1. Fuerst, Mark L.

Article Content

A novel nanoparticle activated by radiotherapy extends survival to 18 months in hard-to-treat elderly, frail, locally advanced head and neck cancer patients.

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"In the head and neck cancer population, the literature suggests that 20-30 percent of patients have a Charlson Comorbidity Index (CCI) that has been adjusted to age (mCCL) of 4 or higher, which is correlated with worse survival," said principal investigator Professor Christophe Le Tourneau, MD, PhD, Professor, Senior Medical Oncologist, and Head of the Department of Drug Development and Innovation at Institut Curie.


"Indeed, the number of elderly patients diagnosed with locally advanced head and neck squamous cell carcinoma (LA-HNSCC) is continuously increasing, yet not all are eligible to receive concurrent chemoradiation, the non-surgical standard of care, and they may not benefit from cetuximab," he noted. "The global elderly head and neck population treated with radiotherapy only without concomitant therapy has an overall survival (OS) ranging from 12 to 13 months."


Study Details

Le Tourneau and colleagues designed a study to address this high unmet need in an elderly LA-HNSCC population with a higher burden of disease and comorbidities. The Phase I multicenter, open-label, non-randomized dose-escalation/dose-expansion study evaluated the feasibility, safety, and preliminary efficacy of a potentially first-in-class radioenhancer, the nanoparticle NBTXR3, administered as an intratumoral injection, followed by intensity-modulated radiation therapy, in elderly or fragile patients with LA-HNSCC. Le Tourneau presented the first survival data from this study at the 2021 American Society for Radiation Oncology (ASTRO) Annual Meeting.


Overall, 54 patients were recruited to the dose-expansion part of the study; 41 patients were evaluable for objective tumor response. Patients were elderly (median age 71.8 years) and predominantly male, with tumors of the oral cavity and oropharynx. Most patients were assessed with primary tumor Stage III or IVa. Evaluability in Study 102 Expansion was determined based on the patient receiving at least 80 percent of the intended intratumoral dose of NBTXR3, at least 60 Gy of radiotherapy, and the required imaging to assess the target lesion at baseline and at least once post treatment.


Survival Benefits

The median OS was 18.1 months and median progression-free survival was 10.6 months. Best observed target lesion objective response rate was 85.4 percent and best observed target lesion complete response rate was 63.4 percent.


"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 II/III in soft tissue sarcoma and throughout my participation in Study 102 Expansion," said Le Tourneau. "This first look at survival data has added to my confidence that NBTXR3 could provide a promising new therapeutic option. I look forward to leading the upcoming phase III global registration study, and to have the opportunity to evaluate the promise of this innovation in a larger patient population."


Safety Data

NBTXR3 administration was feasible and well-tolerated overall. A total of eight Grade 3/4 NBTXR3-related adverse events were observed in eight patients, representing 1.3 percent of all observed adverse events. Of these adverse events related to NBTXR3, five serious adverse events (SAEs) were observed including dysphagia, sepsis, soft tissue necrosis, stomatitis, and tumor hemorrhage. Of the SAEs, one death from sepsis assessed by the investigator as possibly related to NBTXR3, radiotherapy, and cancer was observed.


About two-thirds of all patients treated in this study had high mCCI, which is 2-3 times the prevalence of comorbidity in the overall LA-HNSCC population. Despite the prevalence of high mCCI in Study 102 Expansion, these preliminary data support further evaluation of NBTXR3 activated by radiotherapy as a therapeutic option that may translate to a survival benefit for elderly and frail LA-HNSCC patients, Le Tourneau said.


About NBTXR3

NBTXR3 is a novel, potentially first-in-class oncology product composed of functionalized hafnium oxide nanoparticles that is administered via one-time intratumoral injection and activated by radiotherapy. The product candidate's physical mechanism of action is designed to induce significant tumor cell death in the injected tumor when activated by radiotherapy, subsequently triggering adaptive immune response and long-term anti-cancer memory. Researchers believe that NBTXR3 could be scalable across any solid tumor that can be treated with radiotherapy and across any therapeutic combination, particularly immune checkpoint inhibitors.


In February 2020, the FDA granted regulatory Fast Track designation for the investigation of NBTXR3 activated by radiation therapy, with or without cetuximab, for the treatment of patients with locally advanced HNSCC who are not eligible for platinum-based chemotherapy-the same population being evaluated in the planned Phase III study.


Le Tourneau concluded: "Results from this expansion group are consistent with the initial results from the dose-escalation part of the trial that demonstrated NBTXR3 injection is feasible, well-tolerated, and safe in an elderly population with significant comorbidities. The high best objective response rate in target injected lesions, consistent with the dose-escalation part, suggested that NBTXR3 plus radiotherapy is effective in this study population.


"The prevalence of a negative prognostic factor of survival (high mCCI) in our population is higher than the prevalence described in real-word evidence data," he noted. "This suggests that treatment with NBTXR3 plus radiotherapy might result in a higher median OS in a population with lower burden of comorbidities."


To develop a treatment for the elderly population, the Phase III NANORAY-312 study has been implemented to compare NBTXR3/radiotherapy with or without cetuximab versus radiotherapy with or without cetuximab in LA-HNSCC patients unfit for cisplatin. Although the population enrolled in the Phase III study could be different with lower burden of comorbidities, the negative prognostic factor of survival, mCCI, has been determined as a stratification parameter to ensure well-balanced arms in NANORAY-312, Le Tourneau concluded.


Mark Fuerst is a contributing writer.