Please refer to IB v 6.0 Section 5.2.2.9 for a summary of the SAEs from the Sponsor’s Global Drug Safety database from 25 August 2018 to 31 December 2019 for ongoing studies. In addition, at least 2 instances of nodular regenerative hyperplasia have been observed with the use of this agent 79 Abbreviated Title: Neoadjuvant IO for HNSCC Version Date: August 31, 2022 Important identified risks have been identified as IRRs including hypersensitivity, irAEs and skin lesions with hyperkeratosis, keratoacanthoma, cutaneous squamous cell carcinoma possibly due to TGFβ inhibition. The important identified risks with M7824 (bintrafusp alfa) observed to date were overall manageable. Anemia, alterations in wound healing or repair of tissue damage, and embryofetal toxicity remain as important potential risks. Mucosal bleeding events of mild to moderate severity were observed in participants treated with M7824 in ongoing studies and are a potential risk for M7824. Events may include epistaxis, hemoptysis, gingival bleeding or hematuria amongst others. In general, these reactions resolve without discontinuation of treatment. In addition, after discussion among NCI investigators on multiple protocols using M7824, multiple bleeding events ranging from low grade gingival bleeding and epistaxis to more serious hemoptysis, GI bleeding and hematuria have been observed. Some of these events can be attributed to bleeding events related to cancer directly and others bleeding events can be attributed to colitis or cystitis which is a known toxicity of anti-PD-L1 agents including M7824. However, there remains the possibility that M7824 may increase the overall risk of bleeding in ways that may not be directly related to direct tumor bleeding or inflammatory bleeding events described with checkpoint inhibitors like M7824. It is hypothesized that this possible increased bleeding risk may be due to TGF beta inhibition which has an effect on angiogenesis; bleeding has also been observed in patients receiving M7824 and may be drug-related (e.g., gum bleeding, nose bleeds, coughing up blood, blood in their urine, or blood in the stool). Accordingly, patients will be notified of the same possible risk in the informed consent document for this study (e.g., gum bleeding, nose bleeds, coughing up blood, blood in their urine, or blood in the stool). Several procedures have been performed on patients receiving M7824 at the NCI and no bleeding complications have been reported. Procedure Number of patients Percutaneous cholecystostomy 1 Nephrostomy tube placement 1 Liver biopsy 5 Thoracentesis 1 Biliary stent placement 1 Epidural catheter 2 Tracheostomy 1 Resection of CNS metastasis 1 Endoscopic biopsies under anesthesia 10 80 Abbreviated Title: Neoadjuvant IO for HNSCC Version Date: August 31, 2022 (13 biopsies per occurrence) Complete debridement of papillomas 4 14.2.3 Formulation and Preparation M7824 is provided as a sterile liquid formulation and packaged at a 10 mg/mL concentration in USP/ Ph Eur type I 50R vials that are filled with drug product solution to allow an extractable volume of 60 mL (600 mg/60 mL). The vials are closed with rubber stoppers in serum format complying with USP and Ph Eur with an aluminum crimp seal closure.