Background

In 1st-line trials, the relative Progression Free Survival (PFS) benefit of adding CDK4/6 inhibitors to AI was consistent across all subgroups of patients (pts), including those with lower ER expression. However, little is known about the absolute PFS obtained under CDK4/6i and AI in pts with low ER expression and whether PR and HER2 expression impact PFS in this setting.

Methods

PADA-1 is a phase III trial (NCT03079011) testing the clinical utility of ESR1_mut detection in blood in ER ≥ 10% HER2- MBC pts receiving 1st- line Pal + AI. We investigated the association of locally-assessed ER (%), PR (%) and HER2 (0,1+,2+) IHC expression on the most recent tumor sample with PFS under Pal + AI.

Results

Of 1017 pts, 12 (1.2%), 34 (3.5%), 181 (18.5%) & 751 (76.8%) had an ER% expression of [10-20%], [21-50%], [51-80%] & [81-100%], respectively. N=249 pts (29.2%), 148 (17.3%), 186 (21.8%) & 270 (31.6%) had a PR% of [0-20%], [21-50%], [51-80%] & [81-100%], respectively (Allred scores will be presented). Available HER2 IHC scores were 0 & 1+/2+ in 357 (54.6%) & 296 (45.4%) pts, respectively. In univariate analysis, after a mFU of 28.1 months and 527 PFS events (51.8%) under Pal + AI, mPFS in pts with [10-50%], [51-80%] & [81-100%] ER IHC were 14.1, 21.6 & 30.1 months, respectively. mPFS in pts with [0-50%], [51-80%] & [81-100%] PR IHC were 20.6, 27.1 and 42.6 months, respectively. Longer PFS were observed in HER2(1/2+) vs (0) MBC (HR=0.79 [0.64;0.98]). In multivariate analysis, aside standard prognostic factors (PS, age, visceral disease, number of metastatic site, DMFI), both ER% and PR% had an independent prognostic impact: each +10% gain in ER% was associated with a reduced 10% risk of PFS event under Pal + AI (HR=0.90, 95%CI [0.84;0.96], p=0.002); each +10% gain in PR% was associated with a reduced 8% risk of PFS event under Pal + AI (HR=0.92, 95%CI [0.90;0.95], p<0.001).

Conclusions

ER and PR IHC % have significant, independent and similar impact on PFS achieved under 1^st line by Pal + AI. The 14.1 months absolute mPFS obtained among pts with ER IHC <50% suggests that CDK4/6i + AI remains a good treatment option in this patient population.

Clinical trial identification

NCT03079011.

Legal entity responsible for the study

Unicancer & Arcagy-Gineco.

Funding

Pfizer.

Disclosure

T. De La Motte Rouge: Financial Interests, Personal, Financial Interests, Advisory Board: AstraZeneca; Financial Interests, Personal, Financial Interests, Advisory Board: Clovis Oncology; Financial Interests, Personal, Financial Interests, Advisory Board: GSK; Financial Interests, Institutional, Financial Interests, Advisory Board: MSD; Financial Interests, Personal, Financial Interests, Advisory Board: Mylan; Financial Interests, Personal, Financial Interests, Advisory Board: Pfizer; Financial Interests, Personal, Financial Interests, Advisory Board: Roche; Financial Interests, Personal, Financial Interests, Advisory Board: Tesaro; Financial Interests, Institutional, Financial Interests, Local PI: AstraZeneca; Financial Interests, Institutional, Financial Interests, Local PI: GSK; Financial Interests, Institutional, Financial Interests, Research Grant,: MSD; Financial Interests, Institutional, Financial Interests, Local PI: MSD; Financial Interests, Institutional, Financial Interests, Local PI: Netris Pharma; Financial Interests, Institutional, Financial Interests, Research Grant: Novartis; Financial Interests, Institutional, Financial Interests, Research Grant: Pfizer; Non-Financial Interests, Institutional, Non-Financial Interests, Local PI: Pfizer; Financial Interests, Institutional, Financial Interests, Local PI: Roche; Non-Financial Interests, Institutional, Non-Financial Interests, Principal Investigator: Arcagy; Non-Financial Interests, Non-Financial Interests, Advisory Role: French National Cancer Institute; Non-Financial Interests, Non-Financial Interests, Advisory Role: Unicancer. J. Frenel: Financial Interests, Personal, Other, Consulting fees: Novartis; Financial Interests, Personal, Other, Consulting fees: AstraZeneca; Financial Interests, Personal, Other, Consulting fees: Pfizer; Financial Interests, Personal, Other, Consulting fees: Lilly; Financial Interests, Personal, Other, Consulting fees: Clovis Oncology; Financial Interests, Personal, Other, Consulting fees: GSK; Financial Interests, Personal, Other, Consulting fees: Gilead; Financial Interests, Personal, Other, Consulting fees: Daiichi Sankyo; Financial Interests, Personal, Other, Consulting fees: Seagen; Financial Interests, Institutional, Other, Support for attending meetings and/or travel: Novartis; Financial Interests, Institutional, Other, Support for attending meetings and/or travel: AstraZeneca; Financial Interests, Institutional, Other, Support for attending meetings and/or travel: Pfizer; Financial Interests, Institutional, Other, Support for attending meetings and/or travel: Lilly; Financial Interests, Institutional, Other, Support for attending meetings and/or travel: Clovis Oncology; Financial Interests, Institutional, Other, Support for attending meetings and/or travel: GSK; Financial Interests, Institutional, Other, Support for attending meetings and/or travel: Gilead; Financial Interests, Institutional, Other, Support for attending meetings and/or travel: Daiichi Sankyo; Financial Interests, Institutional, Other, Support for attending meetings and/or travel: Seagen. A. Hardy-Bessard: Financial Interests, Personal, Advisory Role: Novartis; Financial Interests, Personal, Advisory Role: Pfizer; Financial Interests, Personal, Advisory Role: AstraZeneca; Financial Interests, Personal, Advisory Role: Clovis; Financial Interests, Personal, Advisory Role: MSD; Financial Interests, Personal, Advisory Role: Seagen; Financial Interests, Personal, Advisory Role: GSK; Non-Financial Interests, Personal, Advisory Role, Travel/Accommodation/Expenses: Roche. T. Bachelot: Non-Financial Interests, Personal, Non-Financial Interests, Advisory board, travel: Roche; Non-Financial Interests, Personal, Non-Financial Interests, Advisory board, travel: AstraZeneca; Non-Financial Interests, Personal, Non-Financial Interests, Advisory board, travel: Pfizer; Non-Financial Interests, Personal, Financial Interests, Advisory board: Seattle Genetics; Non-Financial Interests, Personal, Non-Financial Interests, Advisory board, travel: Novartis. B. Pistilli: Financial Interests, Personal, Advisory Role: Puma Biotechnology; Financial Interests, Personal, Advisory Role: Novartis; Financial Interests, Personal, Advisory Role: Myriad Genetics; Financial Interests, Personal, Advisory Role: Pierre Fabre; Financial Interests, Institutional, Funding: Daiichi; Financial Interests, Institutional, Funding: Puma Biotechnology; Financial Interests, Institutional, Funding: Novartis; Financial Interests, Institutional, Funding: Merus; Financial Interests, Institutional, Funding: Pfizer; Financial Interests, Institutional, Funding: AstraZeneca; Financial Interests, Institutional, Funding: Sanofi. S. Delaloge: Financial Interests, Institutional, Advisory Board: AstraZeneca; Financial Interests, Institutional, Invited Speaker: AstraZeneca; Financial Interests, Institutional, Advisory Board: Cellectis; Financial Interests, Institutional, Invited Speaker: Exact Sciences; Financial Interests, Institutional, Advisory Board: Isis/servier; Financial Interests, Institutional, Invited Speaker: Lilly; Financial Interests, Institutional, Invited Speaker: MSD; Financial Interests, Institutional, Advisory Board: Novartis; Financial Interests, Institutional, Advisory Board: Orion; Financial Interests, Institutional, Invited Speaker: Pfizer; Financial Interests, Institutional, Advisory Board: Pierre fabre; Financial Interests, Institutional, Advisory Board: Rappta; Financial Interests, Institutional, Advisory Board: Sanofi; Financial Interests, Institutional, Invited Speaker: Seagen; Financial Interests, Institutional, Other, Steering Committee Member: AstraZeneca; Financial Interests, Institutional, Other, Steering Committee Member: BMS; Financial Interests, Institutional, Funding: GE; Financial Interests, Institutional, Other, Local PI: Orion; Financial Interests, Institutional, Other, Steering Committee Member: Pfizer; Financial Interests, Institutional, Other, Steering Committee Member: Puma; Financial Interests, Institutional, Other, Steering Committee Member: Roche; Financial Interests, Institutional, Other, Steering Committee Member: Sanofi; Financial Interests, Institutional, Other, Coordinating PI: Taiho; Financial Interests, Institutional, Member of the Board of Directors: SFSPM. L. Deiana: Financial Interests, Personal, Other, board and travel: AstraZeneca; Financial Interests, Personal, Other, board and travel: Pfizer; Financial Interests, Personal, Other, board and travel: Lilly; Financial Interests, Personal, Other, board and travel: Novartis. F. Del Piano: Financial Interests, Institutional, Other: Novartis; Financial Interests, Institutional, Other: Daiichi Sankyo. D. Genet: Personal, Other: Pfizer. C.B. Levache: Financial Interests, Institutional, Other, Material disposal: Amgen. F.C. Bidard: Financial Interests, Personal and Institutional, Invited Speaker, and advisory board, research grant, principal investigator: AstraZeneca; Financial Interests, Personal, Advisory Board: BioNTech; Financial Interests, Personal, Invited Speaker, and advisory board: Lilly; Financial Interests, Personal, Advisory Board, and advisory board, research grant, principal investigator: Menarini; Financial Interests, Personal and Institutional, Invited Speaker: Novartis; Financial Interests, Personal and Institutional, Invited Speaker, advisory board, research grant, principal investigator: Pfizer; Non-Financial Interests, Institutional, Advisory Board, and principal investigator: Prolynx; Financial Interests, Personal, Advisory Board, and principal investigator: Radius; Financial Interests, Personal and Institutional, Invited Speaker, and advisory board, research grant: Roche; Financial Interests, Institutional, Invited Speaker, and principal investigator: Sanofi. 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.