A potential first-in-class radioenhancer in combination with radiotherapy shows both local and distant tumor regression in more than three-quarters of evaluable cancer patients, regardless of prior immunotherapy exposure. The results of this small investigational study show the combination of the nanoparticle NBTXR3 plus radiotherapy could potentially stimulate an immune response and convert anti-programmed death-1 (PD-1) non-responders into responders.
Anti-PD-1 immunotherapies have shown promising clinical outcomes over the past 2 decades and are often used to treat advanced cancers once other therapies have reached the end of their effectiveness. However, across tumor indications, the significant majority of patients (80-85%) receive only a temporary benefit from anti-PD-1 therapy, as they either develop resistance to the therapy over time or are non-responsive to treatment altogether.
"Improving response rates to immune checkpoint inhibitors is currently a key challenge for the medical and scientific community," said co-author Tanguy Seiwert, MD, Director of the Head and Neck Oncology Disease Group at Johns Hopkins Medicine. "The data we have seen to date suggest that NBTXR3 could bring a completely different local and systemic approach to overcoming this barrier in immunotherapy."
NBTXR3 is a novel, potentially first-in-class oncology product composed of functionalized hafnium oxide nanoparticles administered via one-time intratumoral injection and activated by radiotherapy. The physics-based 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. NBTXR3 shows potential across a variety of solid tumors, including cancers of the head and neck, liver, lung, and soft tissue sarcoma, that can be treated with radiotherapy and across any therapeutic combination, particularly immune checkpoint inhibitors.
At the 2021 ASCO Annual Meeting, Colette Shen, MD, PhD, Assistant Professor of Radiation Oncology at the University of North Carolina Lineberger Comprehensive Cancer Center, presented updated results (Abstract 2590) of a Phase I study of NBTXR3 activated by radiotherapy for patients with advanced cancers treated with anti-PD-1 therapy (Study 1100).
This multicenter, open-label, non-randomized Phase I dose-escalation with dose-expansion study included 16 patients in three cohorts: inoperable locoregional recurrent or recurrent/metastatic head and neck cancer (7 patients), lung metastasis (6 patients), and liver metastasis (3 patients).
Research Efficacy
Of the 16 patients, 13 patients were evaluable for response. Tumor regression was observed in 76.9 percent (10/13) of evaluable patients, regardless of prior anti-PD-1 exposure, including 80 percent (4/5) of anti-PD-1 naive patients; 60 percent (3/5 patients) had investigator-assessed objective response, including one complete response (CR).
In patients with prior primary or secondary resistance to anti-PD-1, 75 percent (6/8 patients) had tumor regression and half (4/8 patients) had investigator-assessed objective response. These included one CR and two partial responses, along with one additional investigator-assessed pathological CR. Some patients in the study showed delayed tumor response and/or abscopal effect, suggesting NBTXR3 may potentially prime an immune response.
Patient Safety
NBTXR3 administration by intratumoral injection was feasible and well-tolerated. The overall adverse event profile did not differ from what is expected with radiotherapy or anti-PD-1 agents, Shen noted. A total of 16 serious adverse events were observed, including four that were identified as NBTXR3- or injection-related.
"These updated data support the potential for NBTXR3 plus radiotherapy in combination with anti-PD-1 to yield a sustained immune response in both anti-PD-1 naive patients and patients who have progressed on prior anti-PD-1 therapy," Shen stated. "NBTXR3 plus radiotherapy could stimulate immune response, convert anti-PD-1 non-responders into responders, and could be a promising next step for patients who develop immune checkpoint inhibitor resistance."
NBTXR3 is being evaluated in locally advanced head and neck squamous cell carcinoma (HNSCC) as the primary development pathway. A phase III global registrational study is planned to launch in 2021. 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.
The manufacturer of NBTXR3 is sponsoring a Phase I clinical study evaluating NBTXR3 activated by radiotherapy in combination with anti-PD-1 checkpoint inhibitors for patients with locoregional recurrent or recurrent/metastatic HNSCC and lung or liver metastases from any primary cancer eligible for anti-PD-1 therapy. Currently, two Phase II trials are actively recruiting head and neck cancer patients using the radioenhancer plus radiotherapy in combination with anti-PD-1 therapy at The University of Texas MD Anderson Cancer Center.
Co-author of the 1100 study, Jared Weiss, MD, Associate Professor of Medicine at the University of North Carolina Lineberger Comprehensive Cancer Center, noted that "NBTXR3 plus radiotherapy offers multiple hypothetical mechanisms of immune stimulation that potentially hold weight. What's interesting about the clinical data at ASCO is both distant control and regression in non-treated lesions. This is clinical proof of principle of a synergistic effect and warrants further investigation."
Weiss believes the combination of the radioenhancer plus radiotherapy will ultimately be approved and may become the standard of care for certain head and neck cancer patients.
"If large studies confirm the results seen thus far, this is a winner. It will become first-line therapy for PD-L1 resistant patients," he stated. "It looks like the mechanism of action is broadly applicable and I foresee tumor-agnostic use."
Mark L. Fuerst is a contributing writer.