NANORAY-312: A Phase III Pivotal Study of NBTXR3 Activated by Investigator's Choice of Radiotherapy Alone or Radiotherapy in Combination with Cetuximab for Platinum-Based Chemotherapy-Ineligible Elderly Patients with Locally Advanced HNSCC

Abstract

<h3>Purpose/Objective(s)</h3> Elderly patients with locally advanced head and neck squamous cell carcinoma (LA-HNSCC) are largely underrepresented in clinical trials (CT). This population lacks broad access to CTs due to an increased prevalence of comorbidities and age-related conditions. However, as population aging increases, more elderly patients will be diagnosed with LA-HNSCC although many will not be eligible to receive standard cisplatin-based concurrent chemoradiation (CRT). Toxicities, treatment burden and compliance associated with cisplatin are a concern. NBTXR3, a first-in-class radioenhancer, is composed of functionalized hafnium oxide nanoparticles, administered by a one-time intratumoral injection and activated by radiotherapy (RT). It has EU marketing approval for preoperative treatment of locally advanced soft tissue sarcomas. NBTXR3 locally amplifies tumor-killing effects of radiotherapy without adding toxicity to surrounding healthy tissue. NBTXR3 has been shown to prime the adaptive immune response in cancer models. In a Phase I trial of NBTXR3 + RT alone in elderly LA-HNSCC patients, this combination was shown to be safe and an Objective Response Rate (ORR) of 85.4% and CRR of 51.2% was reported at ASTRO 2021. A pivotal randomized phase III study is now recruiting. <h3>Materials/Methods</h3> NANORAY-312 is a global, open-label, randomized (1:1), 2-arm, Phase III (Pivotal Stage) study to investigate the efficacy and safety of NBTXR3/RT ± cetuximab versus RT ± cetuximab (Investigator's choice) in treatment-naïve, platinum-ineligible, elderly patients with LA-HNSCC. 500 patients will be enrolled. Eligible patients are ≥65 years with at least one measurable (RECIST 1.1) biopsy-confirmed T3-4 (AJCC v8) SCC of the oral cavity, oropharynx, hypopharynx, or supraglottic larynx which is amenable for intratumoral injection. Patients will receive IMRT (70 Gy in 35 fractions / 7 weeks). For patients with oropharyngeal cancer, human papilloma virus (HPV) status must be declared. In addition to the primary tumor, a single accessible LN in the neck is considered an eligible site for intranodal injection. <h3>Results</h3> The primary endpoint is PFS. The key secondary endpoint is OS. Other secondary endpoints include ORR, safety and tolerability, and quality of life. Exploratory endpoints include tumor immune response biomarkers, and radiographic change in the size of the tumor after 50 Gy of RT. Enrollment began in January 2022 and continues. <h3>Conclusion</h3> NBTXR3/RT ± cetuximab is under investigation in elderly patients with LA-HNSCC, a population which is underrepresented in clinical trials and with limited treatment options. This study has the ClinicalTrials.gov identifier NCT04892173.