Frontline Efti Combo Yields Meaningful Survival in PD-L1–Low HNSCC

Efti plus pembrolizumab demonstrated no new safety signals in the TACTI-003 trial.

Combining eftilagimod alfa (efti) with pembrolizumab (Keytruda) demonstrated an overall survival (OS) benefit in the first-line treatment of a small cohort of patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) harboring a PD-L1 combined positive score (CPS) of less than 1, according to a press release on cohort B findings from the phase 2b TACTI-003/KEYNOTE-C34 trial (NCT04811027) .¹

With a data cutoff date of March 31, 2025, the median OS among 31 evaluable patients was 17.6 months. According to the press release, the outcomes achieved with the efti combination compare favorably with historical results observed with current standard-of-care therapies for first-line HNSCC with a PD-L1 CPS of less than 1. These results include a median OS of 10.7 months with cetuximab (Erbitux) plus chemotherapy, 11.3 months with an anti–PD-L1 agent plus chemotherapy, and 7.9 months with anti–PD-L1 therapy alone.

Previously, developers announced that the efti combination demonstrated an objective response rate (ORR) of 35.5% and a disease control rate (DCR) of 58.1% in cohort B.² These responses rates exceeded a historical ORR of 5.4% and DCR of 32.4% with anti–PD-L1 treatment alone.

Efti plus pembrolizumab demonstrated no new safety signals in the TACTI-003 trial.

“We are excited to see this strong survival benefit for [patients with] head and neck cancer with such cold tumors. 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 to historical results from anti–PD-1 monotherapy,” Marc Voight, chief executive officer of Immutep, the developer of efti, stated in the press release.¹ “Driving durable responses that translate into clinically meaningful survival holds tremendous promise for these patients in need of more tolerable and efficacious therapies.”

The FDA previously granted fast track designation to efti plus pembrolizumab as a frontline treatment for recurrent or metastatic HNSCC in April 2021.³ Developers have requested a meeting with the agency to discuss a potential approval pathway and other next steps for the regimen in this patient population. Additionally, investigators of TACTI-003 are currently conducting patient follow-up, data collection, and cleaning and analysis; developers anticipate more updates from the study later in 2025.

“There is a high unmet need in [patients with frontline] HNSCC with cold tumors and PD-L1 CPS [of 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 efti in combination with pembrolizumab, we will meet with regulators to discuss next steps and potential paths to approval,” Voight stated.¹

Investigators of the open-label, multi-center phase 2b TACTI-003 trial evaluated patients with metastatic or recurrent HNSCC across 2 cohorts. In cohort A, patients with a PD-L1 CPS of 1 or higher were randomly assigned 1:1 to receive efti plus pembrolizumab or pembrolizumab alone.⁴ Patients with a PD-L1 CPS of less than 1 were assigned to receive efti plus pembrolizumab in cohort B.

The trial’s primary end point was ORR per RECIST v1.1 criteria. Secondary end points included OS, DCR, progression-free survival, safety, and quality of life.

Patients 18 years and older with histologically or cytologically confirmed recurrent disease not amenable to curative treatment with local or systemic therapy, or metastatic HNSCC of the oral cavity, oropharynx, hypopharynx, or larynx considered incurable with local therapies were eligible for enrollment on the study. Having an ECOG performance status of 0 or 1 was another requirement for study entry.

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. May 5, 2025. Accessed May 6, 2025. https://tinyurl.com/bddkxh8b
2. Immutep reports positive results in first line head and neck squamous cell carcinoma patients with negative PD-L1 expression. News release. Immutep. July 12, 2024. Accessed May 6, 2025. https://tinyurl.com/yj7vvezt
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. April 8, 2021. Accessed May 6, 2025. https://tinyurl.com/y7vwfp4b
4. 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 March 3, 2025. Accessed May 6, 2025. https://tinyurl.com/53vp7vwc