A recent phase 2 window-of-opportunity study has provided insights into the pharmacodynamic effects of amcenestrant, a novel oral selective estrogen receptor degrader (SERD), in postmenopausal women with newly diagnosed, operable estrogen receptor-positive, HER2-negative (ER+/HER2-) breast cancer. The AMEERA-4 trial, published in Breast Cancer Research in 2023, compared two doses of amcenestrant to letrozole over a 14-day preoperative treatment period.
The multicenter, international, open-label, randomized study was conducted at 32 sites across 8 countries (Belgium, France, Italy, Japan, Russia, Spain, Ukraine, and the USA). Funded by Sanofi, the trial aimed to evaluate the antiproliferative activity of amcenestrant compared to the aromatase inhibitor letrozole, as measured by changes in the cellular proliferation marker Ki67.
Enrollment began in February 2020 but was impacted by the COVID-19 pandemic, leading to slower than expected recruitment. The study was terminated early in April 2021 before full enrollment was reached. As a result, formal statistical analyses were not conducted, and only descriptive statistics are provided in the published results.
The study enrolled postmenopausal women with newly diagnosed, ER+/HER2-, localized (stage I, II, or operable stage III) primary breast cancer who were eligible for upfront breast surgery. Key inclusion criteria were an Eastern Cooperative Oncology Group performance status of 0 or 1, tumor size ≥10 mm by ultrasound, and baseline Ki67 level ≥15% as measured by immunohistochemistry in a diagnostic biopsy per local assessment. ER positivity was defined as ≥1% tumor cell staining by immunohistochemistry.
A total of 105 patients were randomized 1:1:1 to receive amcenestrant 400 mg, amcenestrant 200 mg, or letrozole 2.5 mg once daily for 14 days prior to planned breast surgery. The primary endpoint was change in Ki67 between baseline and day 15 (day of surgery). Key secondary endpoints included the proportion of patients with ≥50% relative decrease in Ki67, absolute change in estrogen receptor (ER) H-score, and safety/tolerability.
Baseline characteristics were well-balanced between the three treatment arms. The median age was 62 years, and the majority of patients were white. Most had stage I or II disease, and all patients had luminal B breast cancer by local assessment (defined as ER+, progesterone receptor [PgR] ±, and Ki67 ≥15%). The median baseline Ki67 was 25% or lower across the treatment groups.
The modified intent-to-treat population, which included patients with both baseline and post-treatment centrally assessed Ki67 values, comprised 95 patients (31 in the amcenestrant 400 mg arm, 35 in the 200 mg arm, and 29 in the letrozole arm). In this population, all three treatments demonstrated substantial antiproliferative activity.
The geometric least squares mean (LSM) estimates for relative change from baseline in Ki67 were -75.9% (95% CI -81.9 to -67.9) for amcenestrant 400 mg, -68.2% (95% CI -75.7 to -58.4) for amcenestrant 200 mg, and -77.7% (95% CI -83.4 to -70.0) for letrozole. The proportion of patients achieving ≥50% reduction in Ki67 was 74.2% (95% CI 55.4-88.1) in the amcenestrant 400 mg arm, 68.6% (95% CI 50.7-83.1) in the 200 mg arm, and 89.7% (95% CI 72.6-97.8) in the letrozole arm.
Importantly, amcenestrant demonstrated potent ER target engagement and degradation, as evidenced by marked reductions in ER H-scores. The LSM estimate of absolute change in ER H-score from baseline was -176.7 (95% CI -201.4 to -152.0) for amcenestrant 400 mg and -202.9 (95% CI -226.1 to -179.7) for amcenestrant 200 mg. In contrast, letrozole was associated with only minor reductions in ER H-score (LSM -32.5, 95% CI -57.2 to -7.7), consistent with its different mechanism of action.
Both doses of amcenestrant were well-tolerated over the 14-day treatment period. In the safety population (n=104), 48.5% of patients in the 400 mg arm, 44.4% in the 200 mg arm, and 51.4% in the letrozole arm experienced at least one treatment-emergent adverse event (TEAE) of any grade. The majority of TEAEs were mild to moderate in severity. Only two patients, both in the amcenestrant 200 mg arm, experienced grade ≥3 TEAEs (one case each of pneumonia and wound infection), which were considered serious but unrelated to study treatment.
Treatment-related adverse events (TRAEs) occurred in 21.2%, 22.2%, and 25.7% of patients in the amcenestrant 400 mg, 200 mg, and letrozole arms, respectively. The most common TRAEs (reported in ≥5% of patients in any arm) were hot flush, headache, feeling cold, arthralgia, asthenia, and diarrhea. No serious TRAEs or TRAEs of grade ≥3 severity were reported. There were no treatment discontinuations due to adverse events and no deaths during the study.
The study had several limitations, most notably the early termination and resulting lack of formal statistical analyses. As a window-of-opportunity study, it was not designed to draw definitive conclusions about clinical efficacy or long-term safety. Additionally, the study was conducted only in postmenopausal women with luminal B-type breast cancer, limiting generalizability to other populations.
Despite these limitations, the authors concluded that amcenestrant demonstrated favorable pharmacodynamic effects and tolerability at clinically viable doses in this patient population. Both amcenestrant and letrozole showed substantial antiproliferative activity as measured by Ki67 reduction. The potent ER degradation observed with amcenestrant supports its mechanism of action as a SERD.
However, the study did not demonstrate a clear advantage of amcenestrant over letrozole in terms of Ki67 suppression. This finding aligns with interim data from the phase 3 AMEERA-5 trial comparing amcenestrant versus letrozole (both in combination with palbociclib) as first-line treatment for advanced/metastatic ER+/HER2- breast cancer.
The potential clinical impact of these results is limited by the subsequent discontinuation of amcenestrant's clinical development program. In August 2022, Sanofi announced the termination of the global clinical development program for amcenestrant based on the totality of clinical data, including the AMEERA-5 interim analysis.
While amcenestrant will not move forward, the AMEERA-4 results provide valuable insights into the biological effects of oral SERDs in early-stage breast cancer. The marked ER degradation and Ki67 suppression observed support further investigation of this drug class. Several other oral SERDs remain in clinical development, including elacestrant, camizestrant, giredestrant, and imlunestrant, which are now in phase 3 trials.
The study also highlights the utility of the window-of-opportunity design for evaluating pharmacodynamic effects of novel agents in breast cancer. Such studies can provide early signals of biological activity to inform larger, long-term clinical trials. The use of centralized assessment of key biomarkers like Ki67 and ER H-score enhances the reliability of these pharmacodynamic endpoints.
In conclusion, while the clinical development of amcenestrant has been discontinued, the AMEERA-4 trial provides proof-of-concept data supporting the biological activity of oral SERDs in early ER+/HER2- breast cancer. The results demonstrate that short-term preoperative treatment with these agents can induce meaningful changes in tumor biology. As the field continues to evolve, similar window-of-opportunity studies are likely to play an important role in the evaluation of emerging therapies for breast cancer.
References
Campone M, Bidard FC, Neven P, et al. AMEERA-4: a randomized, preoperative window-of-opportunity study of amcenestrant versus letrozole in early breast cancer. Breast Cancer Res. 2023;25(1):141. Published 2023 Nov 10. doi:10.1186/s13058-023-01740-2
