Eftilagimod Alpha–Based Triplet Is Well Tolerated, Generates Responses in Soft Tissue Sarcoma

Katarzyna Kozak, MD, PhD

Treatment with eftilagimod alpha plus standard-of-care radiotherapy and pembrolizumab (Keytruda) was shown to be well tolerated and led to encouraging initial efficacy data in patients with soft tissue sarcoma, according to findings from the phase 2 EFTISARC-NEO trial (NCT06128863).¹

Initial efficacy data from the study, which is the first to evaluate eftilagimod alpha in the neoadjuvant setting, as well as the first to combine the agent with radiotherapy, demonstrated that 4 of the 6 patients (67%) had near-complete responses (CRs), which was the primary end point of study. The press release noted that deep responses are rarely seen in patients with soft tissue sarcoma who receive standard therapeutic approaches including radiotherapy.

“The initial pathologic responses from this novel combination are very encouraging and supportive of the potential synergistic effects of this new therapeutic approach. Indeed, we have seen a high degree of hyalinization/fibrosis in the surgical samples which we rarely see with standard treatments,” Katarzyna Kozak, MD, PhD, and Paweł Sobczuk, MD, PhD, medical oncologists in the Department of Soft Tissue/Bone Sarcoma and Melanoma at Maria Sklodowska-Curie National Research Institute of Oncology (MSCNRIO) in Warsaw, Poland, and the trial’s principal investigators stated in the news release. “We look forward to continuing this study.”

Soft tissue sarcoma presents a significant medical challenge with a bleak prognosis. The occurrence of this disease shows variability across different geographic areas, with around 23,400 new cases each year and a crude incidence of 4.7 per 100,000 in Europe. In the United States, an estimated 13,400 new cases occur annually, resulting in approximately 5,140 deaths. This necessitates further research into novel treatment options for patients.

The unique targeting and activation of dendritic cells by eftilagimod alpha promote comprehensive adaptive and innate immune responses against cancer. This includes the expansion of CD8-positive cytotoxic T cells capable of recognizing tumor antigens induced by radiotherapy. When combined with radiotherapy and anti–PD-1 therapy, eftilagimod alpha is hypothesized to have the potential to stimulate a strong anti-tumor immune response within the immunosuppressive tumor microenvironment of soft tissue sarcoma.

“We are pleased to see these early results from EFTISARC-NEO, which has allowed eftilagimod alpha for the first time to be clinically evaluated in a non-metastatic cancer setting,” Frédéric Triebel, MD, PhD, chief scientific officer of Immutep added. “The ability to evaluate tumor specimens is helping elucidate the significant anti-cancer immune response eftilagimod alpha drives through its direct maturation and activation of antigen-presenting cells as an MHC Class II agonist. If the positive trend of strong pathological responses continues in this rare orphan disease, we will pursue all available avenues to bring this innovative therapy to patients with soft tissue sarcoma in need of new, effective therapies in an expeditious manner.”

EFTISARC-NEO, an open-label, single-arm, single-stage study, is anticipated to treat up to 40 patients and is being conducted by MSCNRIO. The study’s primary end point is the pathologic response rate at the time of surgical resection, defined as percentage of tumor hyalinization/fibrosis. Notably, the lower the number of viable tumor cells and the higher the extent of hyalinization/fibrosis observed in patients’ tumor specimens will determine the therapy’s effectiveness.^1,2

Additionally, secondary end points of the study include the number of patients experiencing adverse effects (AEs), the number of patients completing neoadjuvant therapy, disease-free survival, local recurrence-free survival, distant metastasis-free survival, overall survival, and overall response rate.²

Patients eligible for this study must have primary or locally recurrent soft tissue tumors, including undifferentiated pleomorphic sarcoma, myxofibrosarcoma, dedifferentiated liposarcoma, myxoid and round cell liposarcoma, epithelioid sarcoma, angiosarcoma, or soft tissue sarcoma not otherwise specified. Tumors must be classified as grade 2 or 3 and have a size greater than 5 cm as determined by imaging or be locally recurrent regardless of size. Measurable disease based on RECIST v1.1 criteria and non-metastatic disease are also required for inclusion.²

Exclusion criteria include prior treatment with eftilagimod alpha, anti-PD-1, or anti-PD-L1 therapies, as well as previous radiotherapy to tumor-involved sites.²

In eligible patients, pembrolizumab and eftilagimod alpha are concurrently administered with radiotherapy. The systemic treatment extends over 9 weeks (from study week 1 to 9), with radiation therapy spanning 5 weeks (5 days per week) from weeks 2 to 6. Surgery occurs 5 to 6 weeks after the completion of radiation therapy (weeks 11-12). No adjuvant treatments are permitted after surgical intervention during which time patients will undergo regular follow-up for 24 months.²

To date the triplet combination has revealed no new safety signals and has been well tolerated in the first 6 patients who have completed the 10 weeks of treatment followed by surgery.¹

The trial is currently in progress with 14 enrolled patients, and further clinical data are scheduled to be presented at a medical conference in the second half of 2024.¹

References

1. Positive initial clinical data reported from Immutep’s efti combined with radiotherapy and checkpoint inhibitor from phase II trial in soft tissue sarcoma. News release. Immutep. May 2, 2024. Accessed May 2, 2024. https://www.immutep.com/detail/positive-initial-clinical-data-reported-from-immutep-s-efti-combined-with-radiotherapy-and-checkpoint-inhibitor-from-phase-ii-trial-in-soft-tissue-sarcoma.html
2. Pembrolizumab in combination with eftilagimod alpha and radiotherapy in neoadjuvant treatment of patients with soft tissue sarcoma - EFTISARC-NEO trial (EFTISARC-NEO). ClinicalTrials.gov. Updated November 13, 2023. Accessed May 2, 2024. https://classic.clinicaltrials.gov/ct2/show/NCT06128863