This is a multicenter study comprising two phases: a run-in phase, including only patients receiving ficerafusp alfa and nivolumab, and a randomized phase, which corresponds to a randomized, open-label, phase II comparative study.

The primary objective is to compare the objective response rate (ORR) of patients with platinum refractory HNSCC with progressive disease within the 6 months after multimodal curative treatment treated with ficerafusp alfa (BCA 101) and nivolumab versus nivolumab alone.

There is a strong medical justification for combining ficerafusp alfa with nivolumab (anti-PD-1) to provide additional clinical benefit to patients with platinum-refractory HNSCC who are progressing within 6 months of multimodal treatment for locally advanced disease.

In the Run-in phase, patients will receive the following treatment regimens according to the study intervention plan:

Combination of Ficerafusp alfa + Nivolumab

• Ficerafusp alfa 1500 mg every week
• Nivolumab 240 mg every 2 weeks

In the randomized trial:

• ARM A Combination of Ficerafusp alfa + Nivolumab Ficerafusp alfa 1500 mg every week Nivolumab 240 mg every 2 weeks
• ARM B Nivolumab monotherapy Nivolumab 240 mg every 2 weeks

Inclusion Criteria:

• Patient or legally authorized representative, if applicable, has signed and dated informed consent form (ICF) indicating that the patient (or legally authorized representative, if applicable) has been informed of all the pertinent aspects of the study prior to enrollment and the patient must be willing to comply with all study procedures for the duration of the study.
• Patient is >18 years, ≤75 years of age on the day the ICF is signed.
• Patients with Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1 (see Appendix 1).
• Histologically or cytologically confirmed squamous cell carcinoma of head and neck (HNSCC). Eligible primary tumor locations are oral cavity, larynx hypopharynx, or oropharynx (OPSCC).
• Local, regional or metastatic progression within 6 months after the last dose of platinum in a multimodal strategy for locally advanced stage, not amenable to salvage surgery in case of local or regional progression.

Specification regarding inclusion criterion no. 05 : Progression is not assessed as per RECIST. Any of the following will be considered as progression:

• A positive biopsy 3 months after the end of radiotherapy given with curative intent
• Appearance of any new lesion (e.g.: metastases or lymph nodes)
• Any increase in tumor size
• Any persisting tumor (confirmed with a biopsy) not amenable to salvage surgery
• For OPSCC patients, a pathological report determination of human papillomavirus (HPV) status by p16 expression must be p16 negative -Measurable tumor lesion(s) assessed by H&N-computed tomography scan (CT-scan) or magnetic resonance imaging (MRI), based on RECIST v 1.1 (see Appendix 3). Tumor lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated.

Exclusion Criteria:

• Primary tumor of nasopharyngeal, paranasal sinuses, nasal cavity or salivary gland, thyroid or parathyroid gland pathologies, skin, squamous cell carcinoma of unknown primary or non-squamous histologies (e.g., mucosal melanoma).
• Patients having received prior systemic treatment for metastatic or recurrent disease.
• Patients having received prior treatment with anti-EGFR antibody.
• Patients having received prior treatment with anti-TGF-β therapy.
• Patients having received prior therapy with anti-PD1, anti-PD-L1 (or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways).
• Known to be diagnosed and/or treated for any other additional malignancy within 2 years prior to registration/randomization with the exception of the following: curatively treated basal cell carcinoma or squamous cell carcinoma of the skin, and curatively resected in situ cervical cancer, and curatively resected in situ breast cancer, and low-risk early stage prostate cancer defined as follows: Stage T1 up to T2a with a Gleason score ≤6 and prostatic specific antigen <10 ng/mL either treated with definitive intent or untreated in active surveillance that has been stable for the past year prior to registration/randomization. Other exceptions may be considered with the Sponsor's consultation. The time requirement for no malignancy for 2 years does not apply to the cancer for which a patient is enrolled in the study.
• Any of the following <6 months before starting study treatment: ST-elevation myocardial infarction, severe/unstable angina, uncontrolled cardiac ventricular arrythmia, coronary/peripheral artery bypass graft or stent, cerebrovascular accident/stroke less than 6 months prior to enrollment or NYHA Class III/IV congestive heart failure. Subjects with deep vein thrombosis who are hemodynamically stable can enroll if they are on a stable dose of anticoagulants for at least 3 months.
• Serious systemic infection (bacterial, viral, or fungal) within 4 weeks before first dose of study treatment, or active systemic infection requiring either hospitalization or parenteral anti-infective therapy within 2 weeks before first dose of study treatment.
• History of (non-infectious) pneumonitis/ interstitial lung disease or has current pneumonitis/ Interstitial lung disease.
• Active central nervous system (CNS) metastases or carcinomatous meningitis. Known active central nervous system metastases, history of spinal cord compression from tumor involvement, a history of carcinomatous meningitis, or leptomeningeal disease are excluded. Patients with a history of treated central nervous system metastases (by surgery or radiation therapy) may be eligible if central nervous system metastases have been stable for at least 4 weeks, i.e., without evidence of progression by repeat imaging and without requirement of steroid treatment for at least 14 days prior to first dose of study treatment.
• History of uncontrolled seizures, CNS disorders or psychiatric disability judged by the investigator to be clinically significant, precluding informed consent, or interfering with compliance.

The study will be conducted in Europe with GORTEC as sponsor. Pseudonymized participant data may be shared with the owner of the product ficerasup alfa.