Neoadjuvant HPV16-specific viral immunotherapy (HB200) plus chemotherapy with response-adapted de-escalation in HPV16+ oropharyngeal squamous cell carcinoma: TARGET-HPV trial.

6097 Background: Neoadjuvant immunotherapy is an emerging strategy in head and neck squamous cell carcinoma to enhance systemic antitumor immunity and enable response-adapted de-escalation. In HPV associated oropharyngeal squamous cell carcinoma (OPSCC), virally encoded oncoproteins represent shared, tumor-specific antigens and a rational immunologic target well suited for the neoadjuvant setting in the presence of intact tumor antigen. We conducted a phase I/II trial evaluating neoadjuvant HPV16-specific viral immunotherapy (HB200; HB201 and HB202 HPV16 therapeutic vaccines) plus chemotherapy followed by response-adapted definitive treatment in non-metastatic HPV16+ OPSCC (NCT05108870). Methods: This investigator-initiated phase I/II trial enrolled patients with previously untreated, non-metastatic HPV16+ OPSCC (N1-3 or T3-4; smokers permitted). All patients received three cycles of neoadjuvant HB200 (HB201 alone or alternating HB202/201) with carboplatin/paclitaxel, followed by radiographic response assessment. Patients with T1-2 tonsil or well-lateralized base of tongue tumors achieving ≥50% tumor shrinkage underwent transoral robotic surgery (TORS) alone. Remaining patients received response and risk adapted radiotherapy (50-70Gy based on risk/response) with or without cisplatin. The primary endpoint was deep response rate (DRR; ≥50% tumor shrinkage). Secondary endpoints included survival and toxicity. Exploratory endpoints included circulating tumor HPV-DNA (ctHPV-DNA), HPV16-specific immunity, and spatial transcriptomics. Results: Thirty-five patients were enrolled (median age 58; 89% male); Twelve patients (34%) received HB201 alone and 23 (66%) received alternating HB202/201. Nineteen patients (54%) were current or former smokers, and 49% had stage II-III (AJCC 8 th edition). The DRR was 87.9% (95% CI, 71.8-96.6). Thirty (86%) received de-escalated definitive therapy. At a median follow-up of 23 months, 2-year PFS and OS were 86% and 100% respectively. Most common AEs during neoadjuvant HB200/chemo were fatigue (97%), nausea (91%), and fever (76%). Detectable ctHPV-DNA following treatment was significantly associated with disease recurrence ( p <0.01). HPV16-specific immune responses and spatial transcriptomic analyses will be presented. Conclusions: Neoadjuvant HB200 combined with chemotherapy resulted in high deep response rates, frequent treatment de-escalation, and excellent survival outcomes in locoregionally advanced HPV16+ OPSCC. These findings support further evaluation of HPV directed immune therapy in neoadjuvant setting. Clinical trial information: NCT05108870 .