Phase 1 study of oral selective estrogen receptor degrader (SERD) amcenestrant (SAR439859), in Japanese women with ER-positive and HER2-negative advanced breast cancer (AMEERA-2)

by Selleckchem | Sep 16 2023

Background: This AMEERA-2 study evaluated the pharmacokinetics, efficacy, and safety of the oral selective estrogen receptor degrader amcenestrant as a monotherapy with dose escalation in Japanese postmenopausal women with advanced estrogen receptor-positive and human epidermal growth factor receptor 2-negative breast cancer.

Methods: In this open-label, nonrandomized, phase I study, patients received amcenestrant 400 mg once daily (QD) (n = 7) and 300 mg twice daily (BID) (n = 3). The incidence of dose-limiting toxicities (DLT), recommended dose, maximum tolerated dose (MTD), pharmacokinetics, efficacy, and safety were assessed.

Results: No DLTs were observed and MTD was not reached in the 400 mg QD group. One DLT (grade 3 maculopapular rash) was reported in a patient treated with 300 mg BID. After repeated oral administration of either dosing regimen, steady state reached before day 8, without accumulation. Four out of 5 response-evaluable patients from 400 mg QD group achieved clinical benefit and showed tumor shrinkage. No clinical benefit was reported in the 300 mg BID group. Overall, most patients (8/10) experienced a treatment-related adverse event (TRAE), with skin and subcutaneous tissue disorders most commonly reported (4/10 patients). No ≥ grade 3 TRAE in 400 mg QD group and 1 grade 3 TRAE in 300 mg BID group were reported.

Conclusions: Amcenestrant 400 mg QD has a favorable safety profile and has been selected as the recommended Phase II dose for monotherapy for evaluating the safety and efficacy of amcenestrant in a larger, global, randomized clinical trial of patients with metastatic breast cancer.

Comments:

The AMEERA-2 study was conducted to evaluate the pharmacokinetics, efficacy, and safety of the oral selective estrogen receptor degrader amcenestrant as a monotherapy in Japanese postmenopausal women with advanced estrogen receptor-positive and human epidermal growth factor receptor 2-negative breast cancer.

The study was an open-label, nonrandomized, phase I trial. The patients were divided into two groups: one group received amcenestrant 400 mg once daily (QD) and the other group received amcenestrant 300 mg twice daily (BID). The primary objectives were to determine the recommended dose, maximum tolerated dose (MTD), and dose-limiting toxicities (DLT) of amcenestrant. Secondary objectives included assessing the pharmacokinetics, efficacy, and safety of the drug.

The results showed that no dose-limiting toxicities were observed in the group receiving amcenestrant 400 mg QD, and the MTD was not reached in this group. However, one patient in the 300 mg BID group experienced a dose-limiting toxicity of grade 3 maculopapular rash. Steady-state plasma concentrations were achieved before day 8, and there was no drug accumulation with repeated oral administration.

Among the patients evaluated for response, four out of five patients in the 400 mg QD group achieved clinical benefit and showed tumor shrinkage. In contrast, no clinical benefit was reported in the 300 mg BID group. Most patients (8 out of 10) experienced treatment-related adverse events (TRAEs), with skin and subcutaneous tissue disorders being the most commonly reported. No grade 3 or higher TRAEs were reported in the 400 mg QD group, while one grade 3 TRAE was reported in the 300 mg BID group.

Based on these findings, amcenestrant 400 mg QD was determined to have a favorable safety profile and was selected as the recommended dose for Phase II monotherapy. This dose will be further evaluated for safety and efficacy in a larger, global, randomized clinical trial involving patients with metastatic breast cancer.