New Data Positions Immutep’s Immunotherapy Combo as First-Line Option for PD-L1-Negative HNSCC

Immutep, the developer of eftilagimod alpha, has reported promising overall survival (OS) results that could pave the way for regulatory approval in first-line head and neck cancer treatment.

In a Phase 2b trial (Keynote-C34, also known as TACTI-003), Immutep demonstrated that combining eftilagimod with Merck & Co.’s checkpoint inhibitor Keytruda helped patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) — specifically those with low PD-L1 expression (combined positive score [CPS]
Immutep plans to engage with the FDA to discuss potential approval of eftilagimod for first-line treatment of PD-L1-negative HNSCC, supported by its existing fast-track designation. CEO Marc Voigt confirmed that the company will meet with regulatory authorities to evaluate next steps toward potential approval of eftilagimod in combination with Keytruda.

This combination therapy presents a unique value proposition: it offers a chemotherapy-free immunotherapy alternative for PD-L1-negative patients, a group currently limited to chemo-based options. Eftilagimod, a LAG-3 fusion protein, activates antigen-presenting cells to boost immune response, according to Immutep.

The FDA first approved Keytruda with chemotherapy for initial HNSCC treatment in 2019, including patients with PD-L1-negative tumors. That approval was based on data showing a 23% reduction in mortality risk compared to Eli Lilly’s EGFR inhibitor Erbitux combined with chemotherapy, across all PD-L1 expression levels. Keytruda was also approved as a standalone treatment, but only for patients with CPS ≥1.

Post hoc analysis from the Keynote-048 trial revealed worse outcomes for PD-L1-negative patients treated with Keytruda and chemotherapy compared to Erbitux and chemotherapy. Median OS was 11.3 months for the Keytruda-chemo group vs. 10.7 months for Erbitux-chemo. Moreover, the risk of death was 21% higher in the Keytruda-chemo group for PD-L1-negative patients. However, researchers cautioned that the sample size for this subgroup was too small to draw definitive conclusions.

Against this backdrop, the 17.6-month median OS seen with the eftilagimod-Keytruda combination stands out, even though cross-trial comparisons should be interpreted cautiously.

These new survival data build on previous tumor response findings. Immutep earlier reported an objective response rate (ORR) of 35.5% in Cohort B of TACTI-003, including a 12.9% complete response rate. For comparison, Keynote-048 reported a 30.8% ORR and 2.6% complete response rate in the PD-L1-negative subgroup treated with Keytruda plus chemotherapy.

Voigt emphasized that the potential of this combination lies in delivering durable responses and significant survival benefits for a patient population in urgent need of more effective and tolerable options.

Immutep is aiming to serve the PD-L1-negative HNSCC segment, which it estimates comprises about 20% of all first-line HNSCC cases. Voigt noted that no current trials are investigating chemotherapy-free treatment approaches for this specific group.

Meanwhile, Keytruda continues to be evaluated in combination with other therapies. It is being paired with Exelixis’ investigational tyrosine kinase inhibitor, zanzalintinib, in the Phase 3 STELLAR-305 trial, which targets only PD-L1-positive HNSCC patients. Separately, Merus is conducting the Phase 3 LiGeR-HN1 trial, assessing its EGFR×LGR5 bispecific antibody petosemtamab with Keytruda in PD-L1-positive first-line HNSCC patients. Petosemtamab holds FDA Breakthrough Therapy designation.