JNJ-90301900 (NBTXR3) Activated by Radiotherapy With or Without Cetuximab in LA-HNSCC

This is a global, open-label, randomized, 2-arm, Investigator's choice Phase 3 (Pivotal Stage) study to investigate the efficacy and safety of JNJ-90301900 (NBTXR3) / radiation therapy (RT)±cetuximab versus RT±cetuximab in treatment-naïve, platinum-ineligible, elderly participants with locally advanced head and neck squamous cell carcinoma (LA-HNSCC).

Inclusion Criteria: * Age greater than or equal to (\>=) 60 years old * Biopsy-confirmed squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx, or supraglottic larynx and a candidate for definitive radiation therapy with or without cetuximab * Clinical stage T3-4 NX or T2 N2-3 disease according to the 8th edition of AJCC * One primary tumor lesion amendable for intratumoral injection * Ineligible to receive platinum-based chemotherapy with radiation (at least one of the following): 1. Estimated creatinine clearance \>= 30 and less than (\= 2 hearing loss or tinnitus, 3. Grade \>= 2 peripheral neuropathy, 4. New York Heart Association Class 3 5. Aged 70-74 years old with Geriatric 8 (G8) score less than or equal to (\= 75 years old * Eastern cooperative oncology group (ECOG) performance status 0 to 1 * Life expectancy \>= 6 months Exclusion Criteria: * Carcinoma of the nasopharynx, paranasal sinus, salivary gland, or thyroid gland; or non-squamous histology or SCC of unknown primary origin * Clinical stage T1-2 N0, T2 N1, or M1 disease according to the 8th edition of AJCC * Loco-regionally recurrent head \& neck cancer that has been previously treated with surgery, radiation therapy, and/or chemotherapy * Prior or concurrent primary malignancy (including second synchronous head \& neck cancer) within the last 2 years of informed consent and whose natural history has the potential to interfere with the safety and efficacy assessment of the investigational agent * Ongoing or active infection requiring treatment with antimicrobial therapy within 2 weeks of randomization