PharmaShots Interview: Laurent Levy, CEO of Nanobiotix Shares Insights and Clinical Updates on its Nanoparticle Therapy

Shots:

Laurent spoke about the study design of its nanoparticle therapy to enhance the cancer-killing effect of radiation, which was presented at ASCO 2022
Laurent also highlighted how this nanoparticle therapy can be a potential radio enhancer in various tumor types and across lines of therapy
The interview summarizes Nanobiotix’s vision to advance nanoparticles across all solid tumor indications where radiotherapy is part of the treatment

Smriti: Explain the details (MoA, RoA, formulation) of NBTXR3.

Laurent: NBTXR3, a potential first-in-class radio enhancer, is an aqueous suspension of functionalized crystalline hafnium oxide nanoparticles that are delivered via one-time, intratumoral injection and activated by radiotherapy. The NBTXR3 mechanism of action is universal and physics-based. While the nanoparticles are biologically inert outside of the presence of radiation, when exposed to radiation therapy the nanoparticles absorb more radiation within the tumor than the tumor cells do alone, and then deliver up to 9 times the dose within the tumor cells where it is present. This reaction triggers significant cell death within the tumor through the destruction of DNA by free electrons, without increasing the damage to surrounding healthy tissues beyond what you would expect from radiotherapy alone. Subsequent to the tumor cell destruction triggered by NBTXR3's physics-based MoA, the product has also shown a potential to "prime" the immune system by activating several adaptive and innate immune pathways within the body. Given that certain types of immunotherapy agents such as immune checkpoint inhibitors require active immune pathways to deliver efficacy, our hypothesis is that the priming effect of NBTXR3 could make the radio enhancer a fundamental combination therapy with these and other immunotherapy agents.

The local effect of NBTXR3 has been confirmed in a randomized European phase III trial evaluating the radio enhancer for patients with soft tissue sarcoma, and the subsequent immune priming effect is currently being evaluated in a US phase I study.

Smriti: Please outline the study design of the NANORAY-312 P-III trial evaluating NBTXR3 as a monotherapy.

Laurent: NANORAY-312, a global, open-label, two-arm, randomized, Investigator’s Choice phase III registration study that is designed to investigate the efficacy and safety of radiotherapy-activated NBTXR3 with or without cetuximab versus radiotherapy with or without cetuximab in high-risk, chemotherapy-ineligible elderly patients with locally advanced head and neck squamous cell carcinoma (LA-HNSCC). The study is co-led by principal investigators Sue Yom, MD, Ph.D., Professor and Vice Chair, Strategic Advisory Department of Radiation Oncology; Professor, Otolaryngology-Head and Neck Surgery at The University of California, San Francisco, and Christophe Le Tourneau, MD, Ph.D., senior medical oncologist and head of the Department of Drug Development and Innovation (D3i) at Institut Curie (Paris).

Eligible participants for NANORAY-312 will be treated with NBTXR3 at a 1:1 ratio after an Investigator’s Choice of radiotherapy alone or radiotherapy in combination with cetuximab. NANORAY-312 aims to enroll 500 patients across sites in the United States, Europe, and Asia. The primary endpoint of the pivotal study is Progression-free Survival (PFS) and key secondary endpoints include Overall Survival (OS), response rates, and quality of life.

Smriti: Nanobiotix presented a study design poster at ASCO, can you highlight the recruitment status so far and when can we expect full results?

Laurent: The first patient in NANORAY-312 was randomized in January 2022. The study is actively enrolling and sites are currently being activated globally. A futility analysis is expected 18 months after the first patient is randomized and an interim analysis is expected at 30 months.

Smriti: Would it be possible for you to share any insights on the results of NANORAY-312 (P-III) so far? Just highlights or anything which you can share.

Laurent: Not at this time given that study is in the early stages of recruitment. However, NANORAY-312 builds on Nanobiotix Study 102, a phase I dose escalation and dose expansion trial evaluating the safety and early signs of efficacy for radiotherapy-activated NBTXR3 in high-risk elderly LA-HNSCC patients who are chemotherapy-ineligible and intolerant to cetuximab. Preliminary data, presented at the 2021 Annual Meeting of the American Society for Radiation Oncology (ASTRO 21), continued to support NBTXR3 administration as feasible and well-tolerated. At a median follow-up of 9.5 months, evaluable patients (n=41) demonstrated a best-observed target lesion objective response rate (ORR) of 85.4% and a best-observed target lesion complete response rate (CRR) of 63.4%.

A recent review of the data, as of February 2022, showed an ongoing median overall survival (mOS) of 17.9 months in all treated populations (n=56) and 23.0 months in evaluable patients (n=44), demonstrating continued improvement relative to the analysis presented at ASTRO 21 and consistency with previously reported data from Study 102.

Smriti: Is Nanobiotix planning to assess NBTXR3 beyond the neoadjuvant setting in head and neck cancer?

Laurent: We are not assessing neoadjuvant use in head and neck cancers at this time — only definitive RT, chemo-RT, or IO therapy.

With our hypothesis about the broad applicability of NBTXR3 across tumor indications, therapeutic combinations, and lines of therapy, we see ample potential opportunity for industry collaboration. As previously noted, we are currently in a preclinical and clinical development collaboration with MD Anderson, and we also have a development collaboration in Asia with LianBio. The potential immune priming effect of NBTXR3 that is being evaluated in the clinical studies listed above, could also lend to collaborations with several different types of immune checkpoint inhibitors. There is the possibility to explore the utilization of NBTXR3 with RT for patients with head and neck cancer in the neoadjuvant setting, in dose de-escalation trials, in volume de-escalation trials, and to explore treating particular tumors that may be radioresistant.

Smriti: Does Nanobiotix have a plan to expand its pipeline in other indications?

Laurent: Given the universal mechanism of action of NBTXR3, combined with its intratumoral delivery and activation by radiotherapy, we are developing NBTXR3 as an agent that can integrate across all solid tumor indications where radiotherapy is part of the treatment regimen and intratumoral injection is feasible. Currently, Nanobiotix is prioritizing the development of NBTXR3 for elderly and frail patients with locally advanced head and neck cancer who are ineligible for platinum-based chemotherapy through our ongoing pivotal phase III study, NANORAY-312, and in combination with anti-PD-1 checkpoint inhibitors (pembrolizumab and nivolumab) for patients with locoregional recurrent head and neck cancer, liver metastases, and/or lung metastases in a phase I study. Our collaborators at MD Anderson are evaluating the radio enhancer in parallel with several active clinical studies including:

NBTXR3 as a single agent activated by radiotherapy for patients with locoregional recurrent non-small cell lung cancer that are amenable to re-irradiation.
NBTXR3 as a single agent activated by radiotherapy for patients with locally advanced or borderline resectable pancreatic cancer.
NBTXR3 in combination with concurrent chemoradiation for patients with esophageal cancer.
NBTXR3 in combination with anti-PD-1 immune checkpoint inhibitors (pembrolizumab) for patients with inoperable locoregional recurrent head and neck cancer that are amenable to re-irradiation.
NBTXR3 in combination with anti-PD-1 immune checkpoint inhibitors for patients with recurrent/metastatic head and neck cancer.

Nanobiotix has already achieved clinical proof of concept for NBTXR3 in a randomized phase III study evaluating the radio enhancer as a single agent activated by radiotherapy patients with soft tissue sarcoma that led to the product's first European market approval (CE mark), under the brand name Hensify®.

Source: Canva

About the Author:

Laurent Levy is the co-founder, CEO, and chairman of the executive board of Nanobiotix. Levy has authored more than 35 international scientific publications and regularly speaks on the topic of using nanoparticles to fight cancer and other diseases. Since 2017, he has served as President of the Supervisory Board of Valbiotis S.A. He holds a doctorate in Physical Chemistry, specializing in nanomaterials, from the University of Pierre and Marie Curie in Paris and the French Alternative Energies and Atomic Energy Commission.Levy completed his studies with a post-doctoral fellowship at the Institute for Lasers, Photonics, and Biophotonics at State University of New York at Buffalo