Testing a higher dose (90 mg s.c.) of eftilagimod alpha, a soluble LAG-3 protein, in metastatic breast cancer patients receiving weekly paclitaxel | FPN: 200P |
in AIPAC-003 | |
S. Morales Murillo1; F. Forget2; E. Segui3; N.K. Ibrahim4; B. Doger5; J. Canon6; P. Chalasani 7; K. Papadamitriou8; M. Oliveira9; P. Sanchez Rovira10; F.D. Vogl11; C. Mueller11; F. Triebel12
1Hospital Universitario Arnau de Vilanova, IRB-Lleida, Lleida, Spain; 2Centre Hospitalier de l'Ardenne, Libramont, Belgium; 3Hospital Clinic de Barcelona, Barcelona, Spain; 4The University of Texas MD Anderson Cancer Center, Houston, USA; 5START Madrid: Hospital Universitario Fundación Jiménez Díaz, Madrid, Spain; 6Grand Hopital de Charleroi, Hopital Notre Dame, Charleroi, Belgium; 7George Washington University, Washington, USA; 8Antwerp University Hospital, Antwerp, Belgium; 9Vall d'Hebron University Hospital and Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain; 10Hospital Universitario de Jaen, Jaen, Spain; 11Immutep GmbH, Berlin, Germany; 12Immutep SAS, Saint-Aubin, France.
BACKGROUND | RESULTS |
Eftilagimod alpha (efti):
• Mechanism of action: efti is a soluble LAG-3 protein (LAG-3 domains fused Figure 1: MoA of efti to human IgG backbone) and MHC Class II agonist. Activating antigen
presenting cells (APCs: dendritic cells & monocytes) with efti leads to a broad immune response to fight cancer, including increases in activated T cells (CD4/CD8) and other important immune cells/cytokines (Figure 1).
BASELINE CHARACTERISTICS | EFFICACY | |
• Between May-Sep 2023, 6 patients were enrolled into the | • | All responses were confirmed, leading to a confirmed ORR per RECIST 1.1 of 50.0%, including one |
safety lead-in with a minimum follow up of 4.0 months. | complete response (CR) (Table 2 and Figures 3-5). | |
Baseline characteristics are reported in Table 1. | • | DCR of 100% (Table 3). |
Figure 4: Case study of a 35-year-old woman with confirmed CR on continued efti
Neo-adjuvant: EC & | Disease progression | |||
Carbotaxol | Relapse | |||
Mastectomy & | March 2023 | May 2023 | ||
radiotherapy | For metastatic | |||
Initial diagnosis Adjuvant: Capecitabine | disease: Letrozole & Started on AIPAC-003 | C1-C8: combined 90 mg efti + weekly paclitaxel | C9 onwards: 90 mg efti | |
Sep 2019 2019 - 2020 (12-mo) | Ribociclib 2023 (2-mo) | May 2023 |
- Synergistic effect with chemotherapy: efti reinforces long-lasting T cell responses, leading to more durable effects & prolonged survival with minimal related side effects.
Trial Rationale:
- Data from predecessor randomized, phase 2b trial of paclitaxel plus either efti or placebo in HR+ HER2- MBC patients (AIPAC; NCT02614833) linked sustained pharmacodynamic activity to improved overall survival (OS) in the efti arm1.
- To address a high unmet medical need in HR+ HER2-neg/low MBC and metastatic TNBC patients eligible to receive chemotherapy after failure of previous standard of care therapies.
METHODS
Trial Design
AIPAC-003 has multiple components, including an initial safety lead-in component followed by a Phase 2 open-labeldose optimization lead-in and final Phase 3 component as described below and in Figure 2.
- Initial safety lead-in(n=6): evaluate safety of a higher dose of efti (90 mg).
- Dose optimization lead-in(n=66): randomized 1:1 to determine optimal biological dose (OBD) based on safety, tolerability, efficacy & pharmacodynamic/ pharmacokinetic (PK) data.
- Phase 3: randomized, double-blinded; to be further defined after determination of the OBD.
Figure 2: Trial Design & Schedule of Treatments
Table 1: Baseline characteristics
Baseline characteristics, n (%) | (N=6) |
Age, median (range), years | 66.0 (35-78) |
<65 years | 3 (50.0) |
ECOG 0/1 | 5 (83.3) / 1 (16.7) |
HR receptor positivity | |
ER / PR | 6 (100) / 4 (66.7) |
HER2 receptor status | |
Negative / Low | 2 (33.3) / 4 (66.7) |
Pre-menopausal /Post-menopausal | 1 (16.7) / 5 (83.3) |
Cancer stage at initial diagnosis | |
II / III / IV | 3 (50.0) / 2 (33.3) / 1 (16.7) |
Time between initial diagnosis and first | |
onset of metastasis, median (range), | 77.5 (0.1-252.8) |
months | |
(Neo)adjuvant therapy | 4 (66.6) |
Endocrine therapy | 3 (50.0) |
Figure 3: Swimmer plot
Baseline | Week 16 | Week 44 | |||||
• 35-year old woman, pre-menopausal. Diagnosed initially with a stage IIa TNBC.
- Baseline ECOG 0.
- HER2- low, ER+/PR+, EGFR pos, PD-L1 neg, BRCA neg, PIK3CA neg.
- Partial response turned into complete response (CR) during chemo-IO. Ongoing
CR has been maintained for 2 months since patient has been treated with efti monotherapy.
TL SOD | 36 mm | 16 mm | 3.6 mm |
NTL | - | Non-CR/non-PD | CR |
(Right hilar LN) | |||
Overall response | - | PR (-55.6%) | CR (-91.7%)* |
(Change from baseline %) | |||
*Shrinkage of both lymph nodes target lesions to <10mm along short axis led to complete response of ~92%.
Figure 5: Th1 biomarker ≥1.4* fold change from baseline | Figure 6: Efti PK profile |
A) Key trial components of AIPAC-003
-
Treatment phases & schedule of treatments
Treatment phases
Key Inclusion/ Exclusion Criteria
- Female patients with MBC HR+ HER2-neg/low* or mTNBC.
- ECOG performance status 0-1.
- No prior chemo in the metastatic setting.
- Measurable disease.
Assessments and Statistical Analysis
Schedule of treatments
Primary Objective:
- Safety & tolerability of 90 mg efti combined with paclitaxel.
Secondary Objectives:
- ORR by RECIST 1.1, PFS, OS and PK profile.
Chemotherapy* | 4 (66.6) |
Duration of prior CDK 4/6i + ET for | |
metastatic disease, median (range), | 7.3 (0.6-82.1) |
months | |
Endocrine resistance | 6 (100) |
CDK: cyclin-dependent kinase; ECOG: Eastern Cooperative Oncology Group;
ER: estrogen receptor; HR: hormone receptor; PR: progesterone receptor.
*including 2 patients treated with taxanes.
SAFETY
- No dose-limiting toxicities or treatment-emergent adverse events (TEAEs) of grade 3 or higher severity were recorded. Most frequent TEAEs are listed in Table 2.
Table 2: TEAEs with incidence ≥2 patients
Preferred term, n (%) | Grade 1-2 | Grade ≥3 |
Anemia | 2 (33.3) | NA |
Neutropenia | 2 (33.3) | NA |
Polyneutropathy | 2 (33.3) | NA |
Table 3: Confirmed best overall response
Response1, n (%) | N=6 |
Complete Response | 1 (16.7) |
Partial Response | 2 (33.3) |
Stable Disease | 3 (50.0) |
Progression | 0 |
ORR | 3 (50.0) |
DCR | 6 (100) |
1Response was investigator-assessed per RECIST 1.1.
IMMUNO-MONITORING
- Efti's 90 mg pharmacodynamic effects showed an increase of circulating levels of immune cells such as CD8 and CD4 T cells. Plasma TH1 biomarker levels were also increased (Figure 5).
PHARMACOKINETICS
• 90 mg efti remains detectable at a pharmacologically-active dose (≥1 ng/mL) up to 96 |
*To detect a clinically-relevant change in biomarkers, the minimum fold change increase presented was at least ≥1.4.
SUMMARY & CONCLUSION
- Initial results from the safety lead-in of the AIPAC-003 study suggest 90 mg efti plus weekly paclitaxel can be safely combined & is well-tolerated in metastatic breast cancer patients.
- Encouraging confirmed ORR of 50% (including 1 confirmed CR) and DCR of 100%.
- The 90 mg dose of efti plus weekly paclitaxel is being evaluated further in the randomized OBD component (n=66), which will compare 90 mg vs 30 mg of efti to determine the optimal biological dose.
- Data cut-off date was April 3, 2024, for safety and efficacy analyses; and March 28, 2024 for immuno-monitoring & PK analyses.
*Estrogen and/or progesterone receptor positivity is defined as ≥1%, HER2 receptor negativity is defined in line with ASCO/CAP guidelines2,3.
Asthenia | 2 (33.3) | NA |
hours after administration (Figure 6). |
Recruitment for this study is ongoing. For more info, please visit: Clinicaltrials.gov.
ABBREVIATIONS | HR... hormone receptor | MHC… Major Histocompatibility Complex | PD-1... Programmed cell death protein 1 | REFERENCES | ACKNOWLEDGEMENTS | DISCLOSURES | Copies of this presentation obtained through QR, | ||
AIPAC… Active Immunotherapy PAClitaxel | IO... immuno-oncology therapy | NK… natural killer | s.c… Subcutaneous | ||||||
1 | Wildiers, H. et al. Clin Cancer Res. 2024 Feb 1; 30(3): 532-541. doi: 10.1158/1078-0432.CCR-23-1173. | • We thank all the participating patients & their families. | First author: Serafin Morales Murillo | AR and/or text key codes are for personal use only | |||||
DOL… Dose optimization lead-in | RECIST… Response Evaluation Criteria In Solid Tumors | OBD… Optimal biological dose | Th1… T helper type 1 | ||||||
ECOG… Eastern Cooperative Oncology Group | I.V… intravenous | ORR… objective response rate | 2 | Burnstein, H. et al. J Clin Oncol. 2021 Dec 10;39(35):3959-3977. doi: 10.1200/JCO.21.01392. | • We thank the dedicated clinical trial investigators & their team members. | COI: no COI to disclose. | and may not be reproduced without written | ||
ET… Endocrine-based Therapy (ET) | LAG-3... Lymphocyte Activation gene-3 | PD-L1...Programmeddeath-ligand 1 | 3 | Wolff, A. et al. J Clin Oncol. 2013 Nov 1;31(31):3997-4013. doi: 10.1200/JCO.2013.50.9984. Epub 2013 | Oct 7. | • This study is sponsored by Immutep. Corresponding author: Frederic Triebel, frederic.triebel@immutep.com. | permission of the authors. | ||
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Immutep Ltd. published this content on 15 May 2024 and is solely responsible for the information contained therein. Distributed by Public, unedited and unaltered, on 31 May 2024 08:46:03 UTC.