(P 545) NEOADJUVANT PEMBROLIZUMAB AND EFTILAGIMOD ALPHA WITH CONCURRENT RADIOTHERAPY IN PATIENTS WITH SELECTED SOFT TISSUE SARCOMA SUBTYPES (EFTISARC-NEO)

Objective: The efficacy of widely used immune checkpoint inhibitors (anti-PD-1 +/- anti-CTLA4, anti-PD-L1 antibodies) remains modest in patients with advanced soft tissue sarcoma (STS). Only a small proportion of sarcoma patients respond to immunotherapy (ITH), and there are no validated biomarkers of efficacy. To date, the presence of tertiary lymphoid structures appears to be most strongly associated with survival benefits upon treatment with ITH. However, this significantly limits the population of patients who can benefit from ITH. Finding the right combination of immune checkpoint inhibitors remains a major challenge. Therefore, the aim of our study is to evaluate the efficacy and safety of a novel combination of anti-PD-1 antibody and antigen-presenting cell (APC) activator in the neoadjuvant setting. Eftilagimod alpha (Efti) is a dimeric soluble LAG-3 molecule that binds to MHC class II on APCs, thereby inducing T cell proliferation, T helper 1 (Th1) response and NK cell activation (secondary target). Efti is one of the first APC activators that reached phase III clinical trials (advanced breast cancer, head and neck squamous cell carcinoma). Given the low activity of anti-PD-1 monotherapy in STS, we hypothesize that the addition of an APC activator such as Efti may help to activate the cellular immune response mechanism to optimize tumour cell recognition and killing, thus leading to synergistic effects and a higher rate of disease responses. In addition, this dual immunotherapy will be used in combination with radiotherapy (RTH), as preclinical studies have shown that radiotherapy increases the release of tumour-associated antigens, which facilitates cross-presentation of tumour-associated antigens by dendritic cells and priming of antigen-specific T lymphocytes.

Methods: EFTISARC-NEO is an open-label Phase II study evaluating the efficacy and safety of pembrolizumab and Efti in combination with RTH in the neoadjuvant setting in patients with STS. Key eligibility criteria are: 1) primary or locally recurrent extremity, girdles and/or superficial trunk tumour, 2) one of the following subtypes: undifferentiated pleomorphic sarcoma, myxofibrosarcoma, dedifferentiated liposarcoma, myxoid and round cell liposarcoma, epithelioid sarcoma, angiosarcoma, soft tissue sarcoma NOS; 3) Grade 2/3 tumours according to FNCLCC; 4) Size of the primary tumour>5 cm or locally recurrent of any size. Forty pts will be enrolled to receive efti 30 mg sc Q2W (5 cycles) and pembrolizumab 200 mg iv Q3W (3 cycles) with concurrent RT, followed by surgery. The total radiation dose scheduled is 50 Gy administered in conventional fractionation of 2 Gy/day for 5 days a week from week 2 to week 6. Surgery is planned 5-6 weeks after completion of RTH. The primary endpoint is a percent of tumour hyalinization at the time of surgical resection. Historical data from retrospective analyses indicate that the median fibrosis and hyalinization after preoperative RTH is approximately 15% (H0). With the use of pembrolizumab and eftilagimod alpha, we expect to increase the rate to 35% (H1). Secondary endpoints include disease-free survival, overall survival, response rate and incidence of adverse events. The exploratory objective of the study is to evaluate local and systemic immunologic responses to neoadjuvant ITH combined with RTH. The correlation between tissue or blood-based biomarkers and clinical outcomes will also be evaluated. Whole-transcriptome sequencing and multiplex immunofluorescence of tumour samples at baseline and after the treatment will be performed to analyse changes in the tumour microenvironment. Additional translational studies based on serial liquid biopsies are planned. Enrolment for the study is ongoing in Poland (EUDRACT number: 2022-003845-36).

Results: Not applicable

Conclusion: Not applicable