Next-Generation Endocrine Therapy Moves Forward in Breast Cancer Trial

Sara M. Tolaney, MD, MPH

Amcenestrant (SAR439859), a new oral form of endocrine therapy that has shown early signs of efficacy, is being evaluated against the current standards of care in patients with estrogen receptor (ER)– positive, HER2-negative locally advanced or metastatic breast cancer.

The agent, a selective estrogen receptor degrader (SERD), is being compared with physician’s choice of endocrine therapy in the open label, phase 2 trial AMEERA-3 trial (NCT04059484). The control treatment involves choosing monotherapy from a list of agents with different mechanisms of action: anastrozole, letrozole, or exemestane, which are aromatase inhibitors; tamoxifen, a selective estrogen receptor modulator; or fulvestrant (Faslodex), a SERD (Figure).¹

Figure. SAR439859 in Locally Advanced or Metastatic Breast Cancer

Amcenestrant is a next-generation SERD that, in preclinical studies, has demonstrated antitumor efficacy and regression in ER-positive breast cancer models and can be administered as an oral therapy because of its favorable pharmacokinetic profile.² Fulvestrant, which has been available since 2002, must be administered via intramuscular injection because of limitations including low solubility and weak permeation.³

“It’s exciting to have a potential SERD that is oral and has potentially better bioavailability than fulvestrant. So many of us wondered whether these [novel] agents could substitute for fulvestrant in the future and potentially be a better option,” said Sara M. Tolaney, MD, MPH, principal investigator for the AMEERA-3 trial, in an interview with OncLive^®.

SERDs work by serving as competitive antagonists to the ER, inducing conformational changes that lead to degradation of the receptors. “They have dual functions. I think this accounts for their ability to block the signaling in ER-dependent tumors that may be potentially resistant to other endocrine therapies,” said Tolaney, who is associate director of the Susan F. Smith Center for Women’s Cancers and director of Clinical Trials in Breast Oncology at Dana-Farber Cancer Institute in Boston, Massachusetts.

“Amcenestrant has shown activity in patients regardless of ESR1 mutation status, which makes it very intriguing,” added Tolaney, who also is an associate professor of medicine at Harvard Medical School in Boston. “It is blocking the estradiol and binding to the estrogen receptor, which promotes inactivation and degradation. It’s thought to do so more potently than fulvestrant does.”

AMEERA-3 Study Details

The goal of AMEERA-3 is to demonstrate that amcenestrant is superior to the endocrine therapy of physician’s choice in patients who are refractory to endocrine therapy and have metastatic hormone receptor (HR)–positive breast cancer, Tolaney said. The primary end point is progression-free survival (PFS). Secondary end points include overall survival (OS), objective response rate (ORR), disease control rate, clinical benefit rate (CBR), and duration of response (DOR).

Tolaney said the trial design takes into account the options available to patients with HR-driven breast cancer. “In the first-line setting for metastatic hormonal receptor–positive disease, patients get a different endocrine backbone. Some patients are getting an aromatase inhibitor with CDK4/6 inhibition; some are getting fulvestrant with CDK4/6 inhibition. This trial allows for the flexibility for the physician to choose what is most appropriate for the patient based on their prior exposure to endocrine treatment,” Tolaney said.

Amcenestrant is being administered at 400 mg daily in 28-day cycles until unacceptable toxicity, progression, death, investigator decision, or patient request.³ The comparators are being given based on approved labeling.⁴

In terms of eligibility requirements, the trial limits participants to 1 prior targeted therapy with a CDK4/6 inhibitor or 1 prior treatment with chemotherapy for advanced or metastatic disease. The criteria also require patients outside of China to receive a prior CDK4/6 inhibitor if they can get reimbursed for it; the number of participants without previous CDK4/6 inhibitor therapy will be capped at 20%. “It has become standard of care to use CDK4/6 inhibitors with endocrine treatment in the first-line setting for metastatic, hormone receptor–positive disease,” Tolaney noted.

Additionally, eligible patients are required to have progressed after 6 or more months of continuous endocrine therapy for advanced disease or to have relapsed while on adjuvant endocrine treatment for 2 or more years or within 12 months of receiving that therapy. Patients with brain metastases are excluded, as well those who previously received an mTOR inhibitor or a SERD other than fulvestrant, which must be stopped at least 3 months before randomization.

The trial seeks to enroll 282 patients through 126 worldwide locations. An extension is planned with an additional 90 Chinese participants expected to be enrolled. Tolaney said the trial is more than halfway accrued. “It was a little delayed because of COVID [coronavirus disease 2019], but it has been doing well otherwise,” she said. She anticipates enrollment will be completed early in 2021.

Early Clinical Efficacy

The rationale for AMEERA-3 stems from findings from an ongoing first-in human phase 1/2 study (NCT03284957) testing amcenestrant as monotherapy and in combination with other agents in postmenopausal women with ER-positive, HER2-negative metastatic breast cancer.

Investigators presented results for patients who received amcenestrant monotherapy in 2 cohorts of the study at the 2020 American Society of Clinical Oncology Virtual Scientific Program. The pooled data included women who received from 150 mg to 600 mg daily in part A of the study and those who took 400 mg daily in part B of the study. The primary end point in part B was ORR, documented by RECIST v1.1 criteria; secondary end points included overall safety profile; ORR based on ESR1 status (mutated or wild type); and CBR defined as complete and partial responses plus stable disease for 24 weeks or more.⁵

All patients in the study (N = 62) had received prior endocrine therapy in the advanced setting; 48.4% had 3 or more previous lines of therapy. Among 59 evaluable patients, the ORR was 6.8% (90% CI, 2.3%-14.8%), all partial responses. The CBR was 35.6% (90% CI, 25.1%-47.1%), which study investigators said was similar to that of fulvestrant in less heavily pretreated patients. Patients with wild-type ESR1 (n = 30) had better responses than those with mutant ESR1 (n = 28) for ORR (10.0% vs 3.6%, respectively) and CBR (40.0% vs 32.1%).

In a subset of women without prior treatment with a SERD, CDK4/6 inhibitor, or mTOR inhibitor (n = 14), the antitumor activity of amcenestrant was substantially greater and compared favorably with historical results for fulvestrant. The ORR was 21.4% (90% CI, 6.1%-46.6%) and the CBR was 64.3% (90% CI, 39.0%-84.7%).

Amcenestrant had a favorable safety profile with limited treatment-related adverse effects (TRAEs); 61.3% of women in the study had adverse effects, and all were grade 1 or 2, most commonly hot flush (16.1%); constipation (9.7%); and arthralgia (9.7); decreased appetite, vomiting, diarrhea, nausea and decreased appetite (all 8.1%); and fatigue (6.5%). No patients discontinued because of TRAEs.

Future Directions

Amcenestrant has the potential to become the “best-in-class endocrine backbone across treatment lines in HR-positive breast cancer,” according to Paul Hudson, chief executive officer of Sanofi, the company developing the drug.⁶

Amcenestrant also is being evaluated in comparison with letrozole in an ongoing phase 2 “window of opportunity” study (NCT04191382) in newly diagnosed ER-positive, HER2-negative breast cancer.⁷ In this study, patients are being randomized to receive amcenestrant at 400 mg or 200 mg daily, or to receive letrozole at 2.5 mg daily for 14 days prior to surgery. Biopsies will be taken before and after therapy to assess tumor biomarkers.

The primary end point is a change in Ki-67 after a 14-treatment period compared with baselines levels via immunohistochemistry assessment in tumor tissue. Secondary end points include the proportion of patients with relative decrease from baseline in Ki-67 of 50% or more, change in ER expression compared with baseline, and safety and tolerability. Ki-67 is a biomarker of cellular proliferation, and expression of Ki-67 in 14% or more of tumor nuclei is associated with poor prognosis in early breast cancer, investigators noted. This study began enrolling patients in December 2019 and is being conducted at 16 sites worldwide.⁷

Another study, AMEERA-5 (NCT04478266)⁸, is testing amcenestrant in combination with palbociclib (Ibrance), a CDK4/6 inhibitor, versus letrozole plus palbociclib as a firstline therapy for patients with ER- positive, HER2-negative breast cancer. The study, which aims to recruit 810 patients, has a primary end point of PFS and secondary end points of OS, ORR, DOR, and CBR.

Additionally, the Quantum Leap Healthcare Collaborative announced in June 2020 that amcenestrant was selected to be part of a new I-SPY 2 study arm.⁷ The study, known as the I-SPY 2 Endocrine Optimization Protocol (EOP), is focused on patients with molecularly low-risk, clinically high-risk, HR-positive, HER2-negative clinical stage II or III invasive breast cancer. Amcenestrant will be tested as a monotherapy and in combination with up to 3 other agents.

The I-SPY program was designed to identify therapies that are most effective in specific patient subgroups based on biomarker signatures. Sanofi is supplying the drug and providing financial support.⁹

References

1. Phase 2 study of SAR439859 versus physician's choice in locally advanced or metastatic ER-positive breast cancer (AMEERA-3). ClinicalTrials.gov. Updated October 28, 2020. Accessed November 2, 2020. https://clinicaltrials.gov/ct2/show/NCT04059484
2. Fangxian S, Cheng J, Sullivan A, et al. Pre-clinical development of next generation selective estrogen receptor degrader - SAR439859. Cancer Res. 2020;80(suppl 16):3452. doi:10.1158/1538-7445.AM2020-3452
3. El-Ahmad Y, Tabart M, Halley F, et al. Discovery of 6(2,4-dichlorophenyl)-5-[4-[(3 S)1-(3- fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro7 Hbenzo[7]annulene-2-carboxylic acid (SAR439859), a potent and selective estrogen receptor degrader (SERD) for the treatment of estrogen-receptor-positive breast cancer. J Med Chem. 2020;63(2):512-528. 10.1021/acs.jmedchem.9b01293
4. Tolaney SM, Cicin I, Betancourt R, et al. Phase II 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. J Clin Oncol. 2020;38(suppl 15):TPS1107. doi:10.1200/JCO.2020.38.15_suppl.TPS1107
5. Campone M, Bardia A, Ulaner GA, et al. Phase I/II study of SAR439859, an oral selective estrogen receptor degrader (SERD), in estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (mBC). J Clin Oncol. 2020;38(suppl 15):1070. doi:10.1200/JCO.2020.38.15_suppl.1070
6. Sanofi. Oncology strategy and ASCO R&D event. June 2, 2020. Accessed October 30, 2020. https://bit.ly/3eiIL8T 
7. Campone M, Herold CI, Wang Q, Pelekanou V, Cartot-Cotton S, Ling B; ACT16106 Study Investigators. Phase II preoperative window study of SAR439859 versus letrozole in post-menopausal women with newly diagnosed estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) breast cancer. J Clin Oncol. 2020;38(suppl 15):TPS1108. doi:10.1200/JCO.2020.38.15_suppl.TPS1108
8. SAR439859 plus palbociclib as first line therapy for patients with ER(+) HER(-) advanced breast cancer (AMEERA-5). ClinicalTrials.gov. Updated October 27, 2020. Accessed November 2, 2020. https://clinicaltrials.gov/ct2/show/NCT04478266
9. Quantum Leap Healthcare Collaborative announces the selection of Sanofi’s SAR439859 as the oral SERD backbone agent in the Endocrine Optimization Pilot Study of the I-SPY 2 trial for clinically high risk, molecularly low risk stage 2/3 breast cancer. News release. Quantum Leap Health Collaborative. June 8, 2020. Accessed October 23, 2020. https://prn.to/2J2YXjf