Novel Radioenhancer NBTXR3 Activated by Radiotherapy in Cisplatin-Ineligible Locally Advanced HNSCC Patients: Final Results of a Phase I Trial

Abstract

New approaches are needed for frail or elderly patients with locally advanced head and neck squamous cell carcinoma (LA HNSCC) who are unfit to receive cisplatin with concurrent radiotherapy (RT). NBTXR3 is a first-in-class radioenhancer, composed of functionalized hafnium oxide nanoparticles, administered by a single intratumoral (IT) injection and activated by RT. NBTXR3 locally amplifies the anti-tumoral response of RT without adding toxicity to surrounding healthy tissue as shown in a randomized trial in soft tissue sarcoma. This two-part study: dose-escalation followed by the dose-expansion part reported here, evaluated the safety and preliminary efficacy for NBTXR3 activated by RT in elderly or frail patients ineligible to cisplatin. This trial enrolled patients who had previously untreated AJCC 8th Stage III-IVA or T3, T4 SCC of the oral cavity or oropharynx (OPC) ineligible to cisplatin. Eligible patients received a single IT injection of NBTXR3 at the recommended dose (22% of the baseline tumor volume) followed by RT (IMRT 70 Gy in 35 fractions). The primary objectives of the dose expansion part were to test the recommended dose, to confirm its safety, and obtain preliminary evidence of efficacy. The secondary objectives included the evaluation of progression-free survival (PFS) and overall survival (OS). Fifty-sixpatients in the dose expansion part were treated from April 2019-January 2022; 44 patients were evaluable for objective tumor response. In the all-treated population, median age was 71.9 years. 64.3% had age-adjusted Charlson Comorbidity Index scores ≥4, 55.4% had OPC (45.2% HPV+) and 80% had T3-4. Median injected volume of NBTXR3 was 13.6 [0.5-57.1] mL. Grade ≥ 3 adverse events reported as potentially related to NBTXR3 or to injection procedure were 1.2% and 0.4% of all AEs reported, respectively. In the evaluable population, the best objective response rate of the NBTXR3 injected lesion was 81.8% with a complete response rate of 63.6%. The best overall response rate (injected and non-injected lesions) was 79.5%. Final analyses on PFS and OS with long-term follow-up will be presented. NBTXR3 IT injection followed by activation with RT was confirmed to be feasible and well tolerated in elderly or frail patients with LA HNSSC and significant comorbidities. The high rate of best overall response suggests that NBTXR3+RT is effective in this elderly population ineligible to cisplatin with a high unmet medical need. These results support our ongoing phase III study comparing NBTXR3/RT ± cetuximab vs. RT ± cetuximab in platinum-based chemotherapy ineligible elderly patients with LA-HNSCC: NANORAY 312 (NCIT04892173).