soft tissue sarcoma results june 2018€¦ · dendritic cell • sting pathway activation...

Soft Tissue

Sarcoma

Results

June 2018

2 Soft Tissue Sarcoma Results

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• The trial achieved its primary endpoint of pathological Complete Response Rate

(pCRR)

• The trial achieved its secondary endpoint in operability (R0 rate)

• NBTXR3 demonstrates significant superiority and clinical benefits for patients

versus standard of care

• Safety profile confirmed

• This randomized trial validates the first in class mode of action of NBTXR3

NANOBIOTIX ANNOUNCES POSITIVE PHASE II/III TOPLINE DATA

IN SOFT TISSUE SARCOMA WITH NBTXR3


One of the largest oncology markets

with large unmet medical need

Cancer patients

60%

RTx

More than 60% of all cancer patients receive

Radiation Therapy

Unmet medical need

improve local control of tumor

reduce relapse rate

improve metastatic patient outcome

Source: * World Health Organization (2014); **RADIATION THERAPY EQUIPMENT – A global strategic business report 08/06

More than 9 million / year


Nanobiotix targets radiation therapy - one of the

largest oncology markets with minimal competition

Conventional radiation therapy

Around 60%* of cancer patients

receive radiotherapy as a local

treatment

Destroys any cancer cell at the right

dose

Important limitations due to toxicity on

healthy tissues

100 photons @ 6 MeV

20 cm20 cm

50 cm

Xray track Energy deposition

How to improve the energy dose within the tumor without

damaging healthy tissues?

TUMOR

Source: * RADIATION THERAPY EQUIPMENT – A global strategic business report 08/2006

100 photons at 6 MEV


Solution:

NBTXR3 maximizes Xray absorption in the tumor

IP: concept and products

protected by 10 patent families until at least 2029

Technology key features:

50nm

HfO2 nanoparticles; electron microscopy picture

Designed to

strongly

absorb Xrays

Designed to

be non-toxic

50 nanometer HfO2* particles were chosen

because they have the best ratio for X-ray

absorption and non-toxicity

Nanosized to

enter cell

* HfO2: Hafnium Oxide

Source: Maggiorella et al. (2012)

3

2

1


NBTXR3 has a physical mode of action:

Increase dose absorption & deposition in the tumor

*Note: Dose enhancement determined by montecarlo simulation (CEA Saclay, France)

9X Dose* around nanoparticles

Radiotherapy Radiotherapy with NBTXR3


NBTXR3 universal MOA triggering

cellular destruction and adaptative immune response

Clustered

Nanoparticles in cytoplasm

large energy deposition

in a nano-volume

physical damage

NBTXR3 +RTx

Direct Cell Death (Apoptosis, Necrosis, …)

• Structural Damage

• DNA damage

• Stress

• Immunogenic Cell Death

• Sting pathway activation Dendritic cell

activation

CD4 & CD8

activation

Tumor Infiltration

and Cell Killing


NBTXR3 First in Class Radioenhancer

Physical Mode of Action that could work

across all solid tumors

Only one administration

Fits into existing standard of care

No change in equipment

No change in current patient flow

No change in protocol

One product fitting in current practice helping

millions of patients every year


NBTXR3 already used in clinical trials across

EU, US and Asia

Advanced development

/ pre-commercialization

STS, H&N, Prostate, Rectum,

NSCLC, HCC, Liver Mets

• 7 clinical trials – 10 patient

populations

• More than 200 patients recruited in

clinical trials

• 400 MDs involved in clinical trials

• More than 70 clinical centers (US,

EU, Asia)

CE mark filed for first Proof-of-

Concept application (STS)

74 clinical centers using NBTXR3


PII/III in Soft Tissue Sarcomas (STS)

Topline Data


Sarcomas: a complex family of rare cancers Cancers of the connective tissues are categorized in two major groups: soft

tissue sarcoma (STS) and bone sarcoma

60% start in the arms and legs, 30% in the abdomen or torso and 10% in the

head or neck.

STS develops from the muscles, fibrous tissues, fat, blood vessels, nerves, etc.

50 different subtypes of STS

Incidence of sarcomas in 2016:

Ref: Datamonitor ref. DMKC0185529

Soft Tissue Sarcoma: epidemiology

EUROPE (ALL) 55,000 cases

NORTH

AMERICA 25,000 cases All Study population

North America 25,000 9,000

Europe 55,000 20,000


Soft tissue sarcoma of the extremities* and trunk wall

Locally advanced soft tissue sarcoma, newly diagnosed or

relapsed tumor:

High risk tumor

Borderline unresectable tumor or unfeasible carcinological

surgical resection

Neoadjuvant radiotherapy is used as a Standard of Care in

this population

Main advantages (long term):

• Lower late morbidity (fibrosis, bone fracture, etc.)

• Improved long-term functional outcome

• Improved quality of life

Unmet medical need for locally advanced soft tissue sarcoma

* Arms and legs

Soft tissue sarcoma: patient population


Soft Tissue Sarcoma: treatment objectives

Surgery

Ideal patient outcome in preoperative setting

• Removal of tumor

• No remaining tumor cells in the body after surgery

Surgically remove (resect) tumor to improve

patients’ survival and quality of life


Design of Phase II/III study in soft tissue sarcoma

Population: Patients with locally advanced soft tissue sarcoma of the extremity and trunk wall

Multi center, open-label, randomized trial with active control

Test arm

NBTXR3 with RTx 50Gy

Stratification population:

myxoid Lps vs others 1:1

RTx 50Gy

Comparator arm

Ran

do

miz

ati

on

Study design STS phase II/III

180 patients recruited

162 patients evaluable

43 sites

13 countries EU and

Asia

> 10 STS subtypes


Phase II/III Study in Soft Tissue Sarcoma

Flowchart and study design

Day 1

One time

Intratumoral injection

Surgery

End of treatment

Session of RTx according to standard of care

(25 x 2 Gy)

RTx +

NBTXR3 (87 patients)

RTx (89 patients)

Surgery

Population:

• Patients with locally advanced soft tissue sarcoma of the extremity and trunk wall

• Locally advanced soft tissue sarcoma, newly diagnosed or relapsed tumor

• High risk tumor

• Unresectable tumor or unfeasible carcinological surgical resection


Primary endpoint:

Pathological complete response rate (pCRR) as

per EORTC Guidelines

Secondary endpoints:

Safety

Operability (surgery margin, R0, …)

Pathological Response (pR)

Amputation rate

Other exploratory endpoints will be available later

Phase II/III study in STS: Endpoints

Topline data


Two important clinical end points in STS

Pathological response & Surgery Margin

Pathological response: % of dead tumor cells

Pathological complete response:

95% dead tumor cells (≤ 5% viable tumor cells)

Primary Endpoint

Pathological response

≤ 5% viable cells > 5% viable cells


R0 Negative margin

Two important clinical end points in STS

Pathological response & Surgery Margin


Pathological complete response:

95% dead tumor cells (≤ 5% viable tumor

cells)

Primary Endpoint

Pathological response

Secondary Endpoint

Surgery (Resection) margin

≤ 5% viable cells > 5% viable cells


Pathological response:

a direct measure of efficacy…


Pathological complete response: 95% dead tumor cells (≤ 5% viable tumor cells)

pR: pathological Response Measures the efficacy of cell killing

pCRR: pathological Complete Response Rate Measures the optimum efficacy of cell killing

Is a potential surrogate for systemic efficacy


Pathological response as a surrogate for survival

Schaefer et al., 2017

pCRR (defined as < 5% viable cancer cells) shows a global trend in relation with OS

Unlike in Breast Cancer, pCRR is not significantly correlated with survival in STS given the

current state of data


Surgery / Resection margin:

a key endpoint for clinical benefit

R0

R1

R2

Amputation

Negative margin

Positive margins


R0 / Resection margin

increases PFS & OS for patients

Positive margin Negative margin Resection limits

R0 R1 R2

Amputation

Negative margin

Positive margin

Negative margins: R0 surgery significantly correlated to patient benefits

like Progression Free Survival (local and

distant) and Overall Survival

Local recurrence-free survival

(Local relapse)


R0 Resection margins in Study site in line with

French STS Center of Excellence

Limbs sarcomas operated (n > 240, France)

Qu

alit

y o

f in

itia

l su

rge

ry (

% o

f p

atie

nts

)

Adapted from Blay et al., 2018 (add full reference

R0 Resection Margin in:

Specialized centers 56%

Non specialized centers 13%

0

10

20

30

40

50

60

70

R0 R1 R2

Resection Margin in 301 Study

RT (Control Arm) N=89

0

10

20

30

40

50

60

70

R0 R1 R2

Resection Margin by center

Outside NETSARCNon-specialized Center

Within NETSARCSpecialized Center

STS Study Control Arm

Qu

alit

y o

f in

itia

l su

rge

ry (

% o

f p

atie

nts

)


NBTXR3 impact on the standard of care

(planned radiation and surgery)

cvc

*Relative radiation therapy Dose Intensity =

(Actual Dose Intensity / Planned Dose Intensity) ITT FAS (Full Analysis Set)

No impact on planned radiation and surgery

No change in Median Relative Radiation therapy dose intensity

No change in Median Duration of radiotherapy schedule (days)

No change in % of surgery performed

The study confirmed:

• Feasibility of injection

• No change in dosage and schedule of current radiotherapy standard of

care

• Good local tolerance (similar radiation safety in both arms)

• Manageable acute immunological reaction occurring at the time of

injection


16.1

7.9

0

2

4

6

8

10

12

14

16

18

Complete Pathological Response

Pathological Complete Response

NBTXR3 activated by radiotherapy (N=87)

Radiotherapy alone (N=89)

pCRR: the study met its primary end point

p-value 0.0448*

• Statistically significant at an adjusted α of 0,04575

• ITT FAS (Full Analysis Set)

% o

f p

atie

nts

with

pC

R

More than twice as many patients having a Pathological Complete Response

(≤ 5% viable cells)

16.1

7.9


Tumor necrosis > 90% following preoperative treatment (i.e. < 10% viable cancer

cells) was associated with decreased recurrence risk and superior OS.

Salah et al. (2018) – Meta-analysis on 1663 STS patients

Pathological Response > 90%

correlates with superior OS


R0 rate: the study also met its secondary endpoint

77

64

0

10

20

30

40

50

60

70

80

90

R0

Resection Margin

NBTXR3 activated by radiotherapy (N=87)

Radiotherapy alone (N=89)

p-value 0.0424*

• Statistically significant at an α of 5%

• ITT FAS (Full Analysis Set)

% o

f p

atie

nts

with

R0

re

se

ctio

n m

arg

ins

Significant 20% relative increase in R0 rate in the NBTXR3 arm


PI quotes

Pr. Sylvie Bonvalot, MD, Head of the Sarcoma and Complex Tumor Surgery Unit at Institut Curie,

Paris, France and Principal Investigator of the PII/III study commented “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 radiation is used alone.”

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.”

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 chemo-radiation 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.”


NBTXR3 Phase II/III 301 study in Soft Tissue Sarcoma

Conclusion

• The trial achieved its primary endpoint pathological Complete

Response Rate (pCRR)

• The trial achieved its secondary endpoint in operability (R0 rate)

• NBTXR3 demonstrates significant superiority and clinical benefits

for patients versus standard of care

• Safety profile confirmed

• This randomized trial validated the first in class Mode of Action of

NBTXR3

soft tissue sarcoma results june 2018€¦ · dendritic cell • sting pathway activation...

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