At the time of publication or shortly thereafter. 6.2.2 Genomic Data Sharing Plan Unlinked genomic data will be deposited in public genomic databases such as dbGaP in compliance with the NIH Genomic Data Sharing Policy. 6.3 RESPONSE C RITERIA For the purposes of this study, patients will be followed-up every 3 months +/- 1 week. Patients will be contacted by phone call or e-mail for questioning regarding disease progression, adverse events, and survival every 3 months until the patient is 2 years out from surgery. Primary outcome response measures will be obtained by comparing pre-treatment clinical staging determined by imaging according to Response Evaluation Criteria in Solid Tumors RECIST) guideline (version 1.1) guidelines to the post-treatment pathologic staging obtained from pathologic analysis of the surgically resected specimen. The screening/baseline imaging will be used to determine the pre-treatment TNM classification and stage. Both primary endpoint criteria are based upon results from pathologic analysis of surgically resected tissues. For patients that have surgery outside of the NIH Clinical Center, tissue blocks and/or slides will be obtained from the institution where the patient underwent surgery after the patient signs that institution’s release document. These tissue blocks and/or slides will be reviewed by the NCI Laboratory of Pathology. Outside pathology reports may also be obtained from the corresponding institution after the patient sign’s that institution’s medical release document. In cases where there is discordance between the pathologic staging as determined by an outside institution and the NCI Laboratory of Pathology, we will use the pathologic staging as determined by the NCI Laboratory of Pathology to determine the primary outcome measures. Secondary outcome response measures will be obtained by comparing CT or MRI of chest and neck obtained at screening/baseline and D21-28. Response or progression when comparing pre- and post-treatment imaging will be evaluated in this study using the new international criteria proposed by RECISTv1.1 guidelines[25]. Changes in the largest diameter (unidimensional measurement) of the tumor lesions and the shortest diameter in the case of malignant lymph nodes are used in the RECIST criteria. 6.3.1 Disease Parameters Measurable disease: Measurable lesions are defined as those that can be accurately measured in at least one dimension (longest diameter to be recorded) as: By chest x-ray: >20 mm; By CT scan: oScan slice thickness 5 mm or under: as >10 mm oScan slice thickness >5 mm: double the slice thickness With calipers on clinical exam: >10 mm. 52 Abbreviated Title: Neoadjuvant IO for HNSCC Version Date: August 31, 2022 All tumor measurements must be recorded in millimeters (or decimal fractions of centimeters). Malignant lymph nodes. To be considered pathologically enlarged and measurable, a lymph node must be >15 mm in short axis when assessed by CT scan (CT scan slice thickness recommended to be no greater than 5 mm). At baseline and in follow-up, only the short axis will be measured and followed. Non-measurable disease. All other lesions (or sites of disease), including small lesions (longest diameter <10 mm or pathological lymph nodes with ≥10 to <15 mm short axis), are considered non-measurable disease. Bone lesions, leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, and abdominal masses (not followed by CT or MRI), are considered as non-measurable. Note: Cystic lesions that meet the criteria for radiographically defined simple cysts should not be considered as malignant lesions (neither measurable nor non-measurable) since they are, by definition, simple cysts. ‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable lesions, if they meet the definition of measurability described above. However, if non-cystic lesions are present in the same patient, these are preferred for selection as target lesions. Target lesions. All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, representative of all involved organs, should be identified as target lesions and recorded and measured at baseline. Target lesions should be selected on the basis of their size (lesions with the longest diameter), be representative of all involved organs, but in addition should be those that lend themselves to reproducible repeated measurements. It may be the case that, on occasion, the largest lesion does not lend itself to reproducible measurement in which circumstance the next largest lesion which can be measured reproducibly should be selected. A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target lesions will be calculated and reported as the baseline sum diameters. If lymph nodes are to be included in the sum, then only the short axis is added into the sum. The baseline sum diameters will be used as reference to further characterize any objective tumor regression in the measurable dimension of the disease. Non-target lesions. All other lesions (or sites of disease) including any measurable lesions over and above the 5 target lesions should be identified as non-target lesions and should also be recorded at baseline. Measurements of these lesions are not required, but the presence, absence, or in rare cases unequivocal progression of each should be noted throughout follow-up. 6.3.2 Methods for Evaluation of Measurable Disease All measurements should be taken and recorded in metric notation using a ruler or calipers. All baseline evaluations should be performed as closely as possible to the beginning of treatment and never more than 4 weeks before the beginning of the treatment. The same method of assessment and the same technique should be used to characterize each identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is preferred to evaluation by clinical examination unless the lesion(s) being followed cannot be imaged but are assessable by clinical exam. 53 Abbreviated Title: Neoadjuvant IO for HNSCC Version Date: August 31, 2022 Clinical lesions: Clinical lesions will only be considered measurable when they are superficial (e.g., skin nodules and palpable lymph nodes) and 10 mm diameter as assessed using calipers (e.g., skin nodules). In the case of skin lesions, documentation by color photography, including a ruler to estimate the size of the lesion, is recommended.