This new SPORE project builds on the completed phase II ECOG E3311 clinical trial in patients with HPV+ HNSCC of the oropharynx (NCT01898494), which evaluated minimally invasive trans-oral robotic surgery (TORS) by credentialed surgeons, followed by determination of recurrence risk (based on tumor and lymph node pathology) and risk-adapted adjuvant therapy. Although the goal of that trial was to reduce treatment-induced disfigurement and toxicity without negatively impacting survival, approximately 30% of the patients were determined to have high-risk neck disease (extranodal extension(s) greater than 1 mm and/or five or more lymph nodes harboring cancer) and thus received an escalated radiation dose along with cisplatin chemotherapy.
Project 2 is designed to verify whether a four-gene mutational and/or radiomic risk signature, which was identified in preliminary studies on a subset of ECOG E3311 patients, can be used or optimized to differentiate which high-risk neck disease patients can safely receive a lower radiation dose following TORS. The project is utilizing biospecimens, CT images, and clinical data from a larger group of E3311 patients and from a separate cohort of standard-care UPMC Hillman Cancer Center patients. The tumor samples are also being used to define the relationship between mutations, immune infiltrate, and repression of interferon signaling.
To obtain a prospective cohort for validation and generalization of the findings from ECOG E3311 patients, an ongoing investigator-initiated clinical trial in HPV+ HNSCC patients who are found to have high-risk neck disease after TORS (NCT03715946) has been modified. In addition to the original trial design in which patients were randomized to receive adjuvant anti-PD-1 immunotherapy + standard or dose-deintensified radiotherapy, additional arms were added in which patients receive adjuvant cisplatin chemotherapy + standard or dose-deintensified radiotherapy, to match the high risk neck disease arm in the E3311 trial.
Successful completion of Project 2 will produce a validated and immediately applicable predictive signature for patients with high-risk neck disease and an explanation for the repressed immune infiltrate seen in those patients. It will also assess the extent to which quality of life and toxicity are improved in the high-risk patients who receive TORS plus reduced radiation doses.