Soft Tissue Sarcoma Results. June 2018

Soft Tissue Sarcoma Results June 2018

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NANOBIOTIX ANNOUNCES POSITIVE PHASE II/III TOPLINE DATA IN SOFT TISSUE SARCOMA WITH NBTXR3 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 3

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 More than 9 million / year Source: * World Health Organization (2014); **RADIATION THERAPY EQUIPMENT A global strategic business report 08/06 4

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 TUMOR Destroys any cancer cell at the right dose 50 cm Important limitations due to toxicity on healthy tissues 20 cm 100 photons at 6 MEV 100 photons @ 6 MeV Energy deposition 20 cm Xray track How to improve the energy dose within the tumor without damaging healthy tissues? Source: * RADIATION THERAPY EQUIPMENT A global strategic business report 08/2006 5

Solution: NBTXR3 maximizes Xray absorption in the tumor Technology key features: 1 Nanosized to enter cell 50nm 2 Designed to strongly absorb Xrays 3 Designed to be non-toxic HfO2 nanoparticles; electron microscopy picture 50 nanometer HfO 2 * particles were chosen because they have the best ratio for X-ray absorption and non-toxicity IP: concept and products protected by 10 patent families until at least 2029 * HfO2: Hafnium Oxide Source: Maggiorella et al. (2012) 6

NBTXR3 has a physical mode of action: Increase dose absorption & deposition in the tumor Radiotherapy Radiotherapy with NBTXR3 9X Dose* around nanoparticles *Note: Dose enhancement determined by montecarlo simulation (CEA Saclay, France) 7

NBTXR3 universal MOA triggering cellular destruction and adaptative immune response NBTXR3 +RTx large energy deposition in a nano-volume physical damage Clustered Nanoparticles in cytoplasm Dendritic cell activation Structural Damage DNA damage Stress Immunogenic Cell Death Sting pathway activation CD4 & CD8 activation Tumor Infiltration and Cell Killing Direct Cell Death (Apoptosis, Necrosis, ) 8

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 9

NBTXR3 already used in clinical trials across EU, US and Asia 74 clinical centers using NBTXR3 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) 10

PII/III in Soft Tissue Sarcomas (STS) Topline Data 11

Soft Tissue Sarcoma: epidemiology 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: All Study population North America 25,000 9,000 Europe 55,000 20,000 NORTH AMERICA 25,000 cases EUROPE (ALL) 55,000 cases Ref: Datamonitor ref. DMKC0185529 12

Soft tissue sarcoma: patient population 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 13

Soft Tissue Sarcoma: treatment objectives 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 Surgery 14

Randomization Design of Phase II/III study in soft tissue sarcoma Study design STS phase II/III Population: Patients with locally advanced soft tissue sarcoma of the extremity and trunk wall 180 patients recruited 162 patients evaluable Multi center, open-label, randomized trial with active control Test arm NBTXR3 with RTx 50Gy 43 sites 13 countries EU and Asia > 10 STS subtypes 1:1 RTx 50Gy Comparator arm Stratification population: myxoid Lps vs others 15

Phase II/III Study in Soft Tissue Sarcoma Flowchart and study design RTx + NBTXR3 (87 patients) RTx (89 patients) Day 1 One time Intratumoral injection End of treatment Surgery Session of RTx according to standard of care (25 x 2 Gy) 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 16

Phase II/III study in STS: Endpoints Primary endpoint: Pathological complete response rate (pcrr) as per EORTC Guidelines Secondary endpoints: Safety Operability (surgery margin, R0, ) Pathological Response (pr) Amputation rate Topline data Other exploratory endpoints will be available later 17

Two important clinical end points in STS Pathological response & Surgery Margin Primary Endpoint Pathological response 5% viable cells > 5% viable cells Pathological response: % of dead tumor cells Pathological complete response: 95% dead tumor cells ( 5% viable tumor cells) 18

Two important clinical end points in STS Pathological response & Surgery Margin Primary Endpoint Pathological response 5% viable cells > 5% viable cells Pathological response: % of dead tumor cells Pathological complete response: 95% dead tumor cells ( 5% viable tumor cells) Secondary Endpoint Surgery (Resection) margin R0 Negative margin 19

Pathological response: a direct measure of efficacy Pathological response: % of dead tumor cells 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 20

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 21

Surgery / Resection margin: a key endpoint for clinical benefit R0 Negative margin R1 Positive margins R2 Amputation 22

R0 / Resection margin increases PFS & OS for patients R0 R1 R2 Resection limits Negative margin Positive margin Amputation Local recurrence-free survival (Local relapse) Negative margin Positive margin Negative margins: R0 surgery significantly correlated to patient benefits like Progression Free Survival (local and distant) and Overall Survival 23

Quality of initial surgery (% of patients) Quality of initial surgery (% of patients) R0 Resection margins in Study site in line with French STS Center of Excellence R0 Resection Margin in: Specialized centers 56% Non specialized centers 13% STS Study Control Arm 70 Resection Margin by center 70 Resection Margin in 301 Study 60 60 50 40 30 20 10 0 R0 R1 R2 Outside NETSARC Non-specialized Center Adapted from Blay et al., 2018 (add full reference Limbs sarcomas operated (n > 240, France) Within NETSARC Specialized Center 50 40 30 20 10 0 R0 R1 R2 RT (Control Arm) N=89 24

NBTXR3 impact on the standard of care (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 No impact on planned radiation and surgery *Relative radiation therapy Dose Intensity = (Actual Dose Intensity / Planned Dose Intensity) ITT FAS (Full Analysis Set) 25

% of patients with pcr pcrr: the study met its primary end point 18 16 14 12 10 8 6 4 2 0 Pathological Complete Response 16.1 p-value 0.0448* 7.9 Complete Pathological Response NBTXR3 activated by radiotherapy (N=87) Radiotherapy alone (N=89) More than twice as many patients having a Pathological Complete Response ( 5% viable cells) Statistically significant at an adjusted α of 0,04575 ITT FAS (Full Analysis Set) 26

Pathological Response > 90% correlates with superior OS Salah et al. (2018) Meta-analysis on 1663 STS patients Tumor necrosis > 90% following preoperative treatment (i.e. < 10% viable cancer cells) was associated with decreased recurrence risk and superior OS. 27

% of patients with R0 resection margins R0 rate: the study also met its secondary endpoint Resection Margin p-value 0.0424* 90 80 70 60 50 40 30 20 10 0 77 R0 64 NBTXR3 activated by radiotherapy (N=87) Radiotherapy alone (N=89) Significant 20% relative increase in R0 rate in the NBTXR3 arm Statistically significant at an α of 5% ITT FAS (Full Analysis Set) 28

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. 29

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 30