On June 21, 2018 NANOBIOTIX (Euronext: NANO – ISIN: FR0011341205), a late clinical-stage nanomedicine company pioneering new approaches in the treatment of cancer, reported positive topline results of the Phase II/III act.in.sarc trial evaluating NBTXR3 in Soft Tissue Sarcoma (STS) (Press release, Nanobiotix, JUN 21, 2018, View Source [SID1234527418]).
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"Data are exceptional and show without any doubt an improvement of radiation therapy impact with a significant
number of complete response. NBTXR3 can bring real benefit to patients and it can change the standard of care.
This innovation will play a role in many other indications and particularly where radiotherapy is used alone."
Pr. Sylvie Bonvalot, MD, Head of Sarcoma and Complex Tumor Surgery Unit at Institut Curie, Paris, France and
Global Principal Investigator of the PII/III study NBTXR3 is a first-in-class product with a new mode of action physically destroying cancer cells when activated by radiation therapy. NBTXR3 is designed to directly destroy tumors and activate the immune system for both local control and systemic disease treatment.
The Phase II/III study was a prospective, randomized (1:1), multinational, open label and active controlled twoarmed
study of 180 patients with locally advanced STS. The objective of the Phase II/III trial was to evaluate the
efficacy and the safety of NBTXR3 activated by radiotherapy compared to the standard of care (radiotherapy
alone). Patients have been treated with the standard dose of radiation (25×2 Gy) and efficacy endpoints have
been measured on surgically resected tumors.
Primary endpoint achieved in the intend-to-treat population (ITT)
The primary endpoint isthe pathological Complete Response Rate (pCRR) defined asthe rate of patients showing
less than 5% of residual viable cancer cells in the tumor post treatment. This primary endpoint is related to
NBTXR3’s mode of action and product efficacy. Twice as many patients (16.1% vs 7.9%) achieved a pathological
Complete Response (pCR) with NBTXR3 compared to the control arm (p = 0.0448). The significant difference
observed between both arms validates the superiority of the treatment with NBTXR3 versus radiation alone.
Secondary Endpoint achieved in the ITT – Resection margins status and operability
The main secondary endpoint is the resection margin status evaluating the quality of surgery. The main objective
is to achieve compartmental clean margins (negative margin defined as R0) i.e. no more cancer cells found within
the surgical margins. NBTXR3 demonstrated a statistically significant increase in R0 surgical margin rate
compared to radiotherapy alone (relative increase of 20%, p = 0.042). The resection with negative margins is a
validated surrogate endpoint for systemic and long-term benefit for patients such as local progression free
survival (PFS) and distant PFS.
Pr Jean-Yves Blay, MD, Director of the Centre Léon Bérard, Lyon, France, commented, "I am amazed by the
difference of Response Rate, it is extremely uncommon to double the Rate of Complete histological Response and
I do not see any other strategy able to accomplish that. Even more impressive is the R0 rate, which is increased
by more than 20% compared to an average rate of 64%. This difference is really impressive, considering that R0
impacts patients relapses and survival."
Safety and feasibility
NBTXR3 demonstrated a good local tolerance among this patient’s population. Findings showed a very similar
radiation-related safety in both arms. The patients in both the control and tested arms of the study received the
planned radiotherapy (dose and schedule).
Notably, feasibility and follow-up of surgery were also equivalent. Acute immune adverse events of short
duration observed in 7.9% of patients.
The Injection site caused pain in 13.5% of patients. In addition, 6.7% of patients experienced grade 1 injection
site hematoma / ecchymosis.
Regarding long-term toxicity, less serious adverse events were reported for NBTXR3 arm.
Regulatory strategy and CE mark
The positive results from this study support and further validate the European regulatory strategy of the
previously submitted CE marking application in STS. The company will submit the new data as a supplement to
the European Notified Body in a timely manner.
Next steps
The Company will present the results at an upcoming international medical conference.
The clinical validation of NBTXR3’s physical mode of action in a very heterogeneous and hard-to-treat disease
strengthens the universal profile of the product and confirms the development strategy in multiple indications.
Currently, the company is evaluating NBTXR3 in seven clinical trials with a focus on head and neck cancers and
Immuno-Oncology programs.
David Raben MD, Professor of Radiation Oncology, University of Colorado Cancer Center, CO, USA, commented,
"These results from a Phase III study are impressive in a notoriously difficult disease like Soft Tissue Sarcoma.
These cancers are generally less sensitive to radiation and previous attempts to improve local control with chemoradiation regimens were considered too toxic. This study substantiates the medical benefit of safely enhancing
the effect of radiation therapy with novel physics-based approaches delivered locally within the cancer. In
addition, this product may potentiate a pro-inflammatory environment suitable for immune enabling or DNA
damage inhibitor drugs. These findings set the foundation for additional studies in areas such as head and neck
cancer and perhaps in areas such as high-risk prostate, bladder or pancreas cancer."
Webcast and dial-in (English) June 22 at 4pm Paris time: View Source
For more information about the STS study: www.clinicaltrial.gov (Identifier: NCT02379845)
View Source
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About PII/III clinical trial (act.in.sarc study)
Nanobiotix and its partner, PharmaEngine recruited 180 patientsin 43 sites across 13 countriesin Europe and Asia. The Global
Principal Investigator is Pr. Sylvie Bonvalot, MD, PhD (Institut Curie, Paris, France).
Primary endpoint
Pathological complete response rate (pCRR): A pathological Complete Response is defined as the presence of less than 5%
of residual malignant viable cells in the surgically removed tissue. The primary endpoint compared the proportion of patients
presenting pathological Complete Response (pCR) between the two arms. This was determined by an independent
pathological central review according to EORTC score (Wardelmann et al., 2016).
Main secondary endpoint
Resection margin status: The resection margin status is evaluating the quality of surgery. Surgery remains the mainstay of
care for locally advanced soft tissue sarcoma. The primary surgical objective is the complete removal of the tumor with
negative resection margins (R0). Several retrospective studies suggest that surgical margin status predict the risk of local and
distant recurrence. In particular, negative surgical margins are significantly correlated to increased patients’ survival.
About NBTXR3
NBTXR3 is a first-in-class product designed to destroy, when activated by radiotherapy:
• tumors through physical cell death
• metastasis due to immunogenic cell death leading to activation of the immune system.
NBTXR3 has a high degree of biocompatibility, requires one single administration before the whole radiotherapy treatment and has the ability to fit into current worldwide standards of radiation care.
NBTXR3 is actively being evaluated in head and neck cancer with locally advanced squamous cell carcinoma of the oral cavity or oropharynx in elderly and frail patients unable to receive chemotherapy or cetuximab with very limited therapeutic options. The Phase I/II trial has already delivered very promising results regarding the local control of the tumors.
Nanobiotix is running an Immuno-Oncology development program . In the U.S., the Company received the FDA’s approval to launch a clinical study of NBTXR3 activated by radiotherapy in combination with anti-PD1 antibodies in lung, and head and neck cancer patients (head and neck squamous cell carcinoma and non-small cell lung cancer).
The other ongoing studies are treating patients with liver cancers (hepatocellular carcinoma and liver metastasis), locally advanced or unresectable rectal cancer in combination with chemotherapy, head and neck cancer in combination with concurrent chemotherapy, and prostate adenocarcinoma.
The first market authorization process (CE Marking) is ongoing in Europe in the soft tissue sarcoma indication