Immunotherapeutics that target human papillomavirus (HPV) genotype 16 appear to boost the activity of pembrolizumab in advanced head and neck squamous cell carcinoma. Two examples were presented in posters at the 2023 ASCO Annual Meeting.1,2
Katharine A. Price, MD
The phase II VERSATILE-002 trial evaluated PDS0101, which, simply put, is a type of cancer vaccine: a nanoparticle platform containing HPV16 neoantigens. PDS0101 exhibits antitumor activity with checkpoint inhibitors by upregulating type 1 interferons and promoting antigen processing and cross presentation. This allows the generation of polyfunctional HPV16-specific CD8 and CD4 T cells and immune memory, the investigators explained.1
“We are excited about this combination [PDS0101 and pembrolizumab]. It appears from these preliminary data that there is an incremental benefit over pembrolizumab monotherapy. This combination would target patients with HPV-positive head and neck squamous cell cancers who are candidates for first-line single-agent pembrolizumab,” Katharine A. Price, MD, Associate Professor of Oncology Head and Neck Disease Group, Mayo Clinic, Rochester, Minnesota, told The ASCO Post.
We are excited about this combination [PDS0101 and pembrolizumab]. It appears from these preliminary data that there is an incremental benefit over pembrolizumab monotherapy.— Katharine A. Price, MD
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The second study was a multicenter U.S. trial of CUE-101, the first Immuno-STAT (selective targeting and alteration of T cells) biologic to enter clinical trials. These biologics are modular T-cell engagers engineered to selectively activate tumor antigen–specific, CD8-positive cells via targeted delivery of cytokines. CUE-101 is composed of a human leukocyte antigen (HLA) complex (HLA-A*0201), a peptide epitope derived from the HPV16 E7 protein, and four molecules of attenuated interleukin-2 (IL-2); it is designed to bind, expand, and activate HPV16-specific, CD8-positive T cells.
VERSATILE-002 is a phase II open-label nonrandomized adaptive-design study evaluating the combination of PDS0101 and pembrolizumab in patients with HPV16-positive recurrent and/or metastatic head and neck squamous cell carcinoma. Patients had a combined positive score (CPS) of at least 1 and were naive to checkpoint inhibitors. All patients received pembrolizumab at 200 mg intravenously every 3 weeks, with PDS0101 given subcutaneously in two 0.5-mL injections during cycles 1, 2, 3, 4, and 12, for a maximum of five doses.
The intent-to-treat population included 48 patients. Median patient age was 62 years, 94% were male, 94% were White, and 42% had a CPS of at least 20. The median number of PDS0101 doses was four; 23% received all five doses. The median number of pembrolizumab doses was 5, and 27% received at least 10 doses. Efficacy was evaluated in the 34 patients with imaging assessment after treatment.
Outcomes vs Historical Standard
PDS0101 plus pembrolizumab yielded a median progression-free survival of 10.4 months. According to Dr. Price, this “compares favorably with published median progression-free survivals of 2 to 3 months” for approved checkpoint inhibitors used as monotherapy in patients with similar levels of PD-L1. Estimated 12-month overall survival rate was 87.1%, which she considered “quite promising as compared with published results of 36% to 50%” in KEYNOTE-0483 and CheckMate 141.4
By investigator assessment, there were partial responses in 23.5% of patients, complete responses in 2.9%, and 44.1% with stable disease. More than two-thirds of patients experienced reductions in tumor size. No toxicity was observed beyond that known for single-agent pembrolizumab, and no patients went off study because of toxicity.
The analysis is ongoing. Another cohort of patients with checkpoint inhibitor–refractory disease has received the combination, and those data are being analyzed. A global, randomized trial, VERSATILE-003, should be initiated later this year. The U.S. Food and Drug Administration has granted Fast Track status to PDS0101 plus pembrolizumab for recurrent or metastatic HPV16-positive head and neck squamous cell carcinoma.
CUE-101-01 is an ongoing phase I first-in-human study of CUE-101 in patients with HPV16-positive recurrent or metastatic squamous cell carcinoma of the head and neck with an HLA-A*0201 genotype. The 71 patients received escalating doses of CUE-101 monotherapy (0.06–8.0 mg/kg) and in combination with pembrolizumab if they had a CPS of at least 1. The study was then expanded at the recommended phase II dose of 4 mg/kg, with patients whose disease was refractory to at least one platinum-based regimen or checkpoint inhibitor receiving CUE-101 as a single agent and those who were naive to checkpoint inhibitors also receiving pembrolizumab given as a first-line treatment. Treatment was administered every 3 weeks.
Among 16 patients treated with pembrolizumab plus CUE-101 at the recommended phase II dose, the objective response rate was 36%, the disease control rate was 57%, the median duration of response was 35.1 weeks, and the median progression-free survival was 4.9 months. The rate of response to the drug as a single agent was lower. Adverse events ≥ grade 3 occurred in 25% of patients receiving the single agent and in 48% receiving combination treatment.
Christine H. Chung, MD, PhD
“CUE-101 facilitates the targeted delivery of high concentrations of reduced-affinity IL-2 to relevant tumor-specific, CD8-positive T cells,” said presenting author Christine H. Chung, MD, PhD, of Moffitt Cancer Center, Tampa, Florida. “The study showed encouraging safety results in the monotherapy and combination cohorts, which need validation in larger randomized trials.”
DISCLOSURE: Dr. Price reported no conflicts of interest. Dr. Chung has served as a consultant or advisor to AVEO, Brooklyn ImmunoTherapeutics, Exelixis, Fulgent Pharma, Genmab, Merck, and Seagen.
1. Price KAR, Kaczmar JM, Worden FP, et al: Safety and efficacy of immune checkpoint inhibitor naive cohort from study of PDS0101 and pembrolizumab in HPV16-positive head and neck squamous cell carcinoma. 2023 ASCO Annual Meeting. Abstract 6012. Presented June 5, 2023.
2. Chung CH, Dimitrios A, Colevas D, et al: A phase 1 dose-escalation and expansion study of CUE-101, a novel HPV16 E7-pHLA-IL2-Fc fusion protein, given as monotherapy and in combination with pembrolizumab in patients with recurrent/metastatic HPV16+ head and neck cancer. 2023 ASCO Annual Meeting. Abstract 6013. Presented June 5, 2023.
3. Burtness B, Harrington KJ, Greil R, et al: Pembrolizumab alone or with chemotherapy versus cetuximab with chemotherapy for recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-048): A randomised, open-label, phase 3 study. Lancet 394:1915-1928, 2019.
4. Ferris RL, Blumenschein Jr G, Fayette J, et al: Nivolumab vs investigator’s choice in recurrent or metastatic squamous cell carcinoma of the head and neck: 2-year long-term survival update of CheckMate 141 with analyses by tumor PD-L1 expression. Oral Oncol 81:45-51, 2018.
The invited discussant of the VERSATILE-002 and CUE-101-01 trials, Erminia Massarelli, MD, PhD, MS, said both are examples of a growing interest in evaluating immunotherapeutic strategies and treatment sequences in early-stage head and neck squamous cell cancer as well as in metastatic disease. Dr. ...