AMEERA-1 phase 1/2 study of amcenestrant, SAR439859, in postmenopausal women with ER-positive/HER2-negative advanced breast cancer

Abstract

AMEERA-1 is a Phase 1/2 open-label single-arm study evaluating once-daily (QD) amcenestrant, an orally bioavailable selective estrogen receptor (ER) degrader, in postmenopausal women with ER+/HER2- advanced breast cancer (NCT03284957), who were mostly heavily pretreated (including targeted therapies and fulvestrant). In the dose escalation phase (Part A: n = 16), patients received amcenestrant 20-600 mg QD. Based on absence of dose-limiting toxicities, paired functional 18F-fluoroestradiol positron emission tomography, and pharmacokinetics, 400 mg QD was selected as recommended Phase 2 dose (RP2D) for the dose expansion phase (Part B: n = 49). No Grade ≥3 treatment-related adverse events or clinically significant cardiac/eye toxicities were reported. The Part B primary endpoint, confirmed objective response rate (ORR) was 3/45 at the interim analysis and 5/46 (10.9%) at the final analysis. The overall clinical benefit rate (CBR) was 13/46 (28.3%). CBRs among patients with baseline wild-type and mutated ESR1 were 9/26 (34.6%) and 4/19 (21.1%), respectively. Paired tumor biopsy and cell-free DNA analyses revealed ER inhibition and degradation, and a reduction in detectable ESR1 mutations, including Y537S. In conclusion, amcenestrant at RP2D of 400 mg QD for monotherapy is well-tolerated with no dose-limiting toxicities, and demonstrates preliminary antitumor activity irrespective of baseline ESR1 mutation status.

Conflict of interest statement

A.B. has provided consulting or advisory roles for Astra Zeneca/Daiichi Sankyo, Lilly, Foundation Medicine, Gilead, Novartis, Genentech, Pfizer, Spectrum Pharmaceuticals, bioTheranostics, Merck, Radius Health, Immunomedics, Sanofi, and Puma Biotechnology, an institution consulting or advisory role for Immunomedics, Novartis, Genentech/Roche, Pfizer, Radius Health, Sanofi, and Innocrin Pharmaceuticals, and has received research funding from bioTheranostics. S.C. has received research support (to Memorial Sloan Kettering) from Daiichi Sankyo and Paige.ai, clinical trial funding (to Memorial Sloan Kettering) from Sanofi, Novartis, and Lilly, and consulting honoraria (to S.C.) from AstraZeneca, Inivata, Lilly, Novartis Sanofi, and Targeted Oncology. H.M.L. has provided consulting or advisory roles for Eisai and Pfizer, and her institution has received funding from Zionexa, Sanofi, Zentalis, Eisai, and Zymeworks. G.A.U. has provided consulting and/or has received research support from GE Healthcare, Genentech, Sanofi, Novartis, Puma Biotechnology, Siemens, Zionexa, and Lantheus. A.G., S.C-C., P.C., S.D., G.P., M. Celanovic, V.P., J.E.M., N.T., M.B., J.S.L., and A-L.B. are employees of Sanofi and may hold shares and/or stock options in the company. M. Campone has provided consulting, advisory, or speaker roles for AbbVie, Accord Healthcare, AstraZeneca, Daiichi Sankyo, G1 Therapeutics, Lilly, Novartis, Pfizer, Pierre Fabre Oncology, Sandoz, Sanofi, Seagene, and Servier; and has received honoraria for travel from AstraZeneca, Novartis, Pfizer, and Roche.

© 2022. The Author(s).

Figures

Fig. 1. Study flow diagram for Parts A and B.

During Part A, patients were enrolled into a dose escalation phase of amcenestrant monotherapy from 20-600 mg once daily. During Part B, patients were enrolled into a dose-expansion phase at the RP2D determined in Part A. aThe first patient treated at each new DL will be followed for a minimum of 1 week prior to enrolling and treating two additional patients. If none of the three patients experience a DLT, the next cohort starts one DL higher. If one of the three patients experiences a DLT, up to three additional patients are treated at this DL. If two or more patients experience a DLT, the maximum administered dose is reached. bDL2bis is investigated if at least one patient at DL1 shows ≤ 30% inhibition of the target by 18F-FES PET or all patients treated at DL2 have >85% inhibition of the target by 18F-FES PET. DL dose level, DLT dose-limiting toxicity, ER+ estrogen receptor positive, 18F-FES PET 18F-fluoroestradiol positron emission tomography, HER2− human epidermal growth factor receptor 2-negative, MTD maximum tolerated dose, RP2D recommended Phase 2 dose, PK pharmacokinetics, QD once daily.

Fig. 2. Part A dose escalation: amcenestrant plasma concentration-time profiles, pharmacokinetic/pharmacodynamic relationships, and 18F-FES PET/CT images.

a Mean amcenestrant plasma concentration-time profiles observed following repeated oral administration (cycle 1, day 22) under fasting conditions; b pharmacokinetic/pharmacodynamic relationship between plasma concentrations of amcenestrant measured just before 18F-FES radioisotope administration and individual mean percent occupancy of estrogen receptors (mean percent reduction in 18F-FES SUVmax(cor)); c representative 18F-FES PET; and d coronal CT images at screening and on-treatment with amcenestrant 150 mg. 18F-FES PET/CT scans were performed 16–24 h after the previous amcenestrant dose, except for two patients whose scans occurred 8 h after the previous dosea. Of 16 patients, 14 patients had scans at baseline and between 11–15 days after first amcenestrant administration (as per protocol) and two patients had post-baseline scans on days 10 and 28, respectively. The patient with a post-baseline scan on day 10 was included in the pharmacodynamic analysis because the scan occurred after ≥8 days of continuous treatment, but the patient receiving amcenestrant 200 mg with a post-baseline scan on day 28 was excluded from pharmacodynamic analysis and dose escalation decisionsb. cAnnotated example of the reduction in SUVmax(cor) for the first index lesion in the 5th lumbar vertebra; physiologic 18F-FES avidity is noted in the liver, intestines, and bladder. dAnnotated example of the reduction in tumor diameter of a right pelvic lymph node in the associated CT scan. CT computerized tomography, ER estrogen receptor 18F-FES PET 18F-fluoroestradiol positron emission tomography, LLOQ lower limit of quantification, SUVmax(cor) maximum standardized uptake value, standardized by body weight and corrected for background.

Fig. 3. Waterfall and swimmer plots.

a Waterfall plot of best relative change from baseline in the sum of diameters of target lesions in the response-evaluable populations of Part A by local investigators/radiologists review (n = 16) and Part B by independent central review (n = 41; three patients were missing relative change data and two patients had a non-evaluable best overall response) and b Swimmer plot of duration of treatment in the safety populations of Part A (n = 16) and Part B (n = 49) with overall responses assessed by local investigators/radiologists review. CDK4/6i cyclin-dependent kinase 4/6 inhibitor, chemo chemotherapy, ICR independent central review, Local local investigators/radiologists review, mTORi mammalian target of rapamycin inhibitor, SERD selective estrogen receptor degrader. Checkboxes correspond to baseline characteristics.

Fig. 4. Post hoc exploratory biomarker analyses of on-target ER degradation/pathway inhibition during amcenestrant therapy.

Changes from screening to cycle 2, day 28 in a ER nucleus H-score by IHC; b PgR nucleus H-score by IHC; c percent of positive cells showing Ki67 protein expression by IHC; and d ER activation scores by GSVA; and changes from cycle 1, day 1 to cycle 2, day 28 in e allele frequency of ESR1 mutations in cfDNA by ddPCR; and f numbers of ESR1 mutations in cfDNA by ddPCR. *Each line refers to an ESR1 mutation, but several lines may refer to a single patient. C1D1, cycle 1, day 1; C1D15, cycle 1, day 15; C2D28, cycle 2, day 28; CB clinical benefit (complete response + partial response + stable disease ≥ 24 weeks), cfDNA circulating free DNA, ddPC, droplet digital polymerase chain reaction, ER estrogen receptor, ESR1 estrogen receptor 1, GSVA gene set variation analysis, IHC immunohistochemistry, PgR progesterone receptor, PR partial response.