Cue Biopharma reported promising new clinical data for its investigational cancer immunotherapy CUE-101, showing an additional complete response and maintaining a 50% overall response rate when combined with pembrolizumab in patients with recurrent/metastatic HPV+ head and neck squamous cell carcinoma (HNSCC). The updated results from the ongoing Phase 1 trial demonstrate substantial improvements over historical pembrolizumab monotherapy data.
Strong Efficacy Signals Across Patient Populations
The expansion portion of the Phase 1 trial evaluated CUE-101 at the recommended Phase 2 dose of 4mg/kg in combination with pembrolizumab in first-line patients. With a data cutoff of July 14, 2025, the combination achieved an overall response rate (ORR) of 50% in patients with combined positive score (CPS) ≥1, including 2 complete responses and 10 partial responses. This represents a significant improvement compared to the 19% ORR observed with pembrolizumab alone in the historical KEYNOTE-048 trial.
Notably, the therapy maintained its 50% response rate even in patients with low PD-L1 expression (CPS 1-19), suggesting efficacy across different biomarker profiles. This finding could be particularly significant given that many patients with head and neck cancer have low PD-L1 expression levels.
Survival Benefits Show Dramatic Improvement
The survival metrics continued to mature favorably, with 12-month overall survival reaching 88% compared to 57% with pembrolizumab alone in the historical KEYNOTE-048 trial. This represents a substantial reduction in the risk of death with a hazard ratio of 0.23 compared to historical data. The median overall survival extended to 32 months, more than doubling the 12.3 months observed in the KEYNOTE-048 trial.
"We are excited to report an additional CR in a patient that had recurrent metastatic HPV+ head and neck squamous cell carcinoma treated with CUE-101 in combination with pembrolizumab," said Matteo Levisetti, chief medical officer at Cue Biopharma. The patient had maintained durable stable disease for close to two years before demonstrating significant tumor reductions and achieving complete response.
Mechanism Drives Sustained T Cell Response
CUE-101 is designed as an interleukin-2 (IL-2)-based biologic that activates and expands HPV16 tumor-specific T cells through a dual-signal approach. Signal #1 incorporates the HPV E7 protein to provide selectivity through interaction with HPV-specific T cell receptors, while Signal #2 consists of an engineered IL-2 variant to stimulate T cell activity.
The recent complete response case involved a patient with multiple sites of disease, including lung metastases that cleared prior to the complete response observed in the target lesion. Levisetti noted that "the kinetics of tumor reduction and disease eradication in this patient is due to the repeated stimulation and expansion of tumor-specific T cells given the mechanism of action of CUE-101."
Platform Technology Shows Promise
The results support Cue Biopharma's broader Immuno-STAT® (Selective Targeting and Alteration of T cells) platform, which is designed to selectively engage and modulate disease-specific T cells directly within the patient's body. The platform aims to harness the immune system's curative potential without the adverse effects of broad systemic immune modulation.
"The culmination of maturing data further support our conviction that CUE-101, representative of our approach with the CUE-100 series, demonstrates a potential breakthrough therapeutic approach for establishing a new standard of care," said Dan Passeri, chief executive officer at Cue Biopharma.
Trial Design and Patient Population
The fully enrolled Phase 1 open-label, dose escalation and expansion study is evaluating CUE-101 for the treatment of HPV16+ driven recurrent/metastatic head and neck squamous cell carcinoma. The trial includes both monotherapy arms for second-line and beyond patients, as well as first-line combination therapy with pembrolizumab.
The Boston-based clinical-stage biopharmaceutical company is developing CUE-101 as part of its CUE-100 series of therapeutic biologics. The company's management team brings deep expertise in immunology and immuno-oncology, as well as experience in the design and clinical development of protein biologics.
