Summary
The FDA has endorsed further development of Immutep’s eftilagimod alfa (efti) in combination with Keytruda for first-line HNSCC patients with PD-L1 CPS <1, following positive Phase IIb TACTI-003 results. The trial showed improved response rates across PD-L1 expression levels, including a 31.0% ORR in high expressers and promising activity in PD-L1–negative patients. As Immutep considers next steps, clinops teams should note the value of targeting underserved subpopulations with immunotherapy combinations and leveraging FDA feedback to shape future study design and partnerships.
Immutep announced it has received positive feedback from the FDA regarding future clinical development of its first-in-class MHC Class II agonist, eftilagimod alfa (“efti”), for the first-line treatment of patients with recurrent/metastatic head and neck squamous cell carcinoma (1L HNSCC) who have PD-L1 expression below 1 (Combined Positive Score [CPS] <1).1
Agency acknowledges unmet need in PD-L1–negative population
This FDA feedback is based on encouraging data from the Phase IIb TACTI-003 (KEYNOTE-C34) clinical trial (NCT04811027) assessing efti in combination with Merck’s Keytruda (pembrolizumab). The FDA agreed on the combination’s potential to address high unmet need in the CPS <1 patient population and is supportive of further development.
In a press release, Marc Voigt, CEO of Immutep, said: “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 one. 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.”
TACTI-003 trial evaluates efti in PD-L1 positive and negative HNSCC
The Phase IIb TACTI-003 trial is a multicenter, open label, randomized study evaluating efti in combination with Keytruda versus Keytruda alone in the first-line treatment of metastatic or recurrent HNSCC.2
- The study enrolled 171 patients across approximately 35 clinical sites in Australia, Europe, and the US.
- Participants must have PD-L1 positive (CPS ≥1) or PD-L1 negative (CPS <1) tumors.
- Patients in Cohort A (CPS ≥1) were randomized 1:1 to receive either the combination of efti and Keytruda or Keytruda alone.
- Patients in Cohort B (CPS <1) received the combination treatment only.
- Efti will be given subcutaneously at a dose of 30 mg every 2 or 3 weeks for up to 24 months.
- Keytruda is administered intravenously at 400 mg every 6 weeks for up to 24 months.
- The study is assessing both safety and efficacy outcomes in PD-L1 positive and negative patient populations.
In the press release, Voigt continued: “Our primary focus clearly remains the pivotal TACTI-004 Phase III evaluating efti as first line therapy for non-small cell lung cancer and we are excited with its progress to date and the consistent, encouraging feedback we hear from physicians. This focus and additional considerations will be reviewed internally and discussed with stakeholders and potential strategic partners in regards to forward paths in head and neck cancer.”
Combination outperforms monotherapy in key subgroups
Immutep originally shared a positive readout from TACTI-003 in June 2024. According to topline results, the trial met its primary endpoint with the efti-Keytruda combination leading to overall response rates (ORRs) that exceeded Keytruda monotherapy across all levels of PD-L1 expression.3
Additional findings showed:
- In Cohort A, the efti-Keytruda combination achieved an ORR of 31.0%, compared to 18.5% with Keytruda alone.
- This subgroup represents patients with high PD-L1 expression, where the combination showed enhanced efficacy over monotherapy.
- In Cohort B, where chemotherapy-free treatment options are limited, the response rate has notably increased from a previously reported 26.9% ORR in April 2024.
In a press release from the time, Martin Forster, MD, PhD, of the UCL Cancer Institute and University College London Hospital NHS Foundation, London, UK, and TACTI-003 investigator, said: “It is encouraging to see efti safely drive higher response rates in combination with Keytruda in the first line setting for head and neck squamous cell carcinoma patients, regardless of HPV status and levels of PD-L1. The strong, consistent response rates, irrespective of whether patients have high, low, or negative PD-L1 expression, is intriguing and offers a glimpse into this novel combination’s ability to improve patients’ clinical responses and expand patient populations that benefit from anti-PD-1 therapy.”
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://www.immutep.com/immutep-receives-positive-feedback-from-fda-on-late-stage-clinical-development-of-eftilagimod-alfa-in-head-and-neck-cancer-with-cps/
2. 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
3. Immutep Reports Positive Topline Results from TACTI-003 Phase IIb Trial in First Line Head and Neck Cancer. News release. Immutep. June 27, 2024. Accessed August 6, 2025. https://www.immutep.com/immutep-reports-positive-topline-results-from-tacti-003-phase-iib-trial-in-first-line-head-and-neck-cancer/
