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).

Abstract

1058 Background: AMEERA-1 (NCT03284957) investigates amcenestrant, an oral SERD, as monotherapy and combined with targeted therapies in ER+/HER2– mBC. Here we report data from dose escalation (Part C) and dose expansion (Part D) of amcenestrant + palbo. Methods: Patients (pts) were postmenopausal women with ER+/HER2– mBC and ≥ 6 mos prior advanced endocrine therapy (ET) or adjuvant (adj) ET resistance (relapse on adj ET started ≥ 24 mos ago or < 12 mos after completing adj ET). Prior chemotherapy (≤ 1) for advanced disease was allowed; targeted therapies were not except ≤ 1 CDK4/6i in Part C. Part C assessed dose-limiting toxicities (DLTs) and aimed to establish the recommended phase 2 dose (RP2D) for amcenestrant (200 or 400 mg once daily [QD], in 28-day cycles) in combination with palbo (125 mg QD for 21 days on/ 7 days off). Safety (treatment-emergent adverse events [TEAEs] and lab abnormalities per CTCAE v4.03) and pharmacokinetics (PK) were evaluated. Antitumor activity at the RP2D for amcenestrant + palbo was evaluated in a subset of Part C pts and Part D, according to RECIST v1.1, determined locally by investigators. Results: Feb 8, 2021 data cutoff. In Part C (n = 15; 200 mg: 9; 400 mg: 6), no DLTs occurred and amcenestrant 200 mg QD was selected as the RP2D with palbo, based on PK and safety data. In the pooled safety population at the RP2D (n = 39; Part C: 9; Part D: 30), median (range) age was 59 y (33–86) with ECOG PS 0 (74.4%) or 1 (25.6%) and 2 (1–6) organs involved. Immediate prior therapy was neo/adj (41.0%, all ET resistant) or advanced (59.0%, range 1–4 lines). Median (range) exposure was 32 wks (1–66) with 59.0% pts on ongoing therapy. No amcenestrant dose reductions occurred; 25.6% had ≥ 1 palbo dose reduction. Most common non-hematological TEAEs related to amcenestrant were Grade 1–2 nausea and fatigue (17.9% each), asthenia and hot flush (10.3% each); to palbo were fatigue (30.8%), nausea (25.6%), asthenia and dysgeusia (10.3% each). Two pts discontinued due to AEs. The majority (94.9%) had neutrophil count decrease (53.8% Grade ≥ 3). Preliminary antitumor activity after at least 6 cycles of therapy (unless early treatment discontinuation) is reported in the table below. Conclusions: In pts with ER+/HER2– mBC, safety at the RP2D of amcenestrant + palbo was favorable, with no safety signals of bradycardia or eye disorders. Preliminary antitumor activity was observed (ORR: 31.4% and CBR: 74.3%). Clinical trial information: NCT03284957 .[Table: see text]

AMEERA-5: a randomized, double-blind phase 3 study of amcenestrant plus palbociclibversusletrozole plus palbociclib for previously untreated ER+/HER2– advanced breast cancer

“… 25 Preliminary results from an ongoing, first-in-human phase 1/2 trial (AMEERA-1) showed that amcenestrant has promising antitumor activity as monotherapy and in combination with the CDK4/6 inhibitor palbociclib and that no clinically significant cardiac or ocular safety findings occurred. 30 , 37 , 38 …”

“… 38 No clinically significant cardiac or ocular safety findings occurred in either set of cohorts. 30 , 38 …”

Oral Selective Estrogen Receptor Degraders (SERDs) in Breast Cancer: Advances, Challenges, and Current Status

“… 63 An interaction between amcenestrant and palbociclib is possible, with amcenestrant having a moderate cytochrome P450 3A4 induction effect and reducing palbociclib exposure in a dose-dependent manner, hence the recommended dose for amcenestrant is 200 mg in combination with palbociclib, compared with 400 mg as monotherapy. 65 Several oral SERDs are undergoing evaluation in combination with abemaciclib, but no results are reported yet. These include trials of amcenestrant (NCT03284957), camizestrant (NCT03616587 and NCT04964934), imlunestrant (NCT04188548 and NCT04975308) and ZN-c5 (NCT04514159).…”

Accelerating drug development in breast cancer: New frontiers for ER inhibition

“…In the phase I/II AMEERA-1 study, among 59 evaluable patients treated with monotherapy, the ORR was 9% and the CBR was 34%, increasing to 64% among patients without prior SERD, CDK4/6 inhibitors, or mTOR inhibitors [79]. Among 39 patients treated with amcenestrant plus palbociclib, the ORR was 32% and CBR at 24 weeks was 73%, with a median PFS of 15 months (range 11-22.3) [80,81]. The most frequent any-grade toxicities occurring in ≥ 15% of patients were fatigue and nausea; 13% of patients experienced grade ≥ 3 toxicities with amcenestrant alone [79,82].…”