Radiation enhancing NBTXR3 for the treatment of cisplatin-ineligible locally advanced HNSCC patients

Summary

Introduction: The non-surgical standard of care (SOC) for the treatment of locally advanced head and neck squamous cell carcinoma(LA HNSCC) is concurrent chemoradiation with high dose cisplatin or cetuximab in case of contra-indication to cisplatin. However elderly patients, and those with poor performance status, comorbidities, and/or intolerance, may not benefit from these SOC treatments and represent a high unmet need. New approaches are thus needed to improve clinical outcomes without adding toxicity. NBTXR3, a novel radioenhancer, composed of functionalized hafnium oxide nanoparticles, is injected once intratumorally and activated by radiotherapy(RT). NBTXR3 increases the RT energy deposit inside tumor cells and subsequently increases tumor cell death, while sparing healthy tissues compared to RT alone. In addition NBTXR3 subsequently primes an adaptive immune response. Results of the phase I dose expansion study are presented.

Materials and Methods: Patients with stage III-IVA or T3/T4 (AJCC/UICC TNM staging system 8th ed.) HNSCC of the oropharynx or oral cavity, ineligible to cisplatin or cetuximab and amenable for RT, received a single intratumoral injection of NBTXR3 and IMRT (70 Gy in35 fractions /7 weeks). A 3 + 3 dose escalation design tested four doses of NBTXR3, equivalent to 5, 10, 15, and 22% of baseline theoretical tumor volume. The RP2D established as 22% is further tested in the dose expansion part. The primary endpoints of the dose expansion part are objective response rate (ORR) and complete response rate(CRR) of the primary tumor, according to RECIST 1.1. Safety is also evaluated.

Results: As of March 26, 2021, 52 patients have been treated in the phase I dose expansion part. The median age was 71.6 years old (range:44.5–89.9). The median tumor volume was 60.6 mL (range: 2.5–259.4). At a median time of 8.1 months after NBTXR3 injection, the ORR of the primary lesion was 82.5% and the CRR 62.5% in the evaluable population for efficacy (N = 40). RT-related toxicity was as expected with IMRT. Six patients (11.5%) experienced at least 1 G3-4serious adverse event (AE) related to the injection procedure and/orNBTXR3 which represented less than 1% of all reported AEs. Four deaths related to RT were observed. Also,1 death from sepsis possibly related to NBTXR3, RT, and cancer disease was reported. Recruitment is ongoing.

Conclusions: NBTXR3 intratumoral administration followed by IMRT may represent an option in elderly patients or patients with multiple comorbidities with LA-HNSCC who have limited therapeutic options. NBTXR3 activated by RT showed promising anti-tumor efficacy, supporting further evaluation in a phase III randomized trial.