Recurrent or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN) remains a major treatment challenge with few effective options. ROR2, a transmembrane receptor tyrosine kinase, is overexpressed in several tumors, including HNSCC, making it a promising target.

Ozuriftamab vedotin is a novel, conditionally activated ADC that binds ROR2 selectively in the acidic tumor microenvironment (pH <6.7). This pH-dependent targeting minimizes off-tumor toxicity, enhances pharmacokinetics, and may improve safety and efficacy by limiting systemic exposure and tissue-mediated clearance. The FDA has granted Fast Track Designation to ozuriftamab vedotin for R/M SCCHN.

Key data highlights include:

• 40 patients received ozuriftamab vedotin either Q2W (n=20) or 2Q3W (n=20) for a median of 85 days.

• For the efficacy analysis, 22 patients had HPV+ OPSCC (as of May 14, 2025); safety data presented (as of April 13, 2025) were based on the full dataset (n = 40)

• In HPV+ OPSCC patients,ozuriftamab vedotin demonstrated compelling antitumor activity in patients receiving 1.8 mg/kg Q2W

• ORR 45% (5/11), 27% (3/11) confirmed, DCR 100% (11/11), continuing follow-up.

• Median duration of response 9.9 months, median progression-free survival 4.7 months, and median overall survival 11.6 months and ongoing.

• Other studies using standard of care agents (methotrexate, docetaxel, or cetuximab) have reported ORR of 3.4% and OS of 4.4 months among HPV+ OPSCC patients.

• Based on the head and neck cancer dataset (n=40), most adverse events were low grade; fatigue and anemiawere most frequent.

Backed by promising efficacy and safety data, ozuriftamab vedotin shows strong potential to address the unmet need in recurrent/metastatic HPV+ OPSCC. Its Fast Track Designation supports ongoing FDA discussions for a proposed Phase III trial.

KOL insights: 

“Patients with HPV+ OPSCC who experience progression after initial therapy represent a sizable and rapidly growing population that is poorly served by current standard of care agents, including EGFR inhibitors.” – Expert Opinion.

Conclusion:

Ozuriftamab vedotin targets ROR2, which is upregulated by HPV-associated E6 and E7 oncoproteins and highly expressed in OPSCC, providing a strong rationale for its use in this setting. Patients with HPV+ OPSCC who progress after initial therapy represent a growing, underserved population with limited effective options beyond EGFR inhibitors.

In this population, ozuriftamab vedotin has shown promising antitumor activity and durable disease control, even in heavily pretreated, anti–PD-1–refractory patients. Its favorable safety profile, with mostly low-grade adverse events and minimal treatment discontinuation, further supports its potential as a meaningful treatment option. These findings justify continued clinical development in SCCHN, including advancement to a Phase III trial, and highlight the opportunity for accelerated and eventual full approval in HPV+ OPSCC.