Amcenestrant Misses PFS End Point in ER+/HER2– Advanced or Metastatic Breast Cancer

The oral selective estrogen receptor degrader (SERD) amcenestrant (SAR439859) did not improve progression-free survival (PFS) per independent central review vs physician’s choice of endocrine treatment in patients with locally advanced or metastatic, estrogen receptor (ER)–positive, HER2-negative breast cancer who progressed on or following hormonal therapies, missing the primary end point of the phase 2 AMEERA-3 trial (NCT04059484).¹

Notably, the toxicity profile of the agent proved to be consistent with what has been observed in prior studies, with no new safety signals reported.

“This phase 2 trial evaluated amcenestrant as a monotherapy in a patient population with advanced disease where limited treatment options remain,” John Reed, MD, PhD, head of research and development at Sanofi, stated in a press release. “While we are disappointed with the AMEERA-3 results, we continue to investigative amcenestrant in patients with earlier stages of breast cancer with different tumor profiles and where different standard-of-care treatments are used.”

The international, prospective, open-label, randomized trial was launched to evaluate the safety and efficacy of the SERD in patients with ER-positive, HER2-negative metastatic or locally advanced breast cancer that was progressing on 6 or more months of continuous endocrine therapy.^2,3 Patients had to be at least 18 years of age and could not have received more than 1 prior chemotherapeutic or targeted regimen for advanced or metastatic disease. Notably, previous treatment with CDK inhibitors was permitted.

If patients had an ECOG performance status of 2 or higher, a life expectancy of less than 3 months, had concomitant illness and factors potentially impacting the absorption of amcenestrant, they were excluded.

The target enrollment for the trial was 282 patients. Participants were randomized 1:1 to receive either the SERD orally at a once-daily dose of 400 mg or physician’s choice of endocrine therapy, which could have included single-agent treatment with fulvestrant (Faslodex), tamoxifen, or an aromatase inhibitor (AI). Treatment was administered in 28-day cycles until intolerable toxicity, disease progression, death, or patient request.

Patients were stratified based on the presence of visceral metastases, whether they previously received CDK4/6 inhibitors, and their ECOG performance status.

The primary end point of the trial was PFS per RECIST v1.1 criteria, and key secondary end points included overall survival, response rate, duration of response, clinical benefit rate, pharmacokinetics, quality of life, and safety.

Sanofi, the drug developer, shared plans to continue to evaluate data from AMEERA-3 and publish the full results in the future.

Previously, amcenestrant was evaluated both as a single agent and in combination with targeted therapies in patients with ER-positive, HER2-negative metastatic breast cancer, as part of the phase 1/2 AMEERA-1 trial (NCT03284957).⁴ The trial enrolled postmenopausal patients with ER-positive, HER2-negative locally advanced or metastatic breast cancer with measurable disease and who received at least 6 months of previous endocrine therapy in the advanced setting or who had resistance to adjuvant endocrine therapy.

Patients could not receive more than 1 prior line of chemotherapy for advanced disease, nor could they have received more than 2 prior lines of endocrine therapy for advanced disease in part D. Patients also could not have received more than 1 prior CDK4/6 inhibitor for advanced disease in part C. Those in part D were not allowed to receive any CDK4/6 inhibitors, PI3K inhibitors, or AKT inhibitors. Patients needed to have an ECOG performance status that was less than 2.

At the 2021 ASCO Annual Meeting data from parts C and D of the trial were reported. In part C, the dose-escalation cohort was comprised of 15 patients who received amcenestrant at a once-daily dose of 200 mg (n = 9) or 400 mg (n = 6) in 28-day cycles. In part D, the dose-expansion cohort was comprised of 30 patients who received the agent at the recommended phase 2 dose (RP2D) established in part C, but in combination with a standard dose of palbociclib (Ibrance), which was 125 mg for 21 days on, and 7 days off.

Among the 39 patients who comprised parts C and D, the median age was 59 years (range, 33-86), 74.4% had an ECOG performance status of 0, 84.6% had secondary resistance to endocrine therapy, and 59.0% received immediate prior therapy for advanced disease.

Moreover, 41.0% did not receive any prior lines of therapy in advanced settings, although 38.5% received 1 prior line. Moreover, 43.6% and 41.0% of patients, respectively, received 0 or 1 prior lines of endocrine therapy in advanced settings. Regarding prior treatment received in advanced settings, 23.1% previously received chemotherapy, 59.0% received endocrine therapy, and 15.4% received targeted therapy.

Data showed that in response-evaluable patients who received amcenestrant at the RP2D and who did not previously receive CDK4/6 inhibitors or mTOR inhibitors, the objective response rate was 34.3% (95% CI, 21.1%-49.6%), which included a partial response rate of 34.3%. Moreover, 62.9% of patients achieved stable disease and 2.9% experienced disease progression. The clinical benefit rate in these patients was 74.3% (95% CI, 59.4%-85.9%).

Regarding safety, no dose-limiting toxicities were reported, and no dose reductions of the SERD were required. However, 25.6% of patients required at least 1 dose reduction of palbociclib to 100 mg, and 4 of these patients needed a subsequent reduction to 75 mg.

A total of 3 patients discontinued treatment because of toxicity, 2 of which were determined to be associated with study treatment. Amcenestrant and palbociclib treatment-related adverse effects were experienced by 71.8% and 89.7% of patients, respectively; these effects were grade 3 or higher in 15.4% and 46.2% of patients, respectively. One patient had a grade 3 serious toxicity of deep vein thrombosis that was found to be related to the SERD.

Amcenestrant is currently under evaluation in the phase 3 AMEERA-5 trial (NCT04478266), which was designed to determine whether the addition of amcenestrant to palbociclib would improve PFS vs letrozole plus palbociclib in patients with ER-positive, HER2-negative advanced breast cancer who have not previously received systemic therapy for advanced disease.

Additionally, the phase 3 AMEERA-6 trial (NCT05128773), is evaluating the safety and efficacy of amcenestrant vs tamoxifen in patients with hormone receptor–positive early breast cancer who discontinued an adjuvant AI because of treatment-related toxicity.

References

1. Sanofi provides update on phase 2 study evaluating amcenestrant in ER+/HER2- advanced or metastatic breast cancer. News release. Sanofi; March 14, 2022. Accessed March 14, 2022. https://bit.ly/3IfWb2O
2. Phase 2 study of amcenestrant (SAR439859) versus physician’s choice of locally advanced or metastatic ER-positive breast cancer (AMEERA-3). ClinicalTrials.gov. Updated March 7, 2022. Accessed March 14, 2022. https://clinicaltrials.gov/ct2/show/NCT04059484
3. Tolaney S, Cicin I, Betancourt R, et al. AMEERA-3, a phase 2 trial of SAR439859 vs endocrine monotherapy in pre- and post-menopausal, estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (her2-), locally advanced or metastatic breast cancer (BC) with prior exposure to hormonal therapies. Cancer Res. 2021;81(suppl 4):OT-09-09. doi:10.1158/1538-7445.SABCS20-OT-09-09
4. Chandarlapaty S, Linden HM, Neven P, et al. AMEERA-1: phase 1/2 study of amcenestrant (SAR439859), an oral selective estrogen receptor (ER) degrader (SERD), with palbociclib (palbo) in postmenopausal women with ER+/human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (mBC). J Clin Oncol. 2021;39(suppl 15):1058. doi:10.1200/JCO.2021.39.15_suppl.1058