Radiotherapy-Activated NBTXR3 Shows Survival Benefit in Elderly Patients With Head and Neck Squamous Cell Carcinoma

The administration of NBTXR3 monotherapy activated by radiotherapy resulted in encouraging survival improvements in difficult-to-treat elderly and frail patients with locally advanced head and neck squamous cell carcinoma (LA-HNSCC) who are ineligible for cisplatin and intolerant to cetuximab (Erbitux), according to data from the dose-expansion portion of an ongoing phase 1 trial (NCT01946867).¹

Among 41 evaluable patients who received this approach, the median overall survival (OS) was 18.1 months, and the median progression-free survival (PFS) was 10.6 months. In the full population of 54 patients, evaluable and non-evaluable, the median OS was 14.1 months and the median PFS was 9.4 months.

The findings suggest that the lower benefit observed in the full patient population vs the evaluable population could potentially be related to early death linked with a high burden of comorbidity in patients who were not evaluable, according to NANOBIOTIX, the developer of NBTXR3. Evaluability was based on whether the patient received at least 80% of their intended intratumoral dose of NBTXR3, at least 60 Gy of radiation, and the required imaging needed to evaluate the target lesion both at baseline and at least once following treatment.

Moreover, the best observed target lesion objective response rate (ORR) was 85.4%, and the best observed target lesion complete response (CR) rate was 63.4%. These rates proved to be consistent with prior reports from the dose-escalation and -expansion trial.

“I have held the belief that NBTXR3 could have a real impact for patients with solid tumors since reviewing the proof-of-concept data from the phase 2/3 [trial] in soft tissue sarcoma and throughout my participation in Study 102 Expansion,” Christophe Le Tourneau, professor, study principal investigator, senior medical oncologist, and head of the Department of Drug Development and Innovation at Institut Curie, stated in a press release. “The first look at survival data has added to my confidence that NBTXR3 could provide a promising new therapeutic option for the practice. I look forward to leading the upcoming phase 3 global registration study.”

The first-in-class radio-enhancer, NBTXR3, is comprised of functionalized hafnium oxide nanoparticles.² The product was developed to eliminate tumors through physical cell death when activated by radiotherapy.³ The agent has a high degree of biocompatibility and requires 1 administration prior to the first receipt of radiation treatment. The product is also capable of fitting into the standards of care in place for radiation treatment on a global scale.

The phase 1 trial was launched to investigate the feasibility, safety, and preliminary efficacy of NBTXR3 followed by intensity-modulated radiation therapy (IMRT) in elderly patients with LA-HNSCC. In the dose-escalation portion of the research, the product was found to be well tolerated in a total of 19 patients, with no dose-limiting toxicities or NBTXR3-related serious adverse effects (SAEs) observed. The radiation-related toxicities were noted to be as expected with IMRT. Moreover, the recommended phase 2 dose of the agent was determined to be 22% of baseline tumor volume.

The primary end points of the dose-expansion phase of the research were ORR and CR of the primary tumor by imagine and in accordance with RECIST v1.1 criteria.

Screening began on day -28 and on day 1, patients received NBTXR3 via intratumoral injection. From day 2 to week 7, patients underwent radiation treatment. End of treatment is slated for week 15 or 16. Moreover, an MRI is being performed every 3 months for 1 year and then every 6 months thereafter to examine long-term safety of the approach.

Earlier data presented during the 2021 ASCO Annual Meeting showed that of 52 patients recruited to the dose-expansion phase, 40 were evaluable for efficacy. Of the 52 treated patients, the median age was 71.6 years (range, 44.5-89.9), 71.2% were male, the median baseline tumor volume was 43.1 mL (range, 1.3 mL to 222.3 mL), and 53.8% had their cancer located in the oropharynx.

Moreover, 38.5% of patients had histological grade 2 disease, 57.1% had HPV 16–negative status, 40.4% had a primary tumor stage of IVa, 34.6% had a Karnofsky score of 80%, 38.5% were former smokers, 48.1% did not identify as drinkers, and 26.9% were on 8 or more medications at baseline.

The measurement of the modified Charlson Comorbidity Index (mCCI) demonstrated that patients had an important increased risk of early death; 63.5% of patients had an mCCI that was greater than, or equal to, 4 at study entry.

Updated data showed that of the 21 evaluable patients who had a best observed ORR of a CR and who had a mean follow-up of 16.1 months, 6 died from non-oncologic reasons and only 1 patient died from progressive disease.

Regarding safety, the product was found to be feasible and to have acceptable tolerability. In 8 patients, 8 grade 3 or 4 NBTXR3-related SAEs occurred; these accounted for 1.3% of all reported AEs. Five of these SAEs were dysphagia, sepsis, soft tissue necrosis, stomatitis, and tumor hemorrhage. One death from sepsis was noted to potentially be associated with the study product, radiotherapy, and cancer.

“We started with soft tissue sarcoma—a disease indication notoriously resistant to radiotherapy,” Laurent Levy, co-founder and chief executive officer of Nanobiotix, stated in a press release. “After proving we could provide a therapeutic benefit vs radiotherapy alone for patients with locally advanced disease and achieving European market approval, we pivoted to patients with LA-HNSCC that have substantially limited treatment options. The new survival data we are seeing from Study 102 Expansion bolster our confidence in the promise of NBTXR3 as we near the launch of our pivotal phase 3 study in head and neck cancer.”

References

1. NANOBIOTIX announces 18.1 month median overall survival for 41 evaluable elderly and frail patients with HNSCC in phase 1 expansion evaluating NBTXR3 as a single agent activated by radiotherapy. News release. NANOBIOTIX. October 24, 2021. Accessed October 26, 2021. https://bit.ly/3pGYjLo
2. Le Tourneau C, Calugaru V, Takacsi-Nagy Z, et al. Phase I study of functionalized hafnium oxide nanoparticles (NBTXR3) activated by radiotherapy in cisplatin-ineligible locally advanced HNSCC patients. J Clin Oncol. 2021;39(suppl 15):6051. doi:10.1200/JCO.2021.39.15_suppl.6051
3. Nanobiotix announces positive first results from phase I expansion in locally advanced head and neck cancer at ASCO 2020. News release. NANOBIOTIX. May 29, 2020. Accessed October 26, 2021. https://bwnews.pr/3vO6oz5