AMEERA-5: a randomized, double-blind phase 3 study of amcenestrant plus palbociclib versus letrozole plus palbociclib for previously untreated ER+/HER2– advanced breast cancer

Abstract

Background: For estrogen receptor–positive (ER+)/human epidermal growth factor receptor 2–negative (HER2–) advanced breast cancer (ABC), the current standard first-line treatment includes an aromatase inhibitor in combination with a cyclin-dependent kinase 4/6 inhibitor. When resistance occurs, often related to the occurrence of ESR1 mutations, selective estrogen receptor modulators or degraders (SERDs) may be used, alone or in combination regimens. Amcenestrant (SAR439859), an optimized oral SERD, has shown clinical antitumor activity in combination with palbociclib in patients with ER+/HER2– ABC and, as monotherapy, in patients with and without ESR1 mutations. Here, we describe the study design of AMEERA-5, an ongoing, prospective, phase 3, randomized, double-blind, multinational study comparing the efficacy and safety of amcenestrant plus palbociclib versus letrozole plus palbociclib in patients with advanced (locoregional recurrent or metastatic) ER+/HER2– breast cancer. Methods: Patients are pre-/postmenopausal women and men with no prior systemic therapy for ABC. The planned enrollment is 1066 patients. Patients are randomized 1:1 to either amcenestrant 200 mg plus palbociclib 125 mg or letrozole 2.5 mg plus palbociclib 125 mg. Amcenestrant, letrozole, and their matching placebos are taken once daily continuously; palbociclib is taken once daily for 21 days, followed by 7 days off-treatment for a 28-day cycle. Treatment continues until disease progression, unacceptable toxicity, or decision to stop treatment. Pre-/perimenopausal women and men receive goserelin subcutaneously. Randomization is stratified by de novo metastatic disease, menopausal status, and visceral metastases. The primary endpoint is progression-free survival. The key secondary endpoint is overall survival; others are safety, pharmacokinetics, and quality of life. Conclusions: AMEERA-5 is evaluating the efficacy and safety of amcenestrant in combination with palbociclib as first-line therapy in pre-/postmenopausal women and men with ER+/HER2– ABC. ClinicalTrials Identifier: NCT04478266.

The race to develop oral SERDs and other novel estrogen receptor inhibitors: recent clinical trial results and impact on treatment options

“…For tumors that harbor PI3K mutations, oral SERDs are being investigated together with alpelicib as with the oral SERDs such as LSZ 102 [83]. For tumors that are hormonal therapy naïve or first-line therapy, oral SERDs plus CDK4/6 inhibitors are being compared with AIs plus CDK4/6 inhibitors as in AMEERA-5 [87] (amcenestrant), SERENA 4 [88](camizestrant), or with physicians' choice plus CDK4/6 inhibitors as in acelERA Breast Cancer [78] (giredestrant) and in tumors with ESR1 mutation, as in SERENA 6 [89] (camizestrant). In the neoadjuvant setting, oral SERDs are being explored in locally advanced HR + /HER2 − stage III breast cancer against AIs alone as in AMEERA-4 [90] (amcenestrant) or in combination with CDK4/6 inhibitors as in coopERA BC study [80] (giredestrant).…”

Efficacy of the induced pluripotent stem cell derived and engineered CD276-targeted CAR-NK cells against human esophageal squamous cell carcinoma

“…It is important to recognize that the success of investigational products in traditional preclinical models such as cancer cell lines in vitro and in vivo mouse xenograft models does not guarantee success in clinical trials as they often prove invalid ( 47 , 48 ). Conversely, an investigational product that fails to exhibit significant efficacy in traditional preclinical models may still be clinically effective, especially if corresponding patient-derived organoid (PDO) models demonstrate efficacy.…”

Targeting Breast Cancer: An Overlook on Current Strategies

“…It was obtained by a structural modification of raloxifene, with the introduction of an acrylic acid side chain [ 79 ] and is currently under clinical development for the treatment of patients with HR + breast cancer [ 80 , 81 , 82 ]. Amcenestrant (SAR439859) is a nonsteroidal, orally bioavailable, SERD studied in clinical trials (AMEERA) in postmenopausal women with HR + /HER2 − advanced breast cancer [ 83 ] and in association with CDK4/6 inhibitors, such as palbociclib for previously untreated ER + /HER2 − advanced breast cancer [ 84 ]. AZD9833 (camizestrant) is an oral tricyclic indazole that has demonstrated high potency in preclinical cancer models as SERD and pure ER antagonist [ 85 ].…”