head of Global Research and Development at Sanofi, stated: “The Phase 3 AMEERA-5 study builds upon promising preclinical and clinical data, including those to be presented at the ASCO Annual Meeting, which expands our understanding of amcenestrant as a potential best-in-class oral endocrine backbone therapy for ER+/HER2- breast cancer. ER+ breast cancer is the most common type of breast cancer, accounting for approximately currently”Diagnosis75% of all breast cancer cases, therefore more treatment options are needed.”

Dr. Sarat Chandarlapaty, a medical oncologist at Memorial Sloan Kettering Cancer Center, stated: "These early clinical data indicate that the combination of amcenestrant and palbociclib has demonstrated encouraging anti-TumorActivity. Analysis also demonstrated no clinically significant cardiac or ocular findings, and the overall safety profile was consistent with that observed in the monotherapy setting. There is a clear unmet need for new treatment options in ER+ metastatic breast cancer, making the activity observed in this patient population highly compelling.”

Molecular structure of amcenestrant (SAR439859) (Image source: medchemexpress.com)

AMEERA-1 is an open-label, first-in-human phase 1/2 study designed to evaluate amcenestrant as a monotherapy and in combination with targeted therapy for the treatment of postmenopausal women with ER+/HER2- MBC. Part A (dose escalation) and Part B (dose expansion) aim to determine the maximum tolerated dose (MTD) of amcenestrant as a monotherapy. Parts C and D are evaluating dose escalation and expansion of amcenestrant in combination with palbociclib to determine the recommended phase 2 dose (RP2D) for the combination regimen and to characterize its safety profile. The primary efficacy objectives include evaluating anti-tumor efficacy based on objective response rate (ORR) and clinical benefit rate (CBR) according to RECIST v1.1 criteria.TumorAssessment of activity, and the overall safety profile of amcenestrant as monotherapy and in combination with Ibrance. Eligible patients include those with histologicallyDiagnosisFor female patients with ER+/HER2- locally advanced or metastatic breast adenocarcinoma who have previously received at least 6 months of endocrine therapy, including patients with early recurrence during adjuvant endocrine therapy initiated more than 24 months ago, or recurrence within 12 months of completing adjuvant endocrine therapy.

In this preliminary analysis, amcenestrant was evaluated at 200 mg once daily (n=9) and 400 mg once daily (n=6) in the dose-escalation cohort (Part C), and at 200 mg once daily in the dose-expansion cohort (Part D, n=30), all in combination with standard-dose palbociclib. Eligible patients included postmenopausal women with ER+/HER2- MBC who had received endocrine therapy for at least 6 months for advanced disease, or who had developed resistance to adjuvant endocrine therapy.

In the pooled population evaluable for response receiving amcenestrant 200 mg once daily (n=35), the objective response rate (ORR) was 34% (n=12/35; 90% CI: 21.1–49.6), all of which were confirmed partial responses (PR), and the clinical benefit rate (CBR) at 24 weeks was 74% (n=26/35; 90% CI: 59.4–85.9).

Once-daily 200 mg amcenestrant in combination with palbociclib demonstrated a favorable overall safety profile (n=39), with treatment-related adverse events (TRAEs) attributed to amcenestrant similar to those observed in patients receiving monotherapy. For all-grade events, amcenestrant TRAEs occurred in 72% of patients and palbociclib TRAEs in 90%, with Grade ≥3 TRAEs reported in 15% and 46% of patients, respectively. The most common non-hematologic adverse events included fatigue (18%) and nausea (18%), all of which were Grade ≤2. No clinically meaningful cardiac or ocular safety findings were observed. (Bioon.com)

Original source: Early amcenestrant data featured at ASCO support its potential to become a new endocrine backbone therapy for ER+/HER2- breast cancer