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Nabil F. Saba, MD, FACP, Winship Cancer Institute of Emory University, Atlanta, GA, discusses the investigation of treatment modalities for HPV-positive oropharyngeal cancers. The majority of trials within this disease setting focus on both HPV-positive and HPV-negative disease, despite the biological and clinical differences between them. The predominance of HPV-negative disease within clinical trials could therefore dilute the results of HPV-positive disease. To accurately decipher whether a treatment intervention will be beneficial for HPV-positive disease would require investigating the disease alone. One trial currently focusing on HPV-positive disease in the definitive setting is the Phase III EA3161 (NCT03811015) trial. EA3161 is a randomized study of maintenance nivolumab versus observation in patients with locally advanced, intermediate risk HPV-positive oropharyngeal squamous cell carcinoma (OPSCC). Additional treatment modalities are being explored and developed for this patient population, including cellular therapies and vaccines targeting HPV E6/E7 and other HPV-related proteins such as E2/E5. This interview took place at the American Society of Clinical Oncology (ASCO) 2022 Annual Meeting in Chicago, IL.