CUE-101/Pembrolizumab Shows Promising Response, Survival in First-Line HPV+ HNSCC

The investigational agent CUE-101 given at the recommended phase 2 dose of 4 mg/kg as a frontline treatment in combination with pembrolizumab (Keytruda), led to a confirmed overall response rate (cORR) of 50% in patients with human papillomavirus (HPV)-positive, recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) and a PD-L1 combined positive score (CPS) of at least 1.¹

These updated data come from the expansion cohort of the phase 1 CUE-101-01 trial (NCT03978689) and include complete responses (CRs). As of the July 14, 2025, data cutoff, 2 patients had achieved confirmed CRs and 10 had partial responses (PRs), with the most recent CR noted in a patient who initially demonstrated prolonged stable disease. Responses were observed even among patients with lower PD-L1 expression (CPS 1–19), a subgroup typically associated with reduced responsiveness to immunotherapy.

The 12-month overall survival (OS) rate was 88%, and median OS reached 32 months in this cohort, indicating a potentially durable survival benefit.

“We are excited to report an additional CR in a patient that had recurrent metastatic HPV-positive HNSCC treated with CUE-101 in combination with pembrolizumab,” said Matteo Levisetti, chief medical officer of Cue Biopharma, in a press release. “This patient had durable stable disease for close to 2 years and more recently demonstrated significant tumor reductions and now a CR. Notably, the patient had multiple sites of disease, including the lungs that cleared prior to the CR observed in the target lesion.”

These results compare favorably to outcomes from the phase 3 KEYNOTE-048 trial (NCT02358031), where pembrolizumab monotherapy in a similar first-line HNSCC population resulted in a 19% response rate, 57% 12-month OS, and a median OS of 12.3 months. While cross-trial comparisons must be interpreted cautiously, the improved efficacy signals of the CUE-101 combination are notable and warrant further evaluation in larger studies.

“We believe 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. It also serves as a clear example of the differences in timing of the clinical activity often observed with immunotherapy compared to traditional cytotoxic therapies and supports the prolonged median OS observed in this trial,” Levisetti added.

About CUE-101 and the Phase 1 Trial

CUE-101 is a novel, modular T-cell engager developed using Cue Biopharma’s Immuno-STAT™ platform. It selectively targets and activates HPV16-specific CD8-positive T cells through HLA-A*0201–restricted presentation of an HPV16 E7 peptide fused to attenuated interleukin-2 (IL-2). The agent is designed to drive tumor-specific immune activation while minimizing systemic toxicity by avoiding non-specific T cell proliferation.²

In combination with pembrolizumab, CUE-101 may enhance antigen-specific immune engagement and overcome resistance mechanisms in HPV-associated malignancies.

The phase 1 CUE-101-01 trial was conducted in 2 stages: a dose-escalation phase and a dose-expansion phase. Eligibility for the combination arm required patients to have HPV16-positive, HLA-A*0201–restricted HNSCC and a PD-L1 CPS of at least 1. Patients received CUE-101 every 3 weeks in combination with standard pembrolizumab dosing (200 mg every 3 weeks). At the time of enrollment completion, 27 patients had been treated in the combination cohort.

Safety data from the study support the tolerability of the regimen. Most treatment-related adverse events (AEs) were grade 1 or 2, consistent with the expected safety profiles of both pembrolizumab and IL-2–based immunotherapies. Grade 3 or higher treatment-related AEs were infrequent and manageable.

In the second-line setting, CUE-101 monotherapy showed encouraging outcomes as well. Among 20 patients previously treated with platinum-based chemotherapy or immune checkpoint inhibitors, the median OS was 20.8 months (95% CI, 11.0–not applicable), and the 12-month OS rate was 59%.

At the September 7, 2023, data cutoff, 20 of 22 patients receiving second-line CUE-101 plus pembrolizumab were alive, with 13 still on treatment. The disease control rate in the first-line combination cohort was 65%, reflecting both the depth and durability of responses.

Further clinical development is ongoing, and a randomized phase 2 trial may clarify the magnitude of benefit and potential for regulatory approval.

REFERENCES:

1. Cue Biopharma reports new complete response and confirmed 50% overall response rate in ongoing phase 1 trial of CUE-101 and pembrolizumab in recurrent/metastatic HPV+ head and neck cancer. News release. Cue Biopharma. July 16, 2025. Accessed July 16, 2025. https://tinyurl.com/a387yc7m

2. Chung CH, Adkins D, Colevas D, et al. A phase 1 dose-escalation and expansion study of CUE-101, given as monotherapy in 3L and in combination with pembrolizumab in 1L recurrent/metastatic HPV16+ head and neck cancer patients. J ImmunoTher Cancer. 2023;11(suppl 1):674. doi:10.1136/jitc-2023-SITC2023.0674