Amcenestrant Demonstrates Intriguing Activity in Postmenopausal Advanced ER+ Breast Cancer

Amcenestrant (SAR439859) elicited antitumor activity in heavily pretreated, postmenopausal women with advanced or metastatic estrogen receptor (ER)–positive breast cancer, according to phase 1/2 results of the AMEERA-1 trial (NCT03284957) that were presented during the 2020 San Antonio Breast Cancer Symposium.¹

Results showed that the objective response rate (ORR) was 8.5% with amcenestrant with a clinical benefit rate (CBR) of 33.9%. Moreover, in a subgroup of patients who did not receive prior CDK4/6 inhibitors, mTOR inhibitors, or fulvestrant, higher rates of efficacy were observed with amcenestrant, at an ORR of 21.4% and a CBR of 64.3%. In those who had received 3 or more prior lines of therapy, the ORR was 15.2% and the CBR was 42.4%.

"Results showed that among heavily pretreated women, amcenestrant monotherapy demonstrated antitumor activity comparable with historical fulvestrant performance, with an objective response rate of 8.5% and a clinical benefit rate of 33.9%," lead study author Hannah Linden, MD, an academic oncologist and clinical trialist, Seattle Cancer Care Alliance and University of Washington School of Medicine, said in a prerecorded poster presentation of the data.

Patients with ER-positive, HER2-negative breast cancer often develop resistance to endocrine therapy but do continue to express ER and often respond to an alternate form of endocrine treatment. Selective estrogen receptor degraders (SERDs) are considered competitive ER antagonists that also elicit conformational changes and can lead to ER degradation.

Amcenestrant is defined as a potent, oral SERD that has demonstrated encouraging antitumor activity with a tolerable safety profile in prior phase 1/2 data of AMEERA-1; the agent also had activity in patients with ESR1 wild-type and mutant, ER-positive and HER2-negative breast cancer.²

In the open-label, first-in-human, 2-part AMEERA-1 trial, investigators are evaluating the safety and efficacy of single-agent amcenestrant and amcenestrant 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 once-daily 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.

At the 2020 SABCS, updated pharmacokinetics, safety, and antitumor activity were reported with single-agent amcenestrant, as well as post-hoc analyses by prior treatment, baseline ESR1 mutational status, and changes in ESR1 mutations on treatment and at the end of treatment, which was considered on day 22 to day 30 after the final dose administration.

To be eligible for enrollment, patients must have had heavily pretreated, postmenopausal, ER-positive, HER2-negative metastatic breast cancer, measurable disease and have received at least 6 months of prior endocrine therapy in the advanced setting and had at least 3 or at least 1 chemotherapy in the advanced settings in parts A and B, respectively. Prior treatment with an mTOR inhibitor and at least 1 CDK4/6 inhibitor-based therapy was permitted. Patients also had to have an ECOG performance status of less than 2, and consent to collection of plasma blood samples for circulating free DNA (cfDNA) analyses of ESR1 mutation status at baseline and during treatment, at end of cycle 2 in order to be included in the ESR1 biomarker analysis.

PK plasma concentration-time profiles was calculated after repeated oral administration in part A (n = 16; 20 mg-600 mg daily) plus the patients from part B of the trial with full PK (n = 13; 400 mg daily).

Investigators also evaluated safety in the pooled population of 62 patients who received amcenestrant at 150 mg or higher in part A of the trial and at 400 mg in part B, which was administered in 28-day cycles. Efficacy was assessed in 59 response-evaluable patients from the pooled population.

Additionally, exploratory analyses comprised post-hoc analyses of antitumor activity by prior lines of treatment in the response-evaluable population, including those who received 3 or fewer lines of treatment in the advanced setting or who had not received prior targeted therapy; changes in 12 pathogenic ESR1 mutations’ allele frequency in a population of patients receiving amcenestrant alone were analyzed by digital polymerase chain reaction in cfDNA, and ESR1 mutations were also analyzed at baseline and end of treatment.

The median age of patients was 63 years (range, 37-88) and more than half (59.7%) of patients had an ECOG performance status of 0. The median number of prior lines of therapy was 2 (range, 1-8) and 48.4% of patients received 3 or more prior treatments; these regimens included SERDs (46.8%), selective estrogen receptor modulators (29.0%), aromatase inhibitors (95.2%), mTOR inhibitors (33.9%), CDK4/6 inhibitors (62.9%), and chemotherapy (41.9%). Moreover, 93.5% of patients had visceral metastasis.

The pooled population (n = 62) included 13 patients who received amcenestrant at a daily dose of 150 mg or higher and 49 of those who received it at 400 mg daily. As of May 30, 2020, 62 patients had been treated with the 150-mg or higher daily dose, and 4 patients remained on study treatment. The median duration of therapy was 13.9 (range, 1-90) weeks.

PK findings showed that amcenestrant exposure increase did not deviate from dose proportionality over the dose range evaluated, from 20 mg to 600 mg. After multiple 400-mg daily administrations, irrespective of food status, the average steady-state exposure reached Cmax of 4380 ng/mL (coefficient of variation [CV], 28%) and area under the curve 0 to 24h of 43,200 ng*h/mL (CV = 38%), which showed moderate variability.

In the pooled population, the 8.5% ORR comprised an 8.5% partial response (PR) rate; 40.7% and 50.8% of patients had stable disease (SD) and progressive disease (PD), respectively. In the group of patients who received 3 or more prior lines of therapy in the advanced setting (n = 33), the ORR comprised a 15.2% PR rate; there was a 45.5% SD rate and a 39.4% PD rate. Finally, in those who did not receive prior targeted therapy (n = 14), a 21.4% ORR was reported, along with a 21.4% PR rate, a 57.1% SD rate, and a 21.4% PD rate.

Additionally, tumor shrinkage was observed in 45.8% of patients (n = 27/59).

In those with ESR1 status (n = 58), findings showed that the CBR with amcenestrant was similar in both the ESR1 wild-type and ESR1-mutant populations at 36.7% and 32.1%, respectively. Investigators noted that the activity in subset populations by prior treatments showed comparable results.

In those with an ESR1 mutation at baseline in cfDNA (n = 30), those treated with amcenestrant achieved clinical benefit, including in tumors with resilient D538G (62.5%) and Y537S (37.5%). In patients with available data at baseline and at day 28 of cycle 2 (ddPCR, n = 31), 93% of ESR1-mutated patients showed decreases in allele frequency for at

least 1 mutation during amcenestrant treatment. Amcenestrant diminished most ESR1 mutations at day 28 of cycle 2, for patients who achieved a clinical benefit and those who did not, including known resilient alleles D538G and Y537S; some mutations were completely cleared.

In the 44 patients with available data at baseline and at the end of treatment, good control of ESR1 mutations was observed at end of treatment with no new on-target mutations in those who originally achieved clinical benefit. A decrease/clearance of some mutations, which include D538G and Y537S, was also observed. The main drivers of resistance appear to be mechanisms other than ESR1 mutations.

Data also showed that amcenestrant elicited clinical benefit in patients independent of ESR1 mutation status. Moreover, investigators noted that mechanisms other than ESR1 mutations seemingly drive resistance to amcenestrant in heavily pretreated patients.

Regarding safety, 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 flush (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%).

While other oral SERDs have been linked with cardiac toxicities or visual disturbances, these AEs were not reported with amcenestrant.

The mean ± SD relative dose intensity was 98.4 ± 5.4% with a delivered relative dose intensity of 80% to 100% in 96.8% of patients. Five patients required dose reductions at the 400-mg dose and 2 patients had at least 7 consecutive days of dose omission. Amcenestrant was not discontinued in any patients due to TRAEs. Furthermore, all laboratory abnormalities reported as AEs were not found to be related to intake of the study drug.

The ongoing phase 2 AMEERA-3 trial (NCT04059484) is evaluating amcenestrant compared with physician’s choice of treatment in the second-line setting. Other parts of the AMEERA-1 study are exploring amcenestrant in combination with targeted therapies, Linden concluded in the presentation.

Reference

1. Linden HM, Campone M, Bardia A, et al. A phase 1/2 study of amcenestrant (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. Presented at: 2020 San Antonio Breast Cancer Symposium; December 8-11, 2020; virtual. Abstract PD8-08.
2. Campone MC, 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