CUE-101 Plus Pembrolizumab Yields 50% ORR in HPV+ HNSCC With Low PD-L1 Expression

First-line treatment with CUE-101 at the recommended phase 2 dose (RP2D) of 4 mg/kg in combination with pembrolizumab (Keytruda) produced a confirmed overall response rate (cORR) of 50%, including complete responses (CRs), in patients with human papillomavirus (HPV)–positive, recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) with a PD-L1 combined positive score (CPS) of at least 1, according to updated data from the expansion portion of the phase 1 CUE-101-01 trial (NCT03978689).¹

At a data cutoff of July 14, 2025, 2 patients had achieved a CR and 10 had achieved a partial response (PR); an additional CR was reported in a patient with multiple tumors. Responders included patients with a low PD-L1 CPS (between 1 to 19). The 12-month overall survival (OS) rate with CUE-101 plus pembrolizumab was 88% and the median OS was 32 months.

“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,” Matteo Levisetti, chief medical officer of Cue Biopharma, stated in a news 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. 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.”

According to the drug’s developer, Cue Biopharma, these results are favorable compared with historical data from the phase 3 KEYNOTE-048 trial (NCT02358031). Treatment with pembrolizumab monotherapy in this trial produced an ORR of 19%, a 12-month OS rate of 57%, and a median OS of 12.3 months.

Dan Passeri, chief executive officer of Cue Biopharma, added that, “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. With this maturing data, we are further emboldened in our conviction that our Immuno-STAT platform represents transformative potential for selectively modulating the patient’s immune system.”

CUE-101 is a modular T-cell engager designed to selectively activate HPV16-specific CD8-positive T cells through targeted delivery of attenuated IL-2.^1,2 It consists of an HLA-A*0201 molecule presenting an HPV16 E7–derived peptide, fused to 4 reduced-affinity IL-2 molecules.

CUE-101 is currently being evaluated as monotherapy and in combination with pembrolizumab for the treatment of patients with recurrent/metastatic HNSCC in CUE-101-01.²

CUE-101-01 Trial Overview and Additional Data

This phase 1, open-label, dose-escalation and -expansion study requires patients to have the HLA-A*0201 genotype and HPV16-positive disease confirmed by P16 immunohistochemistry and HPV16 mRNA in situ hybridization. Patients in the monotherapy cohort were also required to have disease progression following platinum-based chemotherapy or checkpoint inhibitor therapy and received CUE-101 every 3 weeks. Patients in the combination cohort were treatment-naive for recurrent/metastatic disease and received CUE-101 with pembrolizumab 200 mg every 3 weeks. Notably, eligibility for the combination arm required a PD-L1 CPS of 1 or higher.

Enrollment in both the monotherapy and combination therapy arms of the study is now complete. As of the data cutoff of September 7, 2023, 49 and 27 patients were enrolled onto the first-line monotherapy and second-line combination cohorts, respectively.

Previously reported data from the study showed that the Kaplan-Meier estimate for median OS among patients treated with CUE-101 monotherapy in the second line (n = 20) was 20.8 months (95% CI, 11.0-not applicable); the landmark 12-month OS rate was 59% in this patient population.

Twenty of the 22 patients who received the second-line combination of CUE-101 and pembrolizumab were alive at the data cutoff, with 8 patients surviving for at least 12 months and 13 remaining on treatment. The disease control rate among newly diagnosed patients receiving the combination was 65%.

In terms of safety, adverse effects (AEs) were consistent with the mechanism of action of CUE-101, known profile of pembrolizumab, and underlying disease biology. The risk of grade 3 or higher treatment-related AEs was low; most were no higher than grade 2, reversible, and easily managed with appropriate medical care.

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://cuebiopharma.gcs-web.com/news-releases/news-release-details/cue-biopharma-reports-new-complete-response-and-confirmed-50
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