Immutep : ESMO 2023 - EFTISARC-NEO Trial in Progress Poster (Soft Tissue Sarcoma)

Pembrolizumab in combination with eftilagimod alpha and radiotherapy in neoadjuvant treatment of patients with soft tissue sarcomas - EFTISARC-NEO trial

Katarzyna Kozak, Paweł Sobczuk, Sylwia Kopeć, Tomasz Świtaj, Paweł Teterycz, Aneta Borkowska, Piotr Rutkowski	1987TiP
Department of Soft Tissue, Bone Sarcoma and Melanoma, Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, PL,

BACKGROUND

• Surgery is the mainstay of treatment of primary localized soft tissue sarcoma (STS). However,

despite optimal surgical resection, disease recurrence is common.
• In patients (pts) with high-grade localised STS of the extremity/trunk, and tumor size > 5cm,
radiation therapy (RT) is added to reduce local recurrence. Adjuvant/neoadjuvant AI ChT may be
used to improve survival, but its efficacy is limited to pts with poor prognosis
• Recently, immunotherapy (ITH) has been widely studied in pts with metastatic STS, however
response rates are modest - its efficacy and impact on tumor microenvironment remain unclear
• Combining ITH with RTH may be a promising strategy for synergistic enhancement of treatment
efficacy and the use of such a combination in the preoperative setting provides a unique	Fig. 1. Role of LAG-3 in physiological situation (A), mechanism of action of soluble LAG-3
opportunity to derive biological information related to tumor response.	protoein eftilagimod. (efti) (B) or anti-LAG-3 monoclonal antibody (C).
• As anti-PD1 therapy is not sufficiently effective in many cancers, novel compounds such as
eftilagimod alpha (efti) are being tested in combination with ITH to stimulate antigen-presenting
cells and boost the immune response.
• Efti is a dimeric soluble recombinant LAG-3 protein. In contrast to antagonist anti-LAG-3
antibodies, Efti is an agonist stimulating antigen-presenting cells (APCs) via MHC II. The LAG-3 -
MHC II interaction controls the signalling between T cells and APCs, which are responsible for the
adaptive immune response (Fig. 1, 2)
• Anti-PD-1, such as pembrolizumab, addresses part of the immune escape mechanism i.e.,
the tumor-induced T cell downregulation. On the other hand, the capacity of immune cells
to recognize tumor cells and prime an effector response can be increased by APC
activators providing support for the combination of these two drug classes (Fig. 3 )
	Fig. 2. Mechanism of action of soluble LAG-3 protein - eftilagimod alpha
	TRIAL DESIGN

• We hypothesize that adding combined ITH to RT prior to surgical resection would be safe and improve pathologic response compared to historical cohorts of pts with localized STS treated with RT alone.
• The percentage of hyalinisation and fibrosis, as a surrogate of pathological response, appears to be most closely correlated with treatment outcome.

Fig. 3. Rationale for combining eftilagimod alpha, pembrolizumab and radiotherapy based on cancer-immune cycle.

STUDY ENDPOINTS

Primary:

• The primary efficacy endpoint is a percent tumor hyalinization as a marker of response to treatment assessed at the time of surgical resection.
  H0 - 15% (based on Schaefer M. et al.), H1 - 35%

Secondary:

• Incidence of adverse events graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 5.0
• Number of patients completing neoadjuvant treatment and having a curative surgery according to the protocol
• Disease-freesurvival time (DFS)
• Locoregional disease-free survival (LRFS)
• Distant metastasis-free survival (DMFS)
• Overall survival time (OS)
• Radiologic Response To Neoadjuvant Treatment using RECIST 1.1

Exploratory:

• To evaluate changes in the composition of tumor microenvironment, including immune infiltrates, before and after neoadjuvant treatment
• To evaluate correlations between changes of immune-related biomarkers in the tumor or blood with response to therapy and patients' survival
• To compare changes in tumor microenvironment caused by neoadjuvant radiotherapy and immunotherapy with pembrolizumab and eftilagimod with changes related to other modalities (radiotherapy alone, radiotherapy with chemotherapy in neoadjuvant settings, or immunotherapy +/- other agents in advanced settings).

REFERENCES

Key Inclusion Criteria

• ≥ 18 years of age
• ECOG 0 or 1
• Primary or locally recurrent deep-seated extremities, girdles and/or superficial trunk (thoracic or abdominal wall) tumor;
• One of the following histologies
• • undifferentiated pleomorphic sarcoma (UPS),
  • myxofibrosarcoma,
  • dedifferentiated liposarcoma (DDLPS),
  • myxoid and round cell liposarcoma (MRCLPS),
  • epithelioid sarcoma (ES)
  • angiosarcoma (AS),
  • soft tissue sarcoma NOS.
• Grade 2 or 3 tumors according FNCLCC;
• Size of the primary tumor >5 cm or locally recurrent of any size;
• Measurable disease based on RECIST 1.1;
• No previous systemic treatment for sarcoma;

Key Exclusion Criteria

• Distant metastases
• Previous treatment with eftilagimod alpha, anty-PD-1 or anty-PD-L1;
• Prior radiotherapy to tumor-involved sites;
• Subjects with active, known or suspected autoimmune disease or inflammatory bowel disease, which might impair the subject's tolerance of trial treatment.

The study is ongoing in Poland. To date, 6 patients have been enrolled and recruitment is expected to be completed by December 2024

Fig. 4. EFTISARC-NEO trial design

Fig. 5. Design of translation studies within EFTISARC-NEO trial.

• Schaefer I-M et al. Histologic appearance after preoperative radiation therapy for soft tissue sarcoma: assessment of the European Organization for Research and Treatment of Cancer-soft tissue and bone sarcoma group response score. Int J Radiat Oncol Biol Phys. 2017;98(2):375-83.
• Pasquali S et al. Histopathological response (HR) after neoadjuvant chemotherapy (ChT) for high-risk soft tissue sarcomas (STS): A planned analysis of the ISG-STS-1001 trial. J Clin Oncol 41, 2023 (suppl 16; abstr 11511)
• Lai, J.Z. et al. Local Irradiation Sensitized Tumors to Adoptive T Cell Therapy via Enhancing the Cross-Priming, Homing, and Cytotoxicity of Antigen-Specific CD8 T Cells. Front Immunol, 2019. 10: p. 2857.
• Atkinson, V., et al., Eftilagimod alpha, a soluble lymphocyte activation gene-3(LAG-3) protein plus pembrolizumab in patients with metastatic melanoma. J Immunother Cancer, 2020. 8(2).

DISCLOSURES

Katarzyna Kozak: Speaker honoraria - BMS, MSD, Novartis, Pierre Fabre, Sanofi; advisory board - BMS, MSD;

Pawel Sobczuk: speaker honoraria - BMS, Swixx Biopharma, Gilead; travel grants - BMS, MSD, Novartis, Pierre Fabre; advisory board - Sandoz; Stocks owner - Celon Pharma; Board member - Polish Society of Clinical Oncology; Tomasz Świtaj: Speaker honoraria - BMS, MSD, Novartis, Pierre Fabre, Sanofi; travel grants - BMS, MSD, Novartis, Pierre Fabre; Paweł Teterycz: Speaker honoraria - BMS, MSD, Novartis, Pierre Fabre; travel grants

• BMS, MSD, Novartis, Pierre Fabre; Aneta Borkowska and Sylwia Kopec declare no conflicts of interests; Piotr Rutkowski: Speaker honoraria - BMS, Merck, MSD, Novartis, Pierre Fabre, Sanofi; advisory board - Blueprint

FUNDING

Study is funded by grant from Medical Research Agency - agreement number 2022/ABM/01/00013-00 "Jednoramienne badanie II fazy oceniające skuteczność i bezpieczeństwo pembrolizumabu w połączeniu z agonistą LAG-3 eftilagimodem i radioterapią w leczeniu przedoperacyjnym chorych na mięsaki tkanek miękkich (EFTISARC-NEO)" (PI Katarzyna Kozak).

Immutep has provided eftilagimod alpha.

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Twitter: @pawel_Sobczuk, @katarzynakozak9