A phase I dose expansion study of NBTXR3, radiation enhancing hafnium oxide nanoparticles, for the treatment of cisplatin-ineligible locally advanced HNSCC patients

Summary

Introduction: Non-surgical standard of care (SOC) for locally advanced head and neck squamous cell carcinoma (LA HNSCC) patients is chemoradiation with cisplatin/cetuximab. Elderly patients, and those with poor performance status, comorbidities, and/or intolerance, may not benefit from current SOC, representing a high unmet need. NBTXR3, a novel radioenhancer composed of functionalized hafnium oxide nanoparticles, is activated by radiotherapy (RT). NBTXR3 increases RT energy deposit in tumor cells and subsequent tumor cell death, while sparing healthy tissues compared to RT alone. NBTXR3 subsequently primes an adaptive immune response.

Objectives: The phase I dose expansion study aims to evaluate safety and efficacy of NBTXR3 + RT in patients with stage III–IVA or T3/T4 (TNM-8) HNSCC of the oropharynx or oral cavity, ineligible to cisplatin or cetuximab and amenable for RT.

Methods: Patients received a single intratumoral injection of NBTXR3 + RT (70 Gy, 35 fractions/7 weeks). A 3 + 3 dose escalation design tested four NBTXR3 doses: 5, 10, 15, and 22% of baseline theoretical tumor volume; and established RP2D as 22%. Primary endpoints of the dose expansion part are objective response rate (ORR) and complete response rate (CRR) of the primary tumor (RECIST 1.1).

Results and Conclusion: As of March 26, 2021, 52 patients were treated in the dose expansion part. Median age and tumor volume were 71.6 years and 60.6 mL respectively. ORR of the primary lesion was 82.5% and CRR was 62.5% (N = 40) at a median of 8.1 months after NBTXR3 injection. RT-related toxicity was as expected. Six patients experienced at least one G3–4 serious adverse event (AE) related to injection procedure and/or NBTXR3 (< 1% of all AEs). Four deaths related to RT were observed, also one death from sepsis possibly related to NBTXR3, RT, and cancer disease was reported. NBTXR3 + RT showed promising efficacy, supporting further evaluation in a phase III randomized trial.