Trial Explores Preoperative Window for Amcenestrant Therapy in Early Breast Cancer

Investigators are seeking to determine whether amcenestrant (SAR439859), an investigational oral endocrine therapy, can generate meaningful antitumor activity when administered as short-term preoperative therapy to postmenopausal patients with newly diagnosed early breast cancer.

The phase 2 AMEERA-4 trial (NCT04191382) is testing 2 dose levels of amcenestrant versus letrozole given for 14 days to patients with estrogen receptor (ER)-positive, HER2-negative localized breast cancer who are candidates for breast conserving therapy or upfront mastectomy.¹

The study will measure the impact of the short course of endocrine therapy on Ki-67, a protein biomarker of cellular proliferation that has been shown to be a prognostic indicator of survival and recurrence in patients with early breast cancer, with higher levels associated with worse outcomes.²

Ki-67 expression has been correlated with poor cancer-specific survival at a cutoff point greater than 14% of tumor nuceli.³ AMEERA-4 is a “window of opportunity study,” a validated strategy for rapid exploration of proof-of concept treatment approaches, investigators said in a poster presentation at the 2020 American Society of Clinical Oncology Virtual Scientific Program.⁴

The trial’s goals include determining the best dosage for further study of amcenestrant in this clinical setting, said principal investigator Mario Campone, MD, a medical oncologist at the Institut de Cancérologie de l’Ouest, René Gauducheau, in St Herblain, France.

“Some clinical trials have demonstrated that when you have a decrease in Ki-67 after 2 weeks you have a better outcome compared with the patients who do not have a decrease in this surrogate marker,” he said in an interview with OncologyLive®.

Amcenestrant is a selective ER degrader (SERD), a class of drugs that works by serving as a competitive antagonist to the ER, inducing conformational changes that lead to degradation of the receptors. In preclinical studies, the agent has demonstrated antitumor efficacy and regression in ER-positive breast cancer models.5 Further, amcenestrant can be administered as an oral therapy because of its favorable pharmacokinetic profile, as opposed to fulvestrant (Faslodex), a SERD that must be given via intramuscular injection because of pharmacokinetic limitations.^5,6

AMEERA-4 Study Details

AMEERA-4, an international, open-label study, was initiated in December 2019 and is being conducted at 16 active sites with 34 planned sites, Campone said.

Participants are being randomized 1:1:1 to receive daily amcenestrant at 400 mg, daily amcenestrant at 200 mg, or daily letrozole at 2.5 mg for 14 days, with the last dose administered on the day before surgery. Biopsies are performed at baseline and during surgery (FIGURE).^1,4

The primary end point is a change in Ki-67 expression measured by immunohistochemistry after a 14-day treatment period compared with baseline levels. Secondary end points include the proportion of patients with relative decrease from baseline in Ki-67 expression of 50% or more, change in ER expression compared with baseline, and safety and tolerability.

Efficacy will be assessed via pathological complete response (pCR), which is defined as no histologic evidence of invasive tumor cells in the surgical breast specimen and axillary nodes after treatment. ECOG performance status response will be measured after the 14-day treatment based on breast tumor shrinkage and pCR. Additionally, a preoperative endocrine prognostic index derived from pathologic tumor and node stages, Ki-67 levels, and ER status of the surgical specimen will be assessed after the 14-day treatment period.

Investigators are seeking to recruit 126 patients for the study. So far, 14 patients have been enrolled, and the study could be completed sometime this year, with data analysis projected for 2022, Campone said.

After completion of the AMEERA-4 study, Sanofi, the agent’s developer, plans to initiate a pivotal clinical trial to study amcenestrant in early breast cancer.7 AMEERA-6 will be a registrational study with invasive disease-free survival as the primary end point. This study will be supported in part by data generated from AMEERA-4, which is expected in to be available in 2021, according to a Sanofi spokesperson. AMEERA-6 is expected to begin recruiting patients by the end of 2021.

Early Signs of Efficacy

The use of amcenestrant as monotherapy has shown encouraging signals in the ongoing phase 1/2 AMEERA-1 trial (NCT03284957). In interim results reported at the 2020 San Antonio Breast Cancer Symposium, amcenestrant monotherapy elicited antitumor activity in heavily pretreated, postmenopausal women with advanced or metastatic ER-positive breast cancer.⁸

Results showed that the objective response rate (ORR) was 8.5% with amcenestrant with a clinical benefit rate (CBR) of 33.9% among pooled results from 59 patients who received amcenestrant at 150 mg or more daily. In a cohort of 33 patients who had received 3 or fewer prior lines of therapy in the metastatic setting, the ORR was 15.2% and the CBR was 42.4%. Moreover, in a subgroup of 14 patients who did not receive prior CDK4/6 inhibitors, mTOR inhibitors, or fulvestrant, the ORR was 21.4% and the CBR was 64.3%.⁸

In AMEERA-1, which is a first-in-human study, investigators are evaluating the safety and efficacy of amcenestrant as a single agent and in combination with targeted therapies in patients with ER-positive, HER2-negative metastatic breast cancer. In part A of the trial, which was the dose-escalation phase, investigators evaluated amcenestrant at oncedaily doses ranging from 20 mg to 600 mg. In part B, which was the dose-expansion phase, the recommended dose for amcenestrant as monotherapy was determined to be 400 mg once daily.

Amcenestrant was found to have a favorable safety profile with 62.9% of patients experiencing treatment-related adverse events (TRAEs), none of which were grade 3 or higher. The most common (≥5%) TRAEs in the pooled population of patients who were treated with amcenestrant at the 150-mg or higher daily dose included hot f lush (16.1%), constipation (9.7%), arthralgia (9.7%), decreased appetite (8.1%), vomiting (8.1%), diarrhea (8.1%), nausea (8.1%), and fatigue (6.5%).⁸

Pivotal results are expected in the f irst half of 2021, according to Sanofi. Amcenestrant as a monotherapy may be available as a second- and third-line treatment for patients with metastatic breast cancer in 2022, the company said.⁷

Large Trials in Progress

Amcenestrant monotherapy is also being evaluated versus physician’s choice of therapy in the open label, phase 2 trial AMEERA-3 trial (NCT04059484), which will enroll 372 patients. 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. The primary end point is progression-free survival (PFS). Secondary end points include OS, ORR, disease control rate, CBR, and duration of response (DOR).⁹

Another study, AMEERA-5 (NCT04478266), is testing amcenestrant in combination with palbociclib (Ibrance), a CDK4/6 inhibitor, versus letrozole plus palbociclib as a first-line therapy for patients with ER-positive, HER2negative locoregional or metastatic breast cancer. The study has a primary end point of PFS and secondary end points of OS, ORR, DOR, and CBR.¹⁰

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.

The study, known as the I-SPY 2 Endocrine Optimization Protocol (EOP), is focused on patients with molecularly low-risk, clinically high-risk, hormone receptor–positive, HER2negative clinical stage II or III invasive breast cancer. Amcenestrant will be tested as a monotherapy and in combination with up to 3 other agents.¹¹

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.

References

1. Phase 2 window study of SAR439859 versus letrozole in ER+, HER2- pre-operative post-menopausal primary breast cancer (AMEERA-4). ClinicalTrials.gov. Updated December 8, 2020. Accessed December 21, 2020. https://clinicaltrials.gov/ct2/show/NCT04191382
2. Soliman NA, Yussif SM. Ki-67 as a prognostic market according to breast cancer molecular subtype. Cancer Biol Med. 2016;13(4):496-504. doi:10.20892/j.issn.2095-3941.2016.0066
3. Gallardo A, Garcia-Valdecasas B, Murata P, et al. Inverse relationship between Ki67 and survival in early luminal breast cancer: confirmation in a multivariate analysis. Breast Cancer Res Treat. 2018;167(1):31-37. doi:10.1007/s10549-017-4486-z
4. 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). Abstract TPS1108. doi:10.1200/JCO.2020.38.15_suppl.TPS1108
5. 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
6. 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
7. Oncology strategy and ASCO R&D event. June 2, 2020. Sanofi. Accessed December 21, 2020. https://bit.ly/38sVsvc
8. Linden HM, Campone M, Bardia A, et al. A phase 1/2 study of SAR439859, an oral selective estrogen receptor (ER) degrader (SERD), as monotherapy and in combination with other anti-cancer therapies in postmenopausal women with ER-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (mBC): AMEERA-1. Poster presented at: 2020 San Antonio Breast Cancer Symposium; December 8-11, 2020; virtual. Abstract PD8-08. https://www.abstractsonline.com/pp8/#!/9223/presentation/848
9. Phase 2 study of SAR439859 versus physician’s choice in locally advanced or metastatic ER-positive breast cancer (AMEERA-3). ClinicalTrials.gov. Updated December 8, 2020. Accessed December 21, 2020. https://clinicaltrials.gov/ct2/show/NCT04059484
10. SAR439859 plus palbociclib as first line therapy for patients with ER(+) HER(-) advanced breast cancer (AMEERA-5). ClinicalTrials.gov. Updated December 10, 2020. Accessed December 21, 2020. https://clinicaltrials.gov/ct2/show/NCT04478266
11. 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 Healthcare Collaborative. June 8, 2020. Accessed December 21, 2020. https://prn.to/2J2YXjf