(P 245) PRELIMINARY RESULTS FROM A PHASE 2 EFTISARC-NEO TRIAL OF NEOADJUVANT SOUBLE LAG-3 PROTEIN EFTILAGIMOD ALPHA, PEMBROLIZUMAB, AND CONCURRENT RADIOTHERAPY IN PATIENTS WITH RESECTABLE SOFT TISSUE SARCOMA

Objective: Perioperative radiotherapy has led to better local control in localized soft tissue sarcoma (STS), but long-term outcomes remain unsatisfactory. Recent studies have shown that the addition of anti-PD-1 antibodies can improve patient outcomes, but the benefit is limited to a small subset of patients as the majority of STS is considered to be immuno-cold. 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. We hypothesize that the addition of Efti and anti-PD-1 antibody pembrolizumab (pembro) to neoadjuvant radiotherapy will increase pathological response and thereby improve long-term disease control. EFTISARC-NEO (NCT NCT06128863) is an open-label Phase II study evaluating the efficacy and safety of neoadjuvant efti and pembro in combination with RT in patients with STS.

Methods: Key eligibility criteria include primary or locally recurrent extremity, girdles, and/or trunk grade 2/3 STS (undifferentiated pleomorphic sarcoma [UPS], myxofibrosarcoma [MF], dedifferentiated liposarcoma [DDLPS], myxoid and round cell liposarcoma [MRCLPS], epithelioid sarcoma, angiosarcoma, soft tissue sarcoma NOS) of >5 cm. Patients receive efti 30 mg sc Q2W (5 cycles) and pembrolizumab 200 mg iv Q3W (3 cycles) with concurrent RT (25x2Gy), followed by surgery 4-6 weeks after radiotherapy. The primary endpoint is a percentage of tumor hyalinization at the time of surgical resection. The study is powered to detect an increase of hyalinization from 15% (H0) with radiotherapy to 35% (H1) with the study protocol. Secondary endpoints include disease-free survival, overall survival, response rate, and incidence of adverse events. Here, we report pathological (percent of hyalinization and per EORTC-STBSG response criteria)) and radiological responses (per RECIST 1.1) of the first 13 evaluable patients.

Results: As of June 10, 2024, 24 patients had been screened, and 18 were enrolled in the study. One patient discontinued study treatment due to an SAE (intracranial hematoma) not related to study treatment, 4 patients remained on treatment, and 13 patients completed neoadjuvant therapy, underwent surgery, and were available for efficacy assessment.
Among 13 evaluable patients, the majority were males (8; 61.5%), and the median age was 54 years. The most common subtype was MF (6; 54.5%), followed by MRCLPS (3; 27.3%) and DDLPS (2; 18.2%), UPS, and MPNST (1 patient each). The median tumor size was 8.8 cm, and 84.6% (11) were in the lower extremity.
In the surgical specimens, the median percent of hyalinization/fibrosis was 49% (IQR 36-65), and 76.9% (10) of patients had 35% of hyalinization. Median residual viable tumor was 7% (IQR 4-22). 15.4% (2) of patients achieved response grade B, 46.1% (6) grade C, 30.8% (4) grade D, and 7.7% (1) grade E according to EORTC-STBSG criteria.
In the pre-surgical assessment by MRI, as per RECIST 1.1 criteria, 11 patients achieved stable disease (84.6%), and 2 patients achieved partial response, leading to an ORR of 15.4%. The median tumor size change was -7.4%. All patients except 2 had a decrease of target lesion size. No grade 3 TRAEs were observed. Data on additional patients and preliminary biological correlates will be presented.

Conclusion: Based on the preliminary analysis, combining efti and pembro with radiotherapy demonstrates significant efficacy in the neoadjuvant settings in patients with resectable STS. The combination is safe and leads to higher tumor hyalinization than radiotherapy alone compared to historical data. The EFTISARC-NEO trial is currently ongoing to reach the planned enrolment of 40 patients Q1 2025.