Eftilagimod Alfa Demonstrates Potential in PD-L1–Low Head and Neck Cancer

Eftilagimod alfa (efti), a novel first-in-class soluble LAG-3 protein, has received positive and constructive feedback from the US FDA regarding its late-stage clinical development in first-line recurrent or metastatic head and neck squamous cell carcinoma (HNSCC).¹ This news, stemming from a review of encouraging data from the TACTI-003 phase 2b trial (NCT04052327), is particularly notable for patients with low PD-L1 expression (combined positive score [CPS] <1), a population with a high unmet medical need.

The FDA's feedback positions Immutep to evaluate options for future clinical development pathways. The agency concurred on the potential of efti in combination with pembrolizumab (Keytruda) to address the significant challenges faced by this specific patient segment.

Currently, approved immunotherapy-only regimens are not available for patients with PD-L1 CPS <1. Up to 20% of patients with first-line HNSCC fall into this category, and their treatment options are limited to chemotherapy. The FDA's guidance, therefore, presents a crucial opportunity to explore a potential chemotherapy-free immunotherapy option.

“We are pleased with the FDA’s feedback and guidance that underscores the high unmet need of head and neck cancer patients whose PD-L1 expression level is below 1. The FDA feedback positions Immutep to evaluate options for future collaborative clinical development paths to bring a new, effective and safe treatment option to this underserved patient population,” said Marc Voigt, CEO of Immutep, in a press release.

The FDA has provided 2 potential pathways for late-stage development under its Project FrontRunner initiative, which is designed to encourage drug sponsors to consider drug approval for advanced/metastatic disease in earlier clinical settings. The first option is a randomized registrational trial comparing the efti-pembrolizumab combination against the current standard of care. The second, more streamlined option, is a smaller single-arm study (eg, 70–90 patients) to evaluate safety and response rates, which could potentially lead to accelerated approval.

Data presented at the European Society for Medical Oncology (ESMO) virtual plenary in July 2024 demonstrated an overall response rate (ORR) of 35.5% (n = 11) in patients in cohort B of the TACTI-003 trial, with a complete response (CR) rate of 9.7% (n = 2). A disease control rate (DCR) of 58.1% was also reported. These compared favorably to historic controls of 5.4% ORR, 0% CR rate, and 32.4% DCR with anti-PD-1 monotherapy.²

“This is really significant for patients with head and neck squamous cell carcinomas who have a CPS less than one and for whom chemotherapy is the current first line treatment. Achieving complete responses in this group bodes well for this immunotherapy combination's future potential, especially given the positive trend in response durability. The clinically meaningful response rate and high unmet medical need warrant further investigation of eftilagimod plus pembrolizumab in this patient population,” said Robert Metcalf, MD, PhD, The Christie NHS Foundation Trust, in a presentation of the data.

About TACTI-003

TACTI-003 is a multicenter, open-label, randomized, phase 2 study investigating efti plus pembrolizumab in patients with unresectable recurrent or metastatic HNSCC.³ One hundred seventy-one patients were enrolled across 28 global sites and randomized efti plus pembrolizumab or pembrolizumab alone.

The study’s primary end point is ORR, and secondary end points include overall survival, time to and duration of response, DCR, progression-free survival, occurrence of anti-efti–specific antibodies, adverse events, and quality of life.

Patients were required to have an ECOG performance status of 0 to 1 to be eligible for study enrollment, and those with disease suitable for localized therapy, progressive disease within 6 months of prior systemic therapy, or known active central nervous system metastasis were not eligible to participate.

The study’s estimated completion date is October 2025.

REFERENCES:

1. Immutep Receives Positive Feedback from FDA on Late-Stage Clinical Development of Eftilagimod Alfa in Head and Neck Cancer with CPS <1. News release. Immutep. August 5, 2025. Accessed August 6, 2025. https://tinyurl.com/5n7jd459

2. Immutep reports positive results in first line head and neck squamous cell carcinoma in patients with negative PD-L1 expression. News release. Immutep. July 12, 2024. Accessed August 6, 2025. https://tinyurl.com/33ajjfen

3.. Combination Study With Eftilagimod Alpha (a Soluble LAG-3 Fusion Protein) and Pembrolizumab in Patients With Recurrent or Metastatic HNSCC (TACTI-003). ClinicalTrials.gov. Updated June 26, 2025. Accessed August 6, 2025. https://clinicaltrials.gov/study/NCT04811027