Immutep’s LAG3 drug eftilagimod alfa halted in Phase III for NSCLC due to futility

Edited by Robert McTiernan··3 min read

Sydney-based Immutep Limited announced that the Independent Data Monitoring Committee for its TACTI-004 Phase III trial recommended discontinuation of the study evaluating eftilagimod alfa in combination with pembrolizumab and chemotherapy as first-line treatment for advanced or metastatic non-small cell lung cancer. The recommendation followed a planned interim futility analysis, indicating the addition of eftilagimod alfa to standard pembrolizumab-chemotherapy was unlikely to demonstrate a treatment benefit over the control arm.

Trial specifics

TACTI-004 was a randomized, double-blind, controlled Phase III study designed to enroll approximately 756 patients across more than 150 sites in over 25 countries. Eligible patients had advanced or metastatic NSCLC without EGFR, ALK, or ROS1 genomic aberrations and were enrolled regardless of PD-L1 expression status. Patients were randomized 1:1 to receive either eftilagimod alfa plus pembrolizumab plus chemotherapy, or pembrolizumab plus chemotherapy plus placebo. The dual primary endpoints were progression-free survival and overall survival. The IDMC reviewed available safety and efficacy data at the prespecified interim analysis and concluded the trial met criteria for futility. Immutep did not disclose specific efficacy or safety results from the analysis. The company said enrollment has been halted and an orderly wind-down is underway, including patient follow-up and site closure in accordance with regulatory obligations.

Immutep stated it is conducting a review of the available data to determine next steps for the eftilagimod alfa program. The company noted that discontinuation of TACTI-004 extends its anticipated cash runway beyond the previously guided Q2 2027 timeframe. Eftilagimod alfa holds US FDA Fast Track designation in both first-line NSCLC and first-line head and neck squamous cell carcinoma, and remains under evaluation in other solid tumor indications. Immutep said it will reassess capital allocation once its operational and data reviews are complete.

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Research context

Eftilagimod alfa is a soluble LAG-3 immunoglobulin fusion protein that functions as an MHC Class II agonist. Rather than blocking an inhibitory checkpoint, it binds MHC Class II molecules on antigen-presenting cells such as dendritic cells and monocytes, activating them to prime cytotoxic T cells and generate co-stimulatory signals intended to amplify anti-tumor immunity. The rationale for combining eftilagimod alfa with pembrolizumab, a PD-1 checkpoint inhibitor, was to simultaneously release T cell inhibition and enhance antigen presentation. The futility finding suggests this dual mechanism did not translate into additional clinical benefit over pembrolizumab and chemotherapy alone in this patient population.

First-line treatment for advanced NSCLC without actionable driver mutations is dominated by PD-1 or PD-L1 checkpoint inhibitors combined with platinum-based chemotherapy. Several programs are testing whether additional immune modulation can improve upon this standard. Key competitors include:

  • Roche’s tiragolumab, an anti-TIGIT antibody evaluated in combination with atezolizumab in the Phase III SKYSCRAPER-01 trial for PD-L1-high first-line NSCLC.
  • Arcus Biosciences’ domvanalimab, another anti-TIGIT antibody being studied with the PD-1 inhibitor zimberelimab in the Phase III ARC-10 trial in first-line NSCLC.
  • AstraZeneca and Daiichi Sankyo’s datopotamab deruxtecan, a TROP2-directed antibody-drug conjugate in the Phase III TROPION-Lung07 trial testing combination with pembrolizumab against pembrolizumab plus chemotherapy in first-line NSCLC.

The TACTI-004 result narrows Immutep’s late-stage pipeline and raises questions about whether MHC Class II agonism via LAG-3 engagement can produce measurable efficacy gains in large randomized trials. Of note, clinicaltrials.gov indicates Immutep is continuing to study eftilagimod alfa in the Phase II/III AIPAC-003 trial focused on metastatic breast cancer.