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 (<) 50 milliliters/minute (mL/min) (per Cockcroft-Gault equation),
  2. Grade >= 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 (<=) 14 or Aged >= 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