FDA Grants Orphan Drug Designation to Eftilagimod Alfa for Soft Tissue Sarcoma

The FDA has granted orphan drug designation (ODD) to eftilagimod alfa (IMP321), an investigational immunotherapy, for the treatment of soft tissue sarcoma (STS). The designation is supported by encouraging clinical datafrom the phase 2 EFTISARC-NEO trial (NCT06128863) evaluating eftilagimod alfa in the neoadjuvant setting, according to a news release.¹

The phase 2 trial met its primary end point tumor of hyalinization/fibrosis across multiple sarcoma subtypes with the combination of eftilagimod alfa, radiotherapy, and pembrolizumab (Keytruda) vs historical benchmarks with radiotherapy alone.

The ODD program incentivizes research into therapies for rare diseases affecting fewer than 200,000 people in the United States, with benefits including regulatory support, tax credits for clinical trial expenses, fee exemptions, and a potential 7 years of market exclusivity following approval.

About Eftilagimod Alfa

Eftilagimod alfa is a soluble LAG-3 protein that directly activates antigen-presenting cells (APCs) including dendritic cells and monocytes via the major histocompatibility complex (MHC) class II pathway.² This targeting and activation of dendritic cells promotes comprehensive adaptive and innate immune responses against cancer, including the expansion of CD8-positive cytotoxic T cells capable of recognizing tumor antigens induced by radiotherapy. Eftilagimod alfa’s mechanism harnesses LAG-3's capacity to stimulate the immune response.

The EFTISARC-NEO Trial

The ongoing open-label EFTISARC-NEO phase 2 study is conducted by the Maria Sklodowska-Curie National Research Institute of Oncology in Warsaw, Poland, and is primarily funded through an approved grant from the Polish Medical Research Agency.

The single-arm, single-stage study is evaluating eftilagimod alfa administered concurrently with pembrolizumab and radiotherapy in patients with grade 2 or 3, stage III systemic STS of extremities or trunk. Patients received systemic therapy during weeks 1 to 9, radiotherapy for 5 weeks from weeks 2 through 6, and surgical resection during weeks 11 to 12. EFTISARC-NEO is the first study to evaluate eftilagimod alfa in the neoadjuvant setting and the first to combine the agent with radiotherapy. The trial completed enrollment with a total of 40 patients.³

The trial's primary end point is pathologic response measured by tumor hyalinization/fibrosis at the time of surgical resection, an early surrogate end point that has been correlated with improved overall survival and recurrence-free survival in patients with soft tissue sarcoma.

Trial Results

In the 38 evaluable patients enrolled across multiple STS subtypes, the triplet combination met the study's primary end point by a substantial margin. The combination produced a median tumor hyalinization/fibrosis rate of 51.5% (P <.001) in the evaluable population, exceeding the prespecified target of 35% and more than 3-fold higher than the 15% historical benchmark for radiotherapy alone. Treatment-related adverse events (TRAEs) occurred in 92.5%, mostly attributed to surgery or radiotherapy, with grade 3 or 4 TRAEs in 20.0% of patients, including grade 3 or 4 surgical complications in 17.5%.³

Translational data from the CTOS 2025 Annual Meeting further showed statistically significant increases in multiple cytokines and chemokines consistent with eftilagimod alfa’s mechanism of action, and high levels of interferon-gamma were found to correlate with pathologic responses.² The triplet regimen appeared safe, with no grade 3 or higher toxicities attributed to eftilagimod alfa or pembrolizumab, and no delays to planned surgery were observed.

Context and Next Steps

STS is a rare and aggressive malignancy with limited therapeutic options, particularly for patients who relapse or whose disease proves refractory to available therapies. Existing standard-of-care neoadjuvant radiotherapy has historically yielded limited pathologic response rates, underscoring the need for novel approaches.

"The FDA's designation, based on very encouraging data from the EFTISARC-NEO trial, provides us with a potential direct step forward into a late-stage study in the neoadjuvant setting for STS," said Marc Voigt, MBA, chief executive officer of Immutep, in the news release.¹

In March of 2026, the phase 3 TACTI-004 trial (NCT06726265) of eftilagimod alfa in non–small cell lung cancer was halted after a futility analysis as it was deemed unlikely to meet its primary end points of progression-free survival and overall survival. Voigt stated that the company’s comprehensive review following this discontinuation will influence plans for future clinical trials.⁴

REFERENCES

1. Immutep receives FDA orphan drug designation for eftilagimod alfa in soft tissue sarcoma. News release. Immutep Limited. April 15, 2026. Accessed April 15, 2026. https://tinyurl.com/chxpaczj

2. Translational data and significant pathologic response rates from EFTISARC-NEO phase II highlighted in oral presentation at CTOS 2025. News release. Immutep Limited. November 13, 2025. Accessed April 16, 2026. https://tinyurl.com/hc3cjbej

2. TACTI-004 phase III study in first line NSCLC to be discontinued following futility analysis. News release. Immutep Limited. March 13, 2026. Accessed April 16, 2026. https://tinyurl.com/m2hnpa3u

3. Kozak K, Rogala P, Mariuk-Jarema A, et al. EFTISARC-NEO: A phase II study of neoadjuvant eftilagimod alpha, pembrolizumab and radiotherapy in patients with resectable soft tissue sarcoma. Ann Oncol. 2025;36(suppl 2):S1338. doi: 10.1016/j.annonc.2025.08.3297

4. Immutep’s efti with radiotherapy & Keytruda (pembolizumab) meets primary endpoint in phase II for soft tissue sarcoma. News release. Immutep Limited. May 26, 2026. Accessed May 27, 2025. https://tinyurl.com/yhh2p2fb