Background

With increasing evidence showing the complexity of HER2-positive breast cancer, this study aimed to identify a gene-expression signature with potential prognostic value to assist therapeutic decision in the early disease setting.

Methods

Gene-expression profiles of NeoALTTO tumor biopsies before and after 2 weeks of neoadjuvant treatment were generated by microarrays (Clariom S, ThermoFisher). Genes associated with event free survival (EFS) were selected at the two time points with Cox univariate analysis and combined by multivariate approaches. Independent technical and clinical validation were sought.

Results

Overall, 180 patients were analyzed (NeoALTTO cohort, median follow-up 6.7 yrs [IQR 6.1-6.8]; 53 events). The expression of 18 genes combined by principal component analysis (S18) was significantly associated with EFS in the trastuzumab (T)-arm (Hazard Ratio for each unit increment [HR] 2.4, 95%Confidence Interval [CI] 1.6-3.5) and in the entire NeoALTTO cohort (HR 1.7, CI 1.4-2.2). Notably, S18 showed no overlap with HER2 and/or ESR1 genes and/or their signaling. A more parsimonious signature of five genes (S5) was next developed. Both S18 and S5 retained their prognostic value independently of pathological complete response, age, tumor size, estrogen receptor and node status both in the T-arm and in the entire NeoALTTO cohort. The prognostic value of S18 was technically confirmed by RNAseq in the T-arm (HR 2.1, CI 1.4-3.1) and entire cohort (HR1.3, CI 1.03-1.7) whereas the S5 was confirmed within the T-arm alone (HR 1.5, CI 1.1-1.9). An additional technical validation is currently ongoing by customized open arrays. The prognostic capability of S18 was clinically confirmed by in silico analysis of the Italian GHEA expanded access study of adjuvant trastuzumab (HR 1.9,CI 1.2-2.9). Currently, we are seeking to validate the prognostic value of S5 in the NSABP B-31 study and results are expected to be presented at the congress.

Conclusions

These findings hold the potential to accurately identify patients with early HER2-positive breast cancer at low risk of relapse when treated with trastuzumab-based therapy and may be useful to select patients for single or dual anti-HER2 therapies.

Legal entity responsible for the study

Serena Di Cosimo.

Funding

Fondazione Associazione Italiana Ricerca contro il Cancro (AIRC) IG 20774 to Serena Di Cosimo.

Disclosure

Y. Wang: Financial Interests, Personal, Funding: Wang. 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.