2569 Background: Immune activation is important for survival in cancer. Eftilagimod alfa (E), an antigen-presenting cell (APC) activator, binds to a subset of MHC class II molecules on APCs to mediate lymphocyte, e.g. T cell (CD4/CD8), recruitment/activation. Clinical studies of E in combination with a PD-1 antagonist (P) or chemotherapy (C) have shown promising results in phase 2 studies, and E is currently investigated in a phase 3 study in combination with P and C in first-line NSCLC (NCT06726265). We present cumulative correlation studies of immune activation in blood after administration of E with clinical efficacy in late-stage cancer patients (pts). Methods: Five (5) studies with 569 pts were evaluated. 30 mg E in combination with either P (pembrolizumab IV at 200 mg q3w or 400 mg q6w or 2 mg/kg q3w) or C (paclitaxel 80 mg/m 2 day 1, 8, 15, q4w) was administered SC biweekly for 6 months (mo), then every 2-4 weeks for 6-18 mo in pts with late-stage metastatic NSCLC, HNSCC, melanoma, or breast cancer. Absolute lymphocyte count (ALC) was taken before dosing (day 1 per cycle). ALC response was pre-defined as a change ≥0.2 x 10 9 /L in ≤3 mo on study. Samples for gene expression profile (GEP) were taken pre-dose / 3 mo in a subset (N=111). IFN-g and CXCL10 were assessed pre-dose / after 1 st E admin in a subset (N=79). Clinical efficacy was assessed by iRECIST and survival. Results: Treatment with E led to a rapid (3 mo) and sustained (~12 mo) stat. sign. (p=0.03) ALC gain versus control arm. 54.4% of all pts treated with E were ALC responders (53.6% for E+P; 55.1% for E+C). In ALC responders with E, overall survival (OS) was significantly improved (see Table 1) compared to non ALC responders. Effects were observed irrespective of the combination partner, P or C, with a median increase of 6.8 or 5.2 mo, respectively. In pts treated with P or C alone (control), 40.4% were ALC responders but with no sign. median OS gain. Clinical responders (iPR or iCR as BOR) exhibited consistent upregulation of immune pathways associated with T-cell functions, NK cell functions and cytotoxicity during treatment in GEP analysis. These functions were not upregulated in non-responders. IFN-g and CXCL10 concentrations increased quickly (~8h) and significantly post-first E dosing compared to baseline and levels remained elevated until next E dosing. This effect with E was consistent with P or C. Conclusions: E leads to immediate and sustained ALC increase and TH1 type reaction, which is associated with clinical efficacy in combination with P or C. Treatment Effects Results E (N=408) ALC Responder with E 54.4% (N=222/408) Impact on survival: ALC responder vs. ALC non-responder Median OS+ 7.7 mo(23.4 vs.15.7 mo)HR=0.69; p=0.002 Control arm (N=161) ALC Responder in control arm 40.4% (N= 65/161) Impact on survival: ALC responder vs. ALC non-responder Median OS+2.9 mo(20.4 vs. 17.4 mo)HR=0.98; p=0.93

Eftilagimod alpha (efti), an antigen-presenting cell (APC) activator, may overcome PD-1/PD-L1 inhibitor primary resistance. This phase II study investigated efti plus pembrolizumab treatment in patients with first-line metastatic non–small cell lung cancer (NSCLC) unselected for PD-L1. Patients, naïve to systemic therapy in the metastatic setting, received efti (30 mg subcutaneously every 2 weeks for eight 3-week cycles, then every 3 weeks up to 54 weeks) plus pembrolizumab (200 mg intravenously every 3 weeks for up to 105 weeks). The primary end point was objective response rate (ORR) by immune RECIST. Secondary end points included duration of response (DoR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and tolerability. Exploratory end points included identification and characterization of biomarkers. PD-L1 tumor proportion score (TPS) was assessed centrally. In the intention-to-treat population (n = 114), the median age was 67 years (range, 44-85), 73.7% was male, and 62.3% had an Eastern Cooperative Oncology Group performance status score of 1. Most patients (77.8%) had low/negative (<50%) PD-L1 TPS. The unconfirmed ORR (iRECIST) was 40.4%, leading to a confirmed ORR of 35.1%. The median DoR was 21.6 months, the DCR was 72.8%, and the median PFS (iRECIST) was 6.6 months. The median OS was 20.2 months, with 44.7% patients alive at 24 months. Antitumor activity was seen across all PD-L1 levels. A low proportion of patients had treatment-related adverse events leading to permanent discontinuation (8.8%). The APC activator, efti, on top of pembrolizumab was well tolerated and showed encouraging antitumor activity in patients with first-line NSCLC irrespective of tumor PD-L1 expression.

Immunotherapeutic interventions leading to increased T-cell responses in cancer.

PK concentration to time profiles for 6-mg and 30-mg efti

Global health status over time as assessed by the EORTC QLQC30-BR23 questionnaire

Table S1 Table S2 added (Representativeness of Study Participants), Figures S1 to S3 Figure S4 added to replace data not shown in the main text

(A) AIPAC trial schema, and (B) patient disposition.

Supplement to Methods, Tables S1 to S4, legends to Figures S1 to S7

AbstractPurpose: Eftilagimod alpha (efti), a soluble LAG3 protein, activates antigen-presenting cells (APC) and downstream T cells. TACTI-002 (part C) evaluated whether combining efti with pembrolizumab led to strong antitumor responses in patients with second-line recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) while demonstrating good tolerability. Patients and Methods: In this multinational phase II trial using Simon’s two-stage design, patients who were PD-L(1)-naïve with R/M HNSCC who had failed first-line platinum-based therapy, unselected for PD-L1, received intravenous pembrolizumab (200 mg, once every 2 weeks) combined with subcutaneous efti (30 mg once every 2 weeks for 24 weeks and once every 3 weeks thereafter). The primary endpoint was objective response rate per RECIST 1.1 modified for immune-based therapy by investigator assessment. Additional endpoints included duration of response, progression-free survival, overall survival, and tolerability. Pharmacodynamic effects (absolute lymphocyte count) and Th1 cytokine biomarkers (IFNγ/CXCL10)] were evaluated in liquid biopsies. Results: Between March 2019 and January 2021, 39 patients were enrolled; 37 were evaluated for response. All patients received prior chemotherapy, and 40.5% were pretreated with cetuximab; 53.1% of patients had PD-L1 combined positive score <20. With a median follow-up of 38.8 months, the objective response rate was 29.7%, including 13.5% complete responders. The median duration of response was not reached. Rapid and sustained absolute lymphocyte count increase was observed in patients who had an objective response. Th1 biomarkers increased sustainably after first treatment. No unexpected safety signals were observed. Conclusions: Efti plus pembrolizumab was safe and showed encouraging antitumor activity and pharmacodynamic effects in patients with second-line head and neck squamous cell carcinoma (HNSCC), thus supporting further evaluation of this combination in earlier treatment lines.

. (A) Absolute cell count of CD8+ T cells at baseline and maximal postbaseline by OS status and treatment arm. (B)

Kaplan-Meier plots of PFS by blinded independent central review for AIPAC patient subgroups.

AbstractPurpose: Eftilagimod alpha (efti), a soluble lymphocyte activation gene (LAG-3) protein and MHC class II agonist, enhances innate and adaptive immunity. Active Immunotherapy PAClitaxel (AIPAC) evaluated safety and efficacy of efti plus paclitaxel in patients with predominantly endocrine-resistant, hormone receptor–positive, HER2-negative metastatic breast cancer (ET-resistant HR+ HER2− MBC). Patients and Methods: Women with HR+ HER2– MBC were randomized 1:1 to weekly intravenous paclitaxel (80 mg/m2) and subcutaneous efti (30 mg) or placebo every 2 weeks for six 4-week cycles, then monthly subcutaneous efti (30 mg) or placebo maintenance. Primary endpoint was progression-free survival (PFS) by blinded independent central review. Secondary endpoints included overall survival (OS), safety/tolerability, pharmacokinetics/pharmacodynamics, and quality of life. Exploratory endpoints included cellular biomarkers. Results: 114 patients received efti and 112 patients received placebo. Median age was 60 years (91.6% visceral disease, 84.1% ET-resistant, 44.2% with previous CDK4/6 inhibitor treatment). Median PFS at 7.3 months was similar for efti and placebo. Median OS was not significantly improved for efti (20.4 vs. 17.5 months; HR, 0.88; P = 0.197) but became significant for predefined exploratory subgroups. EORTC QLQC30-B23 global health status was sustained for efti but deteriorated for placebo. Efti increased absolute lymphocyte, monocyte and secondary target cell (CD4, CD8) counts, plasma IFNγ and CXCL10 levels. Conclusions: Although the primary endpoint, PFS, was not met, AIPAC confirmed expected pharmacodynamic effects and demonstrated excellent safety profile for efti. OS was not significantly improved globally (2.9-month difference), but was significantly improved in exploratory biomarker subgroups, warranting further studies to clarify efti's role in patients with ET-resistant HER2− MBC.

BACKGROUND:Eftilagimod alpha (efti) is a major histocompatibility complex class II agonist activating antigen-presenting cells which leads to greater systemic type 1 T helper response and more cytotoxic CD8+ T-cell activation. This phase I trial evaluated the administration of efti, a soluble lymphocyte activation gene-3 (LAG-3) protein, combined with the anti-programmed death-ligand 1 (PD-L1) antibody avelumab in advanced solid tumors.PATIENTS AND METHODS:Patients with heavily pretreated metastatic solid tumors received intravenous avelumab (800 mg) combined with subcutaneously administered efti (6 or 30 mg) for up to 12 cycles, followed by avelumab monotherapy. The primary endpoint was the assessment of the recommended phase II dose (RP2D) of efti in combination with avelumab.RESULTS:Twelve patients with different tumor entities were enrolled (six patients in each cohort). During treatment, no dose-limiting toxicities occurred, and the severity of most adverse events was grade 1 or 2. In total, nine serious adverse events were documented, resulting in a fatal outcome in two cases, but none of them were assessed to be treatment related. Five patients (42%) achieved partial response. The median progression-free survival was 1.96 months and the median overall survival was not reached, with a 12-month survival rate of 75%.CONCLUSION:Subcutaneously administered efti plus avelumab was well tolerated, and efti of 30 mg was determined to be RP2D. The activity is promising and warrants further investigation in future phase II trials.

Background Eftilagimod alpha (E, LAG-3Ig) is a soluble LAG-3 protein binding to MHC class II and stimulates antigen-presenting cells (APC). Thus T cells (CD4/CD8) are recruited, leading to stronger anti-tumor response than with pembrolizumab (P). Clinical studies with E have shown increased IFN-gamma, CXCL10 and absolute lymphocyte count (ALC). We report biomarker results from the 1st line non-small cell lung carcinoma (NSCLC) cohort in TACTI-002 (NCT03625323). Methods Pts with measurable, 1st line metastatic NSCLC unselected for PD-L1 were recruited. Exploratory endpoints included analyses of Th1 biomarkers (IFN-gamma; CXCL10), ALC and gene expression profile (GEP). Pts received E (30 mg SC q2w 8 cycles [1 cycle= 3 weeks], then q3w) with P (200 mg IV q3w). Th1 samples were collected early (pre-dose; 8x within 96 h) and late (pre-dose at 3 and 6 mts). Th1 levels were assessed centrally by electrochemiluminescence immunoassay. ALC was locally tested on day 1 of each cycle. GEP samples were collected (pre-treatment and at 3 mts) for central testing (Nanostring nCounter® PanCancer Immune Profiling Panel). Results 114 pts were enrolled. Median age was 67 yrs (44–85) & 74% were male. ECOG PS was 0 & 1 in 37% & 63% of pts. IFN-gamma and CXCL10 significantly increased soon after first E administration (up to 96 h; table 1) and remained significantly elevated at 3 and 6 mts (table 1) pre-dose. ALC increase from baseline was observed at 1st assessment and was maintained. When separating pts by disease control (CR, PR & SD versus PD, NA & NE, by iRECIST), ALC change was significantly higher in pts with disease control (0.43 vs 0.04; p=0.01). PFS was significantly prolonged in pts with ALC increase (≥0.2 versus <0.2x109/L pre-defined cut-off), on treatment (mPFS 9.8 mts vs. mPFS 6.9 mts, respectively). OS was immature at data cut-off (31-Mar-23). GEP analysis showed upregulated expression of genes related to T-cell functions, cytotoxicity functions, cytotoxic cells, or TH1 cells which are more pronounced in pts with PR/CR. Conclusions Significant early and sustained increases of circulating biomarkers and ALC substantiate the systemic stimulation via the APC activator efti and show that repeated minimally-invasive liquid biopsies, i.e., blood samplings, are key in detecting this systemic stimulation. Acknowledgements We thank all the participating patients & their families. We thank the dedicated clinical trial investigators & their team members. This study is sponsored by Immutep. Corresponding author: Frederic Triebel, frederic.triebel@immutep.com. This study is in collaboration with Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA. Trial RegistrationThe trial identifiers are TACTI-002 (sponsor code), IMP321-P015 (Sponsor code),Keynote-PN798 (MSD code), 2018–001994-25 (EudraCT) and NCT03625323 (ClinicalTrials.gov)

Background Eftilagimod alpha (E) is a soluble LAG-3 protein binding to a subset of MHC class II molecules to mediate antigen-presenting cell (APC) activation & T-cell (CD4/CD8) recruitment/activation. By stimulating APCs with E, T cells are recruited, possibly leading to stronger anti-tumor responses than with pembrolizumab (P) alone, especially in tumors not overexpressing PD-L1. Herein we report results of the 1st line non-small cell lung carcinoma (NSCLC) cohort in the TACTI-002 ("Two ACTive Immunotherapies") trial. Methods Pts with measurable, 1st line metastatic NSCLC unselected for PD-L1 were recruited. The objective response rate (ORR) by iRECIST was the primary endpoint (EP). Secondary EPs include ORR by RECIST 1.1, ORR by blinded independent central read (BICR), duration of response (DoR), progression-free survival (PFS), overall survival (OS), PD-L1 and IFN-gamma, safety & tolerability. Pts received 30mg E SC q2w for 8 cycles (1 cycle= 3 weeks) & then q3w for up to 1 year with P (200 mg IV q3w for up to 2 years). Imaging was done every 8 weeks & assessed by investigator. PD-L1 was assessed centrally (22C3 antibody). The study was powered to detect a 52% increase in ORR compared to historical results for P 80% power & 1-sided alpha of 2.5%. Planned recruitment=110 pts. Results From Mar 2019-Nov 2021, 114 pts were enrolled. Median follow-up was 13 mo (data cut-off Jul 1st 2022). Median age was 67 yrs (44-85) & 74% were male. ECOG PS was 0 & 1 in 37% & 63% of pts. Pts presented with squamous (35%) or non-squamous (63%) carcinoma and 93% had metastatic disease. All PD-L1 subgroups were represented (table 1). Pts received median 9.0 (range 1–18) P & 13.0 (1-22) E. 11 (9.6%) pts discontinued due to related adverse events (AEs). Common (≥15%) AEs were dyspnea (35%), asthenia (33%), decreased appetite (25%), cough (25%), anemia (23%), fatigue (21%), pruritus (21%), constipation (18%), nausea (17%), hemoptysis (16%) & diarrhea (16%). ORR by iRECIST (primary EP) was 39.5% (95% CI 30.5-49.1) & median PFS was 6.9 mo (95% CI 4.9-9.3). Responses were observed in all PD-L1 subgroups (table 1). ORR (iRECIST) for squamous & non-squamous were 37.5% & 38.9%. Median duration of response was 21.6 mo. Results acc. to RECIST 1.1 were comparable. Early & sustained increases of circulating CXCL-10 & IFN-gamma levels were observed. Conclusions E + P is safe & shows encouraging antitumor activity in 1st line metastatic NSCLC patients unselected for PD-L1, warranting late-stage clinical investigation. Acknowledgements We thank all the participating patients & their families. We thank the dedicated clinical trial investigators & their team members. Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA provided pembrolizumab for the study. Sponsored by Immutep. Trial Registration The trial identifiers are TACTI-002 (sponsor code), IMP321-P015 (Sponsor code), Keynote-PN798 (MSD code), 2018-001994-25 (EudraCT) and NCT03625323 (ClinicalTrials.gov). Ethics Approval This has been approved by relevant Competent Authorities, Ethics Committees, and Institutional Review Boards.

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. 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. 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: 171POS for subgroups significant p<0.15 in the multivariate modelSubgroupTreatment groupOS Median [95% CI]Absolute gain; Hazard ratio (HR) [95% CI]; p-value (univariate analysis)High (>3.65) NLR at baselineEfti21.85 [13.6-29.0]+6.9 months; HR 0.61 [0.39-0.94]; p=0.012Placebo14.95 [8.9-17.6]No prior taxanesEfti22.3 [17.3-33.0]+4.8 months; HR 0.74 [0.49-1.12]; p=0.076Placebo17.5 [12.3-23.5]Low (<0.25/nL) monocytes at baselineEfti32.5 [18.2--]+19.6 months; HR 0.44 [0.22-0.88]; p=0.008Placebo12.9 [7.5-20.4]<5 yrs since diagnosisEfti22.31 [11.93-33.0]+4.8 months; HR 0.62 [0.38-1.00]; p=0.025Placebo13.25 [9.0-17.6] Open table in a new tab 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.

BackgroundEftilagimod alpha (efti; IMP321) 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 CD8 T-cells. Weekly paclitaxel is a standard of care chemo-regimen after failure of endocrine-based therapy for metastatic breast carcinoma (MBC). AIPAC (Active Immunotherapy PAClitaxel) investigated the addition of efti to weekly paclitaxel in these patients (pts).MethodsThis placebo-controlled, double-blinded, 1:1 randomized phase IIb trial enrolled pts with measurable disease, HR+ HER2- MBC after endocrine-based therapy. Pts received paclitaxel (80 mg/m² IV on D1, D8, D15) + efti (30 mg) or placebo on D2, D16 (every 2 weeks) for up to 24 weeks following efti/placebo for up to 52 weeks. The primary endpoint (EP) was progression-free survival (RECIST1.1) by BICR. Secondary EPs included overall survival (OS), PFS (local read), overall response rate (ORR), biomarker, quality of life. Exploratory EPs included univariate/multivariate analyses.Results227 pts were randomized (Jan2017-Jul2019). All except 1 received ≥1 treatment and were included in the full analysis set [efti (n=114); placebo (n=112)]. Data cut-off was 14May2021 (min. follow-up= 22 months). Median age was 60 yrs with ECOG 0 in 61.5%. 91.6% had visceral disease. Pts were mostly endocrine resistant (84%) and partially pre-treated with CDK4/6 inhibitors (44.2%). Post-study treatment was similar. Median OS was 20.4 (95% CI: 14.3-25.1) months in the efti group vs. 17.5 (95% CI: 12.9-21.9) in the placebo group. HR was 0.88 (95%CI: 0.64-1.19; p=0.197). In predefined univariate analyses, younger pts, low baseline monocytes and luminal B showed significant/clinically meaningful improvement in OS (table 1).Efti increased PBMC/T cell (CD4/CD8) count vs. placebo, correlating with improved OS (Spearman Rho=0.6, p=0.02 for CD8 T cells). In a whole population multivariate cox regression model, increasing BMI and prior treatment with CDK4/6 were independent significant poor prognostic markers for PFS and OS.TEAEs leading to discontinuation were similar at 5.3%(efti) & 6.3%(placebo). PFS (Primary EP) and safety were reported at SABCS 2020 (Abstract#132).Abstract 948 Table 1Overall survival by subgroups at final analysisConclusionsEfti added to paclitaxel led to a non-significant 2.9 months median OS increase in HR+ HER2- MBC pts after endocrine-based therapy. Effects were significant in pts <65yrs, with low monocytes and more aggressive disease (luminal B). Efti increased circulating CD4/CD8 T cells, which significantly correlated to improved OS. Weekly paclitaxel + efti should be further investigated in MBC.Trial RegistrationThe trial identifiers are IMP321-P011 (code for sponsor), 2015-002541-63 (EudraCT) and NCT02614833 (ClinicalTrials.gov).Ethics ApprovalThe study was approved by relevant ethic committees and institutional review boards.

Sepsis is associated with a dysregulated inflammatory response to infection. Despite the activation of inflammation, an immune suppression is often observed, predisposing patients to secondary infections. Therapies directed at restoration of immunity may be considered but should be guided by the immune status of the patients. In this paper, we described the use of a high-dimensional flow cytometry (HDCyto) panel to assess the immunophenotype of patients with sepsis. We then isolated peripheral blood mononuclear cells (PBMCs) from patients with septic shock and mimicked a secondary infection by stimulating PBMCs for 4 h in vitro with lipopolysaccharide (LPS) with or without prior exposure to either IFN-γ, or LAG-3Ig. We evaluated the response by means of flow cytometry and high-resolution clustering cum differential analysis and compared the results to PBMCs from healthy donors. We observed a heterogeneous immune response in septic patients and identified two major subgroups: one characterized by hypo-responsiveness (Hypo) and another one by hyper-responsiveness (Hyper). Hypo and Hyper groups showed significant differences in the production of cytokines/chemokine and surface human leukocyte antigen-DR (HLA-DR) expression in response to LPS stimulation, which were observed across all cell types. When pre-treated with either interferon gamma (IFN-γ) or lymphocyte-activation gene 3 (LAG)-3 recombinant fusion protein (LAG-3Ig) prior to LPS stimulation, cells from the Hypo group were shown to be more responsive to both immunostimulants than cells from the Hyper group. Our results demonstrate the importance of patient stratification based on their immune status prior to any immune therapies. Once sufficiently scaled, this approach may be useful for prescribing the right immune therapy for the right patient at the right time, the key to the success of any therapy.

Abstract Background:Eftilagimod alpha (efti, IMP321),a soluble LAG-3 protein (LAG-3Ig) that binds to a subset of MHC class II molecules, mediates antigen-presenting cell (APC) activation followed by CD8 T-cell activation. AIPAC (Active Immunotherapy PAClitaxel; NCT02614833) investigatedcombinations of the APC activator efti + weekly paclitaxel compared to paclitaxel + placebo in metastatic breast carcinoma (MBC) patients (pts). Methods:The placebo-controlled, double-blinded, 1:1 randomized, multinational, phase IIb trial enrolled pts with measurable disease, hormone receptor-positive (HR+) MBC with indications for first line weekly paclitaxel without indication for HER2/neu targeted therapy. Pts received paclitaxel (80 mg/m² IV at D1, D8, D15 plus efti (30 mg) or placebo at D2, D16 (injected SC every 2 weeks) for 6 cycles (1 cycle = 4 weeks). Maintenance phase followed in which pts benefitting from treatment received efti or placebo for an additional 52 weeks. Primary endpoint was progression-free survival (PFS) (RECIST1.1) determined by blinded independent central read (BICR). Secondary endpoints included local read PFS, RECIST 1.1 tumor response, pharmacodynamic effects, quality of life and overall survival. The study was powered (80 %) to detect 0.667 hazard ratio (HR) based on 5% one-sided alpha and planned to enroll 226 pts. Results: From Jan 2017-Jul 2019, 227 pts were randomized. All except 1 received ≥ 1 treatment and were included in the full analysis set [(efti (n = 114); placebo (n = 112)]. Data cut-off was 10th Jan 2020 with 12 month median follow-up. HR for PFS assessed by BICR was 0.93 [95 % CI 0.67-1.30], p =0.341. In the efti group 63 % (95% CI 52- 71%) were progression free at 6 months compared to 54 % (95% CI 43-63%) in the placebo group. ORR was 48.3 % in the efti group compared to 38.4 % in the placebo group as assessed by BICR (p=0.118). Efti increased numbers of PBMCs and T cells (CD4 and CD8) significantly compared to placebo. In predefined subgroups such as pts with low monocytes at baseline, luminal B subtype or age <65 years, clinically meaningful improvement in PFS was observed. TEAE rates leading to death (or discontinuation) in the two groups were similar, at 1.8 % (5.3 %) and 2.7 % (6.3 %) for the efti and placebo groups, respectively. Three pts (1.3 %) were withdrawn from treatment due to grade 3-4 immediate hypersensitivity reactions to efti, while 4 pts (1 in efti group vs. 3 in placebo group) were withdrawn from the study due to grade 2-3 hypersensitivity to paclitaxel. The most frequent (≥10%) TEAEs ≥ grade 3 were gamma-glutamyl transferase increase (19.3% vs 29.5%), aspartate aminotransferase increase (8.8% vs 10.7%) and neutropenia (15.8% vs 14.3%) reported in the efti and placebo group, respectively. Injection site reaction (34.2% vs 3.6%) and injection site erythema (30.7% vs 1.8%) were more frequent in efti versus placebo arms. Conclusion: Efti did not prolong overall median PFS in women with HR+ MBC receiving first line chemotherapy. Tested in a randomized setting against placebo in pts receiving paclitaxel, efti is well tolerated and did not add clinically significant toxicity while inducing a sustained, significant increase in CD8 T cells in blood and clinical benefits in some predefined subgroups. Relevant subgroups and overall survival will be investigated. BICRInvestigatorEfti+paclitaxel(N= 114)Placebo+paclitaxel(N= 112)Efti+paclitaxel(N= 114)Placebo+paclitaxel(N= 112)Median PFS, months (95% CI)7.29 (6.64-7.46)7.29 (5.52-7.46)7.16 (5.65-7.39)6.70 (5.52-7.33)HR (95% CI)0.93 (0.67-1.30)0.92 (0.69-1.23)P value0.3410.305Mean PFS [SE], months7.12 [0.37]6.64 [0.38]6.81 [0.33]6.30 [0.31] Citation Format: Hans Wildiers, Anne Armstrong, Eveline Cuypere, Florence Dalenc, Luc Dirix, Steve Chan, Frederik Marme, Carolina Pia Schröder, Jens Huober, Jill Wagemans, Peter Vuylsteke, Jean-Philippe Jacquin, Etienne Brain, Sherko Kümmel, Zsuzsanna Pápai, Luca Perjesi, Christian Mueller, Chrystelle Brignone, Frederic Triebel. Primary efficacy results from AIPAC: A double-blinded, placebo controlled, randomized multinational phase IIb trial comparing weekly paclitaxel plus eftilagimod alpha (soluble LAG-3 protein) vs. weekly paclitaxel plus placebo in HR-positive metastatic breast cancer patients [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD14-08.