Frontline Eftilagimod Alpha/Pembrolizumab Yields Favorable OS in PD-L1–Negative HNSCC

Frontline Eftilagimod Alpha/Pembrolizumab in

PD-L1–Negative HNSCC | Image Credit:

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Updated data from cohort B of the randomized phase 2b TACTI-003/KEYNOTE-C34 trial (NCT04811027) showed a median overall survival (OS) of 17.6 months alongside clinically meaningful responses with first-line eftilagimod alpha (IMP321) plus pembrolizumab (Keytruda) among patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) and a PD-L1 combined positive score (CPS) of less than 1 (n = 31).1

According to Immutep, the drug’s developer, ata data cutoff of March 31, 2025, these mature OS data compare favorably with historical benchmarks for the current standard-of-care options in this patient population. This includes a median OS of 10.7 months with cetuximab (Erbitux) plus chemotherapy, 11.3 months with anti–PD-1 therapy plus chemotherapy, and 7.9 months with anti-PD-1 monotherapy. Moreover, the regimen continues to demonstrate a favorable safety profile with no new safety signals identified.

Such findings further support the first-line clinical activity of the combination, which has produced a high overall response rate (ORR) comprising multiple complete responses (CRs) for patients with HNSCC and a PD-L1 CPS of less than 1.

“We are excited to see this strong survival benefit for [patients with] head and neck cancer with such cold tumors,” Marc Voigt, chief executive officer of Immutep, stated in a news release. “Combining these 2 complementary immunotherapies has led to a 7-fold increase in response rates and a more than doubling of median OS as compared [with] historical results from anti-PD-1 monotherapy. Driving durable responses that translate into clinically meaningful survival holds tremendous promise for these patients in need of more tolerable and efficacious therapies.”

The multicenter, open-label, TACTI-003 trial evaluated the efficacy and safety of the soluble LAG-3 fusion protein eftilagimod alpha in combination with the anti–PD-1 inhibitor pembrolizumab as first-line therapy in patients with relapsed or metastatic HNSCC. The study comprised 2 cohorts: patients with a PD-L1 CPS of 1 or higher (cohort A) and those with a PD-L1 CPS less than 1 (cohort B).2

Patients randomly assigned 1:1 to cohort B received pembrolizumab at 400 mg intravenously every 6 weeks plus eftilagimod alpha at 30 mg subcutaneously every 2 weeks for the first 6 months and every 3 weeks thereafter for up to 2 years.

The trial’s primary end point was ORR per RECIST 1.1 criteria. Key secondary end points included progression-free survival (PFS), OS, ORR by iRECIST criteria, time to response, duration of response, safety, immunogenicity, and quality of life.

Updated data from cohort B, which were presented at the 2024 ESMO Immuno-Oncology Congress, demonstrated an ORR of 35.5% (95% CI, 19.2%-54.6%) per RECIST 1.1 criteria with eftilagimod alpha plus pembrolizumab in patients with PD-L1–negative recurrent or metastatic HNSCC (n = 31). This included a CR rate of 12.9% and a partial response (PR) rate of 22.6%. Best responses also included stable disease (SD) in 22.6% of patients and progressive disease (PD) in 41.9% of patients, yielding a disease control rate (DCR) of 58.1% (95% CI, 39.1%-75.5%).

When assessed using iRECIST criteria, the ORR was 38.7% (95% CI, 21.8%-57.8%), with CRs in 16.1%, PRs in 22.6%, SD in 25.8%, and PD in 35.5% of patients. The DCR based on iRECIST criteria was 64.5% (95% CI, 45.4%-80.8%).

Eftilagimod alpha previously received FDA fast track designation in 2021 for the frontline treatment of patients with recurrent or metastatic HNSCC,3 and in 2022 for use in combination with pembrolizumab as a frontline treatment for patients with stage IIIB/IV non–small cell lung cancer (NSCLC)with a PD-L1 tumor proportion score of at least 1%.4 The agent is currently being evaluated in a variety of solid tumors including NSCLC, HNSCC, and metastatic breast cancer.1

Based on these data, Immutep has requested a meeting with the FDA to discuss potential next steps for the development of eftilagimod alpha, including regulatory pathways for approval in the first-line HNSCC setting for patients with a PD-L1 CPS less than 1. Follow-up, data collection, data cleaning, and analysis are ongoing for TACTI-003, and the company anticipates providing an additional update later in 2025.

“There is a high unmet need in [patients with first-line] HNSCC with cold tumors and PD-L1 CPS [less than] 1, due to the lack of an approved immunotherapy-only treatment regimen and a lack of competitor trials with chemotherapy-free approaches targeting this patient population. Given the strength of the efficacy and safety results generated to date with [eftilagimod alpha] in combination with pembrolizumab, we will meet with regulators to discuss next steps and potential paths to approval,” Voigt concluded.

References

1. Immutep’s Efti in combination with KEYTRUDA (pembrolizumab) drives strong overall survival in head and neck cancer with CPS <1. News release. Immutep Limited. May 5, 2025. Accessed May 5, 2025. https://www.immutep.com/detail/immutep-s-efti-in-combination-with-keytruda-r-pembrolizumab-drives-strong-overall-survival-in-head-and-neck-cancer-with-cps-1.html
2. Forster MD, Laban D, Metcalf R, et al. TACTI-003 cohort B: eftilagimod alpha (soluble LAG-3) and pembrolizumab in first-line recurrent or metastatic head & neck squamous cell carcinoma with PD-L1 negative. Presented at: 2024 ESMO Immuno-Oncology Congress; December 11-13, 2024; Geneva, Switzerland. Abstract 152P.
3. Immutep achieves fast track designation from US FDA for Efti, a soluble Lag-3 protein, in first line recurrent/metastatic head & neck cancer. News release. Immutep Limited. April 8, 2021. Accessed May 5, 2025. https://www.immutep.com/files/content/investor/press-release/2021/Immutep%20Achieves%20Fast%20Track%20designation%20for%20Efti%20from%20US%20FDA%20-%208Apr2021.pdf
4. Immutep receives FDA fast track designation for LAG-3 therapeutic eftilagimod alpha for first line non-small cell lung cancer. News release. Immutep. October 4, 2022. Accessed May 5, 2025. https://www.immutep.com/detail/immutep-receives-fda-fast-track-designation-for-lag-3-therapeutic-eftilagimod-alpha-for-first-line-non-small-cell-lung-cancer.html