Sylvie Bonvalot 1 ; Cécile Le Pechoux 1 ; Thierry De Baere 1 ; Guy Kantor 2 ; Xavier Buy 2 ; Paul Sargos 2 ; Eberhard Stoeckle 2 ; Philippe Terrier 1 ; Nathalie Lassau 1 ; Axel Le Cesne 1 ; Antoine Italiano 2 ; Mikaela Dimitriu 3 ; Laurent Levy 3 ; Jean-Charles Soria 1 ; Eric Deutsch 1 1 Institut Gustave Roussy, Villejuif, France; 2 Institut Bergonié, Bordeaux, France; 3 Nanobiotix, Paris, France THE IMPACT OF NBTXR3 NANOPARTICLES COMBINED WITH RADIOTHERAPY IN ADVANCED SOFT TISSUE SARCOMA (STS): A PHASE I/II STUDY THE IMPACT OF NBTXR3 NANOPARTICLES COMBINED WITH RADIOTHERAPY IN ADVANCED SOFT TISSUE SARCOMA: A PHASE I/II STUDY

Conflict of Interest I am the Principal Investigator of the clinical development supported by the Sponsor: NANOBIOTIX

NBTXR3 nanoparticles maximize Xray absorption in the tumor NBTXR3 acts as a radioenhancer with a physical mode of action NBTXR3 is a sterile aqueous suspension of functionalized hafnium oxide nanoparticles Nanoparticles should exhibit 2 key features 1)Absorb X-ray 2)Good biocompatibility Crystalline HfO 2 coating

NBTXR3: a physical mode of action amplifying RTx Ionizing radiation  Interaction with hafnium oxide  release of e-  free radical generation  cell damages Interaction with water generates limited number of electrons Radiotherapy aloneRadiotherapy with NanoXray Interaction with nanosized Hafnium generates much more electrons Much more electrons generated at the same dose of radiation to healthy tissues and, hence, higher anticancer efficacy NBTXR3 is a radioenhancer and thus different from a radiosensitizer

Antitumor efficacy in animal models Cell lines and patient tumor fragment NBTXR3 creates a significant difference in tumor response Antitumor activity of NBTXR3 activated by X-rays (200kV) in fibrosarcoma (HT1080 model) Antitumor activity of NBTXR3 activated by high energy (Cobalt-60) in Ewing Sarcoma family (A673 model)

Soft Tissue Sarcoma trial flowchart Main objectives: feasibilty and safety for escalade of volume of NBTXR3 at fixed concentration (53.3 g/L) CT Scan Safety evaluation NBTXR3 dispersion and persistence NBTXR3 injection feasibility

Treated population, Tumor Volume and Injected Volume NBTXR3 Volume Escalation (53.3 g/L) 4 dose levels tested in various types and sizes of STS NBTXR3 Volume Escalation (53.3 g/L) Tumor Histology type Tumor Volume (mL) Volume injected (mL) 2.50% Poorly differentiated sarcoma2125,3 Synovial sarcoma55,061,4 Liposarcoma1814,445 Liposarcoma95,882,4 Synovial sarcoma475,2712 Rhabdomyosarcoma158,44 5% Chondrosarcoma (Extraskeletal)100,985 Liposarcoma442,222 Liposarcoma Liposarcoma3682,56184 Liposarcoma692,1433 Liposarcoma85,534,2 10% (Evans sarcoma)36036 Liposarcoma52542,5 Chondrosarcoma ,5 Undifferentiated pleomorphic sarcoma145,0214,5 Leiomyosarcoma44344 Differentiated liposarcoma16016 Pleomorphic sarcoma25025 Clear cell sarcoma % Undifferentiated Sarcoma Myxofibrosarcoma49084,5

NBTXR3: related adverse events AE occurrence by number of patients NBTXR3 - related AE NCI-CTCAE version 4 >=Grade LEVEL 1 : N=6 (NBTXR3 2.5% baseline tumor volume) 0 Abdominal pain 1 Hypotension1 Injection site reaction1 Paraesthesia1 Pyrexia1 LEVEL 2 : N=6 (NBTXR3 5% baseline tumor volume) 0 Headache 1 Injection site pain2 Oedema peripheral 1 Pyrexia1 LEVEL 3 : N=6 (NBTXR3 10% baseline tumor volume) 0 Injection site pain 1 LEVEL 4 : N=2 (NBTXR3 20% baseline tumor volume) 2 Injection site pain 1* Postoperative wound complication 1* * In green bold: One patient (n°0018) had early DLTs at Level 4

Quantification of NBTXR3 by ICP-MS Marginal passage rate of NBTXR3 to the bloodstream during the injection procedure, and very short time of circulation. Quantification of NBTXR3 by ICP-MS (Hafnium) in urine sample confirms the absence of renal excretion NBTXR3 Phase I Body Kinetics of NBTXR3 NBTXR3: PK

Recommended Volume: 10% tumor volume Intratumor bioavailability of NBTXR3 at 10% volume (53,3g/L) Persistence of NBTXR3 during all session of RTx: optimal bioavailability over time

Efficacy evaluation Tumor volume change for resectability (% mean value) Average tumor shrinkage (TV) increasing with NBTXR3 volume. Volume 2,5% average of tumor volume shrunk 18% Volume 5% average of tumor volume shrunk 38% Volume 10% average of tumor volume shrunk 32% Volume 20% average of tumor volume shrunk 51% All patients treated in the study had an enlarged tumorectomy

Efficacy evaluation Volume Level NBTXR3 Patient Number Pathological Response % viable cells Average % viable cells 2.5% * 490* % * * % * % Recommended Volume * Myxoid liposarcoma

Feasibility of the NBTXR3 injection within the tumor mass across different tumor types and volumes (from 55.06ml to ml) is demonstrated 20% volume is considered not feasible owed to tissue expansion limitation No leakage to the surrounding healthy tissues is confirmed Persistence of NBTXR3 during all sessions of RTx with optimal bioavailability over time is demonstrated Very good systemic tolerance and local safety of the product at volume 2,5%, 5%, 10% and 20% was observed The recommended volume for further development is 10% of the tumor volume at baseline Further development of NBTXR3 is warranted in this indication. A phase II/III trial is planned to start in the Q NBTX3 Phase I CONCLUSION