Immutep : ESMO Breast 2024 AIPAC 003 Poster (Metastatic Breast Cancer)

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

1. 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, [e-mail].		permission of the authors.