Background

About 30% of patients (pts) with HR+ EBC on treatment with aromatase inhibitors (AIs), discontinue AIs due to toxicity (Henry et al. JCO 2012). For this population, there are currently limited therapy options, including switch to another AI or tamoxifen. Amcenestrant is an optimized oral selective estrogen receptor degrader (SERD) with potent dual activity which antagonizes and degrades the estrogen receptor (ER), resulting in inhibition of the ER signaling pathway. In the phase 1/2 AMEERA-1 trial (SABCS 2020 PD8-08), amcenestrant showed strong antitumor activity and favorable safety profile in the treatment of HR+ metastatic breast cancer.

Trial design

This is a prospective, randomized, international, double-blind, double-dummy, phase 3 superiority study. Eligible pts are men and pre/peri/post-menopausal women with HR+ stage IIB/III breast adenocarcinoma, irrespective of human epidermal growth factor receptor 2 (HER2) status. Pts will be centrally assessed to have ER+ and/or progesterone receptor (PgR)+ (≥10% positive stained cells) status by immunohistochemistry assay. Pts must have received at least 6 months of adjuvant AIs (≥3 months in the adjuvant setting if they have received prior neoadjuvant AIs) and discontinued them within 30 months of initiation due to treatment-related toxicity. Any anti-HER2 treatment, chemotherapy or cyclin-dependent kinase (CDK) 4/6 inhibitor are allowed if completed or stopped prior to randomization. 3738 pts will be randomized 1:1 to receive either amcenestrant 200 mg daily or tamoxifen 20 mg daily for 5 years and will be followed up for 10 years from randomization. Stratification factors include AIs duration, HER2 status, prior chemotherapy, prior CDK4/6 inhibitors, geographic region, menopausal status. The primary endpoint is invasive breast cancer-free survival (IBCFS) (STEEP v 2.0); key secondary endpoint is invasive disease-free survival and other secondary endpoints are overall survival, safety, patient reported outcomes. Adherence to treatment is an exploratory endpoint. AMEERA-6 opened for recruitment in January 2022.

Clinical trial identification

NCT05128773.

Legal entity responsible for the study

Sanofi.

Funding

Sanofi.

Disclosure

G. Rossi: Financial Interests, Institutional, Royalties: Agendia; Financial Interests, Institutional, Research Grant: AstraZeneca; Financial Interests, Institutional, Research Grant: Roche/Genentech; Financial Interests, Institutional, Research Grant: Tesaro; Financial Interests, Institutional, Research Grant: Novartis; Financial Interests, Institutional, Research Grant: Pfizer; Financial Interests, Institutional, Research Grant: SERVIER; Financial Interests, Institutional, Research Grant: Biovica; Financial Interests, Institutional, Research Grant: GlaxoSmithKline; Financial Interests, Institutional, Research Grant: Sanofi/Aventis. E. Brain: Financial Interests, Personal, Other, Honoraria: Eli Lilly; Financial Interests, Personal, Other, Honoraria: Pfizer; Financial Interests, Personal, Other, Honoraria: Sandoz; Financial Interests, Personal, Other, Honoraria: Seagen; Financial Interests, Personal, Advisory Board: Daiichi; Financial Interests, Personal, Advisory Board: Eli Lilly; Financial Interests, Personal, Advisory Board: Pfizer; Financial Interests, Personal, Advisory Board: Sandoz; Financial Interests, Personal, Other, Travel, accommodations, expenses: Pfizer; Financial Interests, Personal, Other, Travel, accommodations, expenses: Sandoz. H. De Swert: Financial Interests, Institutional, Research Grant: AstraZeneca; Financial Interests, Institutional, Research Grant: Roche/Genentech; Financial Interests, Institutional, Research Grant: Tesaro; Financial Interests, Institutional, Research Grant: Novartis; Financial Interests, Institutional, Research Grant: Pfizer; Financial Interests, Institutional, Research Grant: Servier; Financial Interests, Institutional, Research Grant: BIOVICA; Financial Interests, Institutional, Research Grant: GSK; Financial Interests, Institutional, Research Grant: Sanofi/Aventis; Financial Interests, Institutional, Royalties: Agendia. C. Herold: Financial Interests, Personal, Full or part-time Employment: Sanofi; Financial Interests, Personal, Stocks/Shares: Sanofi; Financial Interests, Personal, Other, Travel, accommodations, expenses: Sanofi. T. Spanic: Financial Interests, Personal, Advisory Board: Roche; Financial Interests, Personal, Advisory Board: MSD; Financial Interests, Personal, Advisory Board: Gilead. A. Arahmani: Financial Interests, Institutional, Research Grant: Novartis; Financial Interests, Institutional, Research Grant: GSK; Financial Interests, Institutional, Research Grant: BIOVICA; Financial Interests, Institutional, Research Grant: Roche/Genentech; Financial Interests, Institutional, Research Grant: Pfizer; Financial Interests, Institutional, Research Grant: TESARO; Financial Interests, Institutional, Research Grant: Sanofi; Financial Interests, Institutional, Research Grant: AstraZeneca; Financial Interests, Institutional, Research Grant: SERVIER; Financial Interests, Institutional, Royalties: Agendia. L. Wang: Financial Interests, Personal, Full or part-time Employment: Sanofi; Financial Interests, Personal, Stocks/Shares: Syndax Pharmaceuticals; Financial Interests, Personal, Stocks/Shares: Ikena Oncology. T. Goulioti: Financial Interests, Personal, Full or part-time Employment, An Immediate Family Member: UCB; Financial Interests, Personal, Stocks/Shares, An Immediate Family Member: GlaxoSmithKline; Financial Interests, Personal, Ownership Interest, An Immediate Family Member: UCB; Financial Interests, Institutional, Research Grant: AstraZeneca; Financial Interests, Institutional, Research Grant: Roche/Genentech; Financial Interests, Institutional, Research Grant: Tesaro; Financial Interests, Institutional, Research Grant: Novartis; Financial Interests, Institutional, Invited Speaker: Pfizer; Financial Interests, Institutional, Research Grant: SERVIER; Financial Interests, Institutional, Research Grant: Biovica; Financial Interests, Institutional, Research Grant: GlaxoSmithKline; Financial Interests, Institutional, Research Grant: Sanofi/Aventis; Financial Interests, Institutional, Royalties: Agendia. S. Anneheim: Financial Interests, Personal, Full or part-time Employment: Sanofi; Financial Interests, Personal, Stocks/Shares: Sanofi. G. Paux: Financial Interests, Personal, Full or part-time Employment: Sanofi; Financial Interests, Personal, Stocks/Shares: Sanofi; Financial Interests, Personal, Royalties: Sanofi. O. Metzger: Financial Interests, Personal, Stocks/Shares: Invitae; Financial Interests, Personal, Other, Honoraria: Grupo Oncoclinicas; Financial Interests, Personal, Other, Honoraria: Merck; Financial Interests, Personal, Advisory Board: Grupo Oncoclinicas; Financial Interests, Personal, Advisory Board: Resilience Care; Financial Interests, Personal, Advisory Board: Alliance for Clinical Trials in Oncology; Financial Interests, Personal, Speaker’s Bureau: AstraZeneca; Financial Interests, Institutional, Research Grant: Eisai; Financial Interests, Institutional, Research Grant: AbbVie; Financial Interests, Institutional, Research Grant: Susan G. Komen for the Cure; Financial Interests, Institutional, Research Grant: Roche/Genentech; Financial Interests, Institutional, Research Grant: Pfizer; Financial Interests, Institutional, Research Grant: Cascadian Therapeutics; Financial Interests, Institutional, Royalties: Sanofi; Financial Interests, Personal, Other, Travel, accommodations, expenses: Grupo Oncoclinicas. D. Cameron: Financial Interests, Personal, Advisory Board: Aptitude Health; Financial Interests, Personal, Advisory Board: Roche Sweden; Financial Interests, Personal, Advisory Board: Pfizer Limited; Financial Interests, Personal, Advisory Board: Celldex Therapeutics Inc.; Financial Interests, Personal, Advisory Board: Carnall Farrar; Financial Interests, Personal, Advisory Board: San Antonio Breast Cancer Consortium; Financial Interests, Personal, Advisory Board: Highfield Communication; Financial Interests, Personal, Advisory Board: AstraZeneca Global Commercial Organisation - Egypt; Financial Interests, Personal, Advisory Board: Celgene Corporation; Financial Interests, Personal, Advisory Board: Chief Scientists Office; Financial Interests, Personal, Advisory Board: Cancer Research UK; Financial Interests, Personal, Advisory Board: HTA; Financial Interests, Personal, Advisory Board: Samsung Bioepis Co Ltd. (Korea); Financial Interests, Personal, Advisory Board: Eli Lilly & Company; Financial Interests, Personal, Advisory Board: Costello Medical Consulting Ltd.; Financial Interests, Personal, Advisory Board: prIME Oncology; Financial Interests, Personal, Advisory Board: AstraZeneca UK Limited; Financial Interests, Personal, Advisory Board: Roche Products Ltd.; Financial Interests, Personal, Advisory Board: Novartis Pharma AG; Financial Interests, Personal, Advisory Board: Novartis Pharmaceuticals Corporation; Financial Interests, Personal, Advisory Board: Pfizer Limited; Financial Interests, Personal, Advisory Board: PFS Ltd.; Financial Interests, Personal, Advisory Board: Novartis Pharmaceuticals UK Limited; Financial Interests, Personal, Advisory Board: Merck Sharp Dohme Limited; Financial Interests, Personal, Advisory Board: Puma Biotechnology, Inc.; Financial Interests, Personal, Advisory Board: Pfizer Limited; Financial Interests, Personal, Advisory Board: F. Hoffmann-La Roche AG; Financial Interests, Personal, Advisory Board: Clovis Oncology; Financial Interests, Personal, Advisory Board: Breast International Group (BIG); Financial Interests, Personal, Advisory Board: Breast Cancer Institute; Financial Interests, Personal, Advisory Board: Daiichi Sankyo, USA; Financial Interests, Personal, Advisory Board: Eisai; Financial Interests, Personal, Advisory Board: Elsevier Ltd.; Financial Interests, Personal, Advisory Board: European Cancer Organisation; Financial Interests, Personal, Advisory Board: Exact Therapeutics; Financial Interests, Personal, Advisory Board: G1 Therapeutics; Financial Interests, Personal, Advisory Board: Galapagos NV; Financial Interests, Personal, Advisory Board: Genentech Inc.; Financial Interests, Personal, Advisory Board: GSK (Glaxo SmithKline); Financial Interests, Personal, Advisory Board: ICON Clinical Research; Financial Interests, Personal, Advisory Board: Prima BioMED; Financial Interests, Personal, Advisory Board: RTI Health Solutions; Financial Interests, Personal, Advisory Board: Seattle Genetics; Financial Interests, Personal, Advisory Board: Synthon Biopharmaceuticals BV: Note name change to Byondis April 2020; Financial Interests, Personal, Advisory Board: Succinct Medical Communications; Financial Interests, Personal, Advisory Board: Seagen; Financial Interests, Personal, Advisory Board: SANOFI; Financial Interests, Personal, Advisory Board: Sapience Therapeutics Ltd.; Financial Interests, Personal, Advisory Board: Bexon/Zymeworks Biopharmaceuticals Inc.; Financial Interests, Personal, Advisory Board: Make Seconds Count. All other authors have declared no conflicts of interest.

Background

Eftilagimod alpha (EF) is a soluble LAG-3 protein (LAG-3Ig) that binds to a subset of MHC class II molecules and mediates activation of antigen-presenting cells followed by T-cells. AIPAC investigated EF + paclitaxel (PA). We hereby report exploratory biomarker and multivariate analyses.

Methods

This double-blinded, 1:1 randomized phase IIb trial enrolled pts with HR⁺ HER2^- MBC. Pts received PA (80 mg/m² IV on D1, D8, D15) + EF (30 mg) or placebo (PL) on D2, D16 per cycle (28 days) for 24 wks + EF/PL for 52 wks. Exploratory EPs were potential biomarkers and their correlation to efficacy. Multivariate analysis used backward selection p>0.15 (univariate cox model). Blood cell subsets (CD4; CD8, PBMCs, monocytes) & Th1 biomarker CXCL-10 were measured centrally. Comparison was done using 2-sided Wilcoxon test.

Results

226 pts [efti n=114; placebo n=112] were included. Pts were endocrine resistant (84%), pre-treated with CDK4/6 inhibitors (44.2%). Post-study treatment was similar. Safety/efficacy were reported at SABCS 2020 #132; SITC 2021 #948 In the multivariate predictive model 4 groups (high Neutrophil/Lymphocyte Ratio [NLR]; no prior taxanes; low monocytes and <5 yrs since diagnosis) were significant for OS (Table) On treatment mean fold-changes of monocytes (5.81 vs. 2.29; p=0.025), PBMCs (2.00 vs. 1.41; p=0.041), T cells (2.28 vs. 1.48; p=0.086), & CXCL10 (2.78 vs. 1.56; p=0.06) were significantly higher (EF vs PL) and linked to higher OS. Post baseline CD4 (median 896/μl vs. 736 μl; p=0.038) & CD8 (median 377/μl vs. 223 μl; p=0.005) T cell count increased significantly in pts with higher OS EF vs. PL. Table: 171P

OS for subgroups significant p<0.15 in the multivariate model

Conclusions

EF + PA elicits significant effects on different immune cells which is significantly associated with higher OS. Multivariate analysis identified potential target populations for phase III.

Clinical trial identification

The AIPAC trial protocol has been published, please see Dirix, L. & Triebel, F. Future Oncol. 2019 Jun;15(17):1963-1973. The trial identifiers are IMP321-P011 (code for sponsor), 2015-002541-63 (EudraCT) and NCT02614833.321-P011 (code for sponsor), 2015-002541-63 (EudraCT) and NCT02614833.

Legal entity responsible for the study

Immutep S.A.

Funding

Immutep S.A.

Disclosure

F. Marmé: Financial Interests, Personal, Other: Roche,AstraZeneca,Pfizer, Tesaro, Novartis, Amgen, PharmaMar, GenomicHealth, CureVac, Eisai, Celegene, Clovis, Janssen-Cilag, Gilead/Immunomedics, GSK, MSD, Seagen, Myriad, Pierre Fabre. H. Wildiers: Financial Interests, Institutional, Research Grant: Roche & Novartis; Financial Interests, Personal, Other, Travel, Accomodations, Expenses: Roche, Pfizer; Other, Personal, Other, Consulting or Advisory Role: Roche, Lilly, Pfizer, AstraZeneca, AbbVie, Daiichi Sankyo, KCE, PSI Cro AG, MSD, AstraZeneca Pharmaceuticals Ireland & Immutep Pty; Other, Personal, Speaker’s Bureau: EISAI, MSD & AstraZeneca. A. Armstrong: Other, Personal, Other, Stock Or Otherownership: spousal shares in AstraZeneca; Other, Institutional, Research Grant: AstraZeneca; Financial Interests, Personal, Other, Conference fees: MSD, Gilead; Other, Institutional, Other, Ad Board Partication: MSD, Gilead. E. De Cuypere: Other, Personal, Other, Travel, Accomodations, Expenses: PharmaMar, MSD. F. Dalenc: Other, Personal, Other, Travel, Accomodations, Expenses: Pfizer, Roche. P. Vuylsteke: Other, Personal, Other, Consulting or Advisory role: Roche, MSD, BMS, Lily, Novartis; Other, Personal, Invited Speaker, Travel,Accomodations, expenses: Roche, Pfizer, Lily, BMS; Other, Personal, Invited Speaker, Speakers Bureau: Roche, Novartis. E. Brain: Other, Personal, Other, Honoraria: Eli Lilly, Pfizer, Seagen; Other, Personal, Other, Consulting or Advisory Role: Bristol Myers Squibb, Pfizer, G1 Therapeutics, Sandoz; Other, Personal, Other, Travel, Accomodations, Expenses: Pierre Fabre, Pfizer, AstraZeneca, Novartis, Roche, Sandoz. S. Kuemmel: Other, Personal, Other, Consulting Fees: Roche, Genomic Health, Novartis, Amgen, Celgene, Daiichi Sankyo, AstraZeneca, Somatex, MSD, Pfizer, PFM Medical, Lilly, Sonoscape, Seagen, Gilead; Other, Personal and Institutional, Other, Contracted Research: Somatex – Research Grant /Funding Institution; Other, Personal, Other, Ownership Interest (stock, stock options, or other ownership interest excluding diversified mutual funds): WSG – Westdeutsche Studiengruppe- Co-Director; Other, Personal, Other, Travel/Accommodation/Expenses: Roche/ Daiichi Sankyo/Sonoscape. C. Mueller: Other, Personal, Other, Employment: Immutep; Financial Interests, Personal, Financial Interests, Stock and Other Ownership Interests: Immutep. C. Brignone: Other, Personal, Other: Immutep SAS; Other, Personal, Other, Stock and Other ownership: Immutep Ltd.; Other, Personal, Other, Patents, Royalties, Other Intellectual Property: Immutep. F. Triebel: Other, Personal, Other, Employment: Immutep SAS; Other, Personal, Other, Stock and Other Ownership Interests: Immutep Ltd.; Other, Personal, Other, Patents, Royalties, Other Intellectual Property: Being an inventor on patents on LAG-3 owned by Immutep SAS. All other authors have declared no conflicts of interest.