Phase 3 Trial of Eftilagimod Alfa in First-Line NSCLC Is Halted After Futility Analysis

Following a planned interim futility analysis, an independent data monitoring committee (IDMC) has recommended halting the phase 3 TACTI-004 trial (NCT06726265) evaluating eftilagimod alfa in combination with pembrolizumab (Keytruda) and chemotherapy as first-line treatment for advanced or metastatic non–small cell lung cancer (NSCLC). Immutep Limited, the trial sponsor, announced the development on March 13, 2026, stating that the IDMC found the regimen unlikely to meet its dual primary end points of progression-free survival (PFS) and overall survival (OS).¹

In response, the company has halted new enrollment and will initiate an orderly wind-down of the study in accordance with regulatory and ethical obligations, including patient follow-up and site closeout.

“We are very disappointed and surprised with the outcome of the futility analysis in light of [eftilagimod alfa’s] performance in every other clinical trial,” said Marc Voigt, CEO of Immutep, in a news release.¹ “We would like to thank the patients, investigators, and clinical teams who contributed to this important study. We are currently conducting a comprehensive review of the available data to better understand the results and determine the appropriate next steps for the program.”

Trial Design and Patient Population

TACTI-004, also designated KEYNOTE-F91, was a randomized, double-blind, placebo-controlled phase 3 trial designed to enroll approximately 756 patients across more than 150 clinical sites.² The study targeted patients with advanced or metastatic NSCLC without EGFR, ALK, or ROS1 genomic tumor aberrations. Patients were enrolled regardless of PD-L1 expression status, and the trial included both squamous and nonsquamous histologic subtypes, a design intended to broaden the regimen’s potential applicability.

Participants were randomly assigned 1:1 to receive either eftilagimod alfa in combination with pembrolizumab and platinum-based chemotherapy, or pembrolizumab plus chemotherapy with placebo. The dual primary end points were PFS per RECIST 1.1 and OS. Secondary end points included objective response rate (ORR), disease control rate, duration of response, health-related quality of life, safety, and biomarker assessments.

As of February 2026, 378 patients had been enrolled—approximately 50% of the trial's enrollment target—across more than 120 active clinical sites in 27 countries, including sites in the United States that had recently received regulatory clearance.²

Mechanism of Action

Eftilagimod alfa is a soluble LAG-3 fusion protein that functions as a first-in-class MHC class II agonist. Unlike checkpoint inhibitors, which act directly on T cells, eftilagimod alfa binds to a subset of MHC class II molecules on antigen-presenting cells (APCs), such as dendritic cells and monocytes. This interaction activates APCs and is intended to initiate a broad antitumor immune response, including expansion of cytotoxic CD8+ T cells and generation of costimulatory signals and cytokines.¹ The agent has received fast track designation from the FDA for first-line NSCLC and first-line head and neck squamous cell carcinoma.

Prior Clinical Evidence

The TACTI-004 design was informed by results from 2 earlier phase 2 studies. The TACTI-002 trial (NCT03625323) evaluated eftilagimod alfa in combination with pembrolizumab as first-line therapy in NSCLC.³ Among patients with a PD-L1 tumor proportion score (TPS) of 1% or greater, the combination yielded an ORR of 48.3%, a median PFS of 11.2 months, and a median OS of 35.4 months. Antitumor activity was also observed across all PD-L1 expression strata, including patients with TPS less than 1%.

The INSIGHT-003 trial (NCT03252938) explored eftilagimod alfa as part of a triple-combination regimen with carboplatin/pemetrexed and pembrolizumab in patients with first-line nonsquamous NSCLC. In patients with TPS less than 50%, that study reported a median PFS of 10.9 months, with OS not yet reached at the time of analysis. Both studies demonstrated acceptable safety profiles. Together, they enrolled more than 165 patients and were cited as the rationale for advancing to a phase 3 registrational study.⁴

REFERENCES

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

2. Study of eftilagimod alfa (Efti) in combination with pembrolizumab and chemotherapy versus placebo in combination with pembrolizumab and chemotherapy in participants with metastatic non-small cell lung cancer (NSCLC) (TACTI-004). ClinicalTrials.gov. Updated February 27, 2026. Accessed March 16, 2026. https://clinicaltrials.gov/study/NCT06726265

3. Felip E, Majem M, Doger B, et al. A phase II study (TACTI-002) in first-line metastatic non–small cell lung carcinoma investigating eftilagimod alpha (soluble LAG-3 protein) and pembrolizumab: updated results from a PD-L1 unselected population. J Clin Oncol. 2022;40(suppl 16)9003. doi:9:10.1200/JCO.2022.40.16_suppl.9003

4. Immutep’s efti shows excellent survival data from INSIGHT-003 trial in non-small cell lung cancer. News release. Immutep. November 14, 2024. Accessed March 16, 2026. https://www.immutep.com/immuteps-efti-shows-excellent-survival-data-from-insight-003-trial-in-non-small-cell-lung-cancer/