Summary

Purpose/Objective(s): NBTXR3, a novel radioenhancer activated by radiotherapy (RT) demonstrated superior efficacy, as preoperative treatment in patients with locally advanced soft tissue sarcoma (LA STS) compared to RT alone. Primary endpoint of pCR rate (16% vs 8%; P = 0.044) and main secondary endpoint of R0 margin rate (16% vs 8%; P = 0.042) were met while no modification of the early RT-associated safety profile was observed, leading to market authorization. Here we report on the long-term safety, limb function and quality of life.

Materials/Methods: This phase II/III randomized (1:1), international trial included adult patients with LA STS of the extremity or trunk wall, requiring preoperative RT. Patients received either a single intratumoral injection of NBTXR3 (equivalent to 10% of tumor volume, at 53.3g/L), plus EBRT (arm A) or EBRT alone (arm B) (50 Gy in 25 fractions), followed by surgery. Here we report on safety of NBTXR3+RT which was evaluated as secondary endpoint. Data were recorded on the “all treated population” during at least a two-year follow-up. Important parameters related to HR-QoL including functional outcome were studied using the EQ-5D, RNLI, TESS and MSTS questionnaires.

Results: Patients had at least two-year follow-up and the lost to follow-up rate was very low (1.9%). RT-related SAEs were observed in 11.2% (10/89) vs 13.3% (12/90) in A vs B. Post-treatment AEs, any grade, were observed in 51.7% (46/89) vs 57.8% (52/90) and serious post-treatment AEs in 13.5% (12/89) vs 24.4% (22/90) of patients in A vs B. Long-term safety continues to demonstrate that NBTXR3 plus RT has no impact on post-surgical wound complications (24.7% vs 36.7%, A vs B). Furthermore, the evaluation of radiation late toxicities in limbs such as fibrosis, arthrosis and edema that may alter limb function showed no difference between arms (4.5% vs 7.7%, 2.2% vs 0.0% and 6.7% vs 2.2% respectively in A vs B). In addition, sequelae or chronic tissue disturbances at the former tumor localization were similar in both treatment arms, confirming that the increase of energy dose deposit and the physical presence of NBTXR3 did not impact post-treatment limb functions. Accordingly, HR-QoL evaluation yielded no difference in functional outcome. Finally, second primary cancer was observed in 1 patient in arm A and 6 patients in arm B and the intratumoral injection of NBTXR3 did not induce cancer cell seeding at the former tumor site.

Conclusion: These results demonstrate that the use of NBTXR3 did not change the late onset toxicity profile of EBRT, nor modified its bystander effect. Taken together, the long-term safety data presented here, and the previously published efficacy data reinforce the favorable benefit-risk ratio of the use of NBTXR3 in patients with LA STS. NCT02379845

Summary

Purpose or Objective: NBTXR3, a novel radioenhancer activated by radiotherapy (RT) demonstrated superior efficacy, as preoperative treatment in patients with locally advanced soft tissue sarcoma (LA STS) compared to RT alone. Primary endpoint of pCR rate (16% vs 8%; p=0.044) and main secondary endpoint of R0 margin rate (16% vs 8%; p=0.042) were met (Bonvalot et al. Lancet Oncol. 2019) while no modification of the early RT-associated safety profile was observed, leading to market authorization. Here we report on the long-term safety, limb function and quality of life.

Materials and Methods: This phase II/III randomized (1:1), international trial included adult patients with LA STS of the extremity or trunk wall, requiring preoperative RT (NCT02379845). Patients received either a single intratumoral injection of NBTXR3 (equivalent to 10% of tumor volume, at 53.3g/L), plus EBRT (arm A) or EBRT alone (arm B) (50 Gy in 25 fractions), followed by surgery. Here we report on safety of NBTXR3+RT which was evaluated as secondary endpoint. Data were recorded on the “all treated population” during at least a two-year follow-up. Important parameters related to HR-QoL including functional outcome were studied using the EQ-5D, RNLI, TESS and MSTS questionnaires.

Results: Patients had at least two-year follow-up and the lost to follow-up rate was very low (1.9%). RT-related SAEs were observed in 11.2% (10/89) vs 13.3% (12/90) in A vs B. Post-treatment AEs, any grade, were observed in 51.7% (46/89) vs 57.8% (52/90) and serious post-treatment AEs in 13.5% (12/89) vs 24.4% (22/90) of patients in A vs B. Long-term safety continues to demonstrate that NBTXR3 plus RT has no impact on post-surgical wound complications (24.7% vs 36.7%, A vs B). Furthermore, the evaluation of radiation late toxicities in limbs such as fibrosis, arthrosis and edema that may alter limb function showed no difference between arms (4.5% vs 7.7%, 2.2% vs 0.0% and 6.7% vs 2.2% respectively in A vs B). In addition, sequelae or chronic tissue disturbances at the former tumor localization were similar in both treatment arms, confirming that the increase of energy dose deposit and the physical presence of NBTXR3 did not impact post-treatment limb functions. Accordingly, HR-QoL evaluation yielded no difference in functional outcome. Finally, second primary cancer was observed in 1 patient in arm A and 6 patients in arm B and the intratumoral injection of NBTXR3 did not induce cancer cell seeding at the former tumor site.

Conclusion: These results demonstrate that the use of NBTXR3 did not change the late onset toxicity profile of EBRT, nor modified its bystander effect. Taken together, the long-term safety data presented here, and the previously published efficacy data reinforce the favorable benefit-risk ratio of the use of NBTXR3 in patients with LA STS.

Summary

Background: NBTXR3, a novel radioenhancer activated by radiotherapy (RT) demonstrated superior efficacy, as preoperative treatment, in patients with locally advanced soft tissue sarcoma (LA STS), compared to RT alone. Primary endpoint of pCR rate was 16% vs 8% (p=0.044) and R0 margin rate was 77% vs 64% (p=0.042) (Bonvalot et al. Lancet Oncol. 2019). No modification of the early safety profile of RT was observed, leading to market authorization. Here we report on the long-term safety, limb function and quality of life.

Methods: This phase II/III randomized (1:1), international trial included adult patients with LA STS of the extremity or trunk wall, requiring preoperative RT (NCT02379845). Patients were treated with either a single intratumoral injection of NBTXR3 (volume equivalent to 10% of tumor volume, at 53.3g/L) plus EBRT (arm A), or EBRT alone (arm B) (50 Gy in 25 fractions), followed by surgery. The primary and main secondary efficacy endpoints were previously reported. Safety of NBTXR3+RT, as preoperative treatment, was evaluated as secondary endpoint. We present the safety analyses done in the “all treated population”, with data recorded during at least a two-year follow-up. Important parameters related to HR-QoL, including functional outcome were studied using the EQ-5D, RNLI, TESS and MSTS questionnaires.

Results: Patients had at least two-year follow-up and the lost to follow-up rate was very low (1.9%). RT-related SAEs were observed in 11.2% (10/89) vs 13.3% (12/90) in A vs B. Post-treatment AEs, any grade, were observed in 51.7% (46/89) vs 57.8% (52/90) and serious post-treatment AEs in 13.5% (12/89) vs 24.4% (22/90) of patients in A vs B. Second primary cancer was observed in 1 patient in arm A and 6 patients in arm B. Long-term safety continues to demonstrate that NBTXR3 plus RT has no impact on post-surgical wound complications (24.7% vs 36.7%, A vs B). Furthermore, the evaluation of radiation late toxicities in limbs such as fibrosis (4.5% vs 7.7%), arthrosis (2.2% vs 0.0%) and edema (6.7% vs 2.2%) that may alter limb function showed no difference between arms. Accordingly, HR-QoL evaluation yielded no difference in functional outcome. In addition, the intratumoral injection of NBTXR3 did not induce cancer cell seeding at the former tumor site. Finally, sequelae or chronic tissue disturbances at the former tumor localization were similar in both treatment arms, confirming that the increase of energy dose deposit and the physical presence of NBTXR3 did not impact post-treatment limb functions.

Conclusions: The long-term safety results demonstrate that the addition of NBTXR3 to EBRT neither added toxicity nor modified the bystander effect of RT. The results presented here associated with the efficacy data reported previously reinforce the favorable benefit-risk ratio of the use of NBTXR3 in patients with LA STS. Clinical trial information: NCT02379845.

Summary

Objectives: A subset of locally advanced soft tissue sarcoma (STS) patients achieve significant therapeutic benefit from preoperative radiation therapy (RT) as shown by Pisters JCO 1996 and Yang JCO 2018. However, the impact of RT on pathological response (pR) and R0 resection is limited, highlighting the need for novel multimodal therapies aimed at local control. NBTXR3 (hafnium oxide nanoparticles), injected intratumorally may represent such an option. Otherwise inert, NBTXR3 augments the effective RT dose deposited within tumor cells when activated by ionizing radiation to increase cancer cell death compared to RT alone. We report here on the results of a phase II/III randomized clinical trial evaluating the preoperative efficacy and safety of NBTXR3 activated by RT in patients with locally advanced STS of the extremity and trunk wall [NCT02379845].

Methods: This is a multi-national phase II/III randomized, open-label clinical trial. Adults with locally advanced STS of the extremity or trunk wall, of any histologic grade, eligible for preoperative RT were randomly assigned 1:1 to receive NBTXR3 as a single intratumoral injection (volume corresponding to 10% of baseline tumor volume at 53.3g/L) followed by external beam RT (EBRT; 50 Gy as 25 fractions of 2 Gy, over 5 weeks) (arm A) or EBRT alone (arm B). Both arms had the chance to go on to receive post-RT surgical resection. The primary objective was to compare the proportion of patients with pathological complete response (pCR; defined as <5% of residual viable cancer cells after surgery), as assessed by a Central Pathology Review Board based on the EORTC guidelines. Key secondary endpoints included negative surgical margin (R0), limb amputation rate and safety. Safety was evaluated in all subjects who received at least one puncture of NBTXR3 or at least one fraction of RT. Subjects are in continued long-term follow-up, focused on safety.

Results: Between March 3rd, 2015 and November 21st, 2017, 180 patients were randomized and 179 received treatment: n=89; arm A and n=90; arm B. The proportion of patients with pCR was 16.1% (14/87) compared with 7.9% (7/89) in arms A and B, respectively (p=0.044). The R0 resection rate was 77.0% (67/87) in arm A versus 64.0% (57/89) in arm B (p=0.0424). The most common grade 3-4 treatment emergent adverse event (AE) was post-operative wound complication, which occurred at a similar rate in each arm (8/89 and 8/90 in arm A and B, respectively). The most common grade 3-4 AE related to NBTXR3 administration was injection site pain (4/89, 4.5%) and hypotension (4/90, 4.4%). Skin injury was the most common grade 3-4 RT-related AE, which was shared between both arms (5/89, 5.6% and 4/90, 4.4% in arm A and B, respectively). Serious AEs were observed in 35 (39.3%) of 89 patients in arm A and 27 (30.0%) of 90 patients in arm B. There were no treatment-related deaths. Follow-up was conducted on 153 patients with a current median follow-up of 18.5 months. Currently 87 patients are still in long-term follow-up.

Conclusion: This registration trial of NBTXR3 combined with EBRT significantly achieved its primary and secondary endpoints of improving pCR, and increasing R0 resection versus EBRT alone. NBTXR3 together with EBRT was well tolerated with a safety profile consistent with EBRT alone. Taken together, these results led to the EU approval (CE Mark) of NBTXR3 + RT for patients with locally advanced STS of the extremity and trunk wall.

Summary

Purpose/Objective(s): Local interventional treatments of cancers include interventional radiology and radiotherapy (RT). NBTXR3, hafnium oxide nanoparticles, is deeply associated to both. Given as a single local administration it increases energy dose deposit inside tumor cells only when activated by ionizing radiation. Various interventional treatments have been used to treat cancers such as liver, lung, bone. Because entirely new therapies such as NBTXR3 are being introduced, implementation of interventional approaches is continuously growing.

Materials/Methods: NBTXR3 is being evaluated in soft tissue sarcoma (STS, extremity, trunk wall) [NCT02379845], head and neck (HN) [NCT01946867, NCT02901483], prostate [NCT02805894], liver [NCT02721056] and rectal cancers [NCT02465593]. NBTXR3 injected volume is a percentage of baseline tumor volume, and therefore heterogeneous. Image guidance allowed for accurate injection. Standard catheters, needles, and syringes were used for preparation and injection. Importantly, percutaneous needle positioning was done within the region to be irradiated to control potential seeding of cancer cells. NBTXR3 was then activated by IMRT (STS, HN), EBRT or combination brachytherapy/EBRT boost (prostate), SBRT (liver), IMRT or IMAT (rectum).

Results: Thus far, NBTXR3 has been administered to 171 patients by intratumoral/lesional, and intraprostate injections depending on indication. NBTXR3 injections have been demonstrated safe and very well tolerated. Local infection, ulceration or massive tumor necrosis were never observed. This has been confirmed by adequate application of treatment schedules, fitting planned irradiation onset 1 to 5 days post-injection. Importantly, grade 1 ecchymosis and hematoma at puncture site (needle entry) observed in few cases always resolved spontaneously and did not impact dosimetry. Indeed, change of tumor/lesion/prostate volume resolved when water (NBTXR3 vehicle) was drained via lymphatic system. So far, inflammatory response to injection procedure itself was mild. Concerning AEs, grade 3 pain was observed in conscious patients under local anesthesia with STS close to joints (limited extensibility), and in needle shift in injection within a subcapsular liver tumor.

Conclusion: Across 7 clinical trials involving tumors in extremity, trunk wall, liver, rectum, prostate and HN, NBTXR3 injection was well tolerated and demonstrated a very good safety profile. The savoir faire of interventional radiology for local treatment of cancers supported implementation of injection procedures with specific parameters according to anatomy. Intratumoral/lesional or intraprostate injection ensures optimum bioavailability at site of irradiation, protecting patients from systemic toxicity. Future clinical research will involve other anatomical sites such as lymph nodes and lung lesions [NCT03589339].

Summary

Purpose/Objectives(s): Preoperative radiotherapy (RT) is an option for a subset of patients with locally advanced primary or relapsed tumors. Yet, its impact on efficacy in terms of pathological response is limited, highlighting the need for novel multimodal therapies aimed at local control with low toxicity. NBTXR3 is made of hafnium oxide nanoparticles which, injected intratumorally (IT) and activated by ionizing radiation, yield a tumor-localized high energy deposit and increase cell death compared to the same dose of RT alone. We report here the results of a phase II/III randomized clinical trial of NBTXR3 given as preoperative treatment to patients with locally advanced soft tissue sarcoma (STS) of the extremity and trunk wall [NCT02379845].

Methods: Act.In.Sarc is an international, multicenter, open-label, active-controlled phase II/III trial in which patients (pts) with locally advanced STS of the extremity or trunk wall were randomized 1:1 to receive a single IT NBTXR3 injection and RT (Arm A) or RT alone (Arm B), followed by surgical resection. RT consisted of Intensity Modulated RT or 3D-RT of 2Gy*25 fractions (total 50 Gy) over 5 weeks. The primary endpoint was pathological Complete Response Rate (pCRR), defined as the proportion of pts presenting <5% of residual viable cancer cells evaluated by a Central Review Board on anonymized tumor specimen. Key secondary endpoints included negative surgical margin (R0) and general safety.

Results: Among the 180 randomized pts, 176 were included in the intent-to-treat full analysis set (ITT-FAS). In the ITT-FAS population, pCRR was 16.1% in Arm A vs 7.9% in Arm B (p=0.0448). R0 margin was achieved in 77.0% of pts in Arm A vs 64.0% in Arm B (p=0.0424). The limb amputation rate, another secondary outcome, was decreased by 50% in Arm A as compared to Arm B. NBTXR3 showed very good local tolerance without any modification of RT alone safety profile. In all the treated pts in Arm A, who received any amount of NBTXR3 or at least one RT dose, the IT administration of NBTXR3 caused injection-site pain in 12 (13.5%) pts. NBTXR3 was also associated with grade 3-4 acute immune reactions in 7 (7.9%) pts, but these adverse events were of short duration, manageable, and, in some cases, resolved spontaneously. Long-term efficacy and safety results will be presented.

Conclusion: In this study both the primary and secondary endpoints (pCRR and R0 rate, respectively) were met with a safety profile of NBTXR3 activated by RT comparable to that of RT alone. As pCR is associated with improved progression-free and overall survival, NBTXR3 activated by RT represents a new preoperative treatment option for locally advanced STS. These data support ongoing studies investigating NBTXR3 in recurrent/metastatic HNSCC or metastatic non-small cell lung cancer [NCT03589339]; HNSCC [NCT01946867; NCT02901483]; prostate cancer [NCT02805894], liver cancer [NCT02721056] and rectal cancer [NCT02465593].

Summary

Soft tissue sarcoma (STS) is a rare type of cancer, which occurs in tissues connecting, supporting and/or surrounding other structures of the body, like muscle, fat, etc. More than 50 subtypes of STS exist, characterized by a strong propensity to local recurrence and metastatic spreading. Consistently, the immune microenvironment in sarcomas is highly variable. A new class of high electron density material, hafnium oxide, was designed at the nanoscale to efficiently absorb ionizing radiation from within the tumor cells and increase the dose deposition into the tumor.

These nanoparticles (HfO2-NP), delivered into the tumor by a single injection and activated by radiotherapy, have the ability to enhance immunogenic cell death and immune response in preclinical studies. Here, we explore in a phase II/III trial in patients with locally advanced STS, the effects of nanosized hafnium oxide exposed to RT in terms of tumor immune profile changes in patients, when compared to RT alone.

Regarding immune cells infiltrates (post- vs pre-treatment), promising results are reported for patients treated with HfO2-NP activated by RT, when compared to RT. So far, these results show that HfO2-NP + RT induces a specific adaptive immune pattern. As such, it may convert immunologically “cold” tumor into “hot” tumor and be effectively combined with immunotherapeutic agents across oncology. More tissue samples are under evaluation to reinforce these findings.

Summary

NBTXR3, injectable hafnium oxide nanoparticles, was designed to increase the energy deposit of the irradiation when activated by radiotherapy for the treatment of solid tumors. It is currently evaluated in a phase II/III clinical trial in soft tissue sarcoma (STS) [NCT02379845] of the extremity and trunk wall, to compare its efficacy when intratumorally injected and activated by radiotherapy versus radiotherapy alone. In this study, treatment planning depends on the Gross Tumor Volume (GTV) and dosimetric calculations, measured before injection of NBTXR3. A change in the GTV volume during radiotherapy treatment could impact the dosimetric coverage. In order to evaluate this change in GTV volume during radiotherapy treatment an ancillary study was put in place.

NBTXR3 nanoparticles are activated by current standard radiotherapy without changing the applied dose and to increase the probability of interaction with incoming radiations to ameliorate the energy dose deposition from within tumor cells. The results of this study on the modifications of volumes during the radiotherapy treatment and their potential dosimetric impact will allow an objective evaluation of the dosimetric coverage all along the treatment period.

Summary

To improve radiotherapy (RT) in terms of tumor response and to reduce irradiation of healthy tissues, innovative therapeutic approaches are needed. In response, NBTXR3, injectable hafnium oxide nanoparticles, was developed for the treatment of solid tumors.

Once injected intratumorally, NBTXR3 can deposit high energy within tumors only when activated by an ionizing radiation source, like current standard RTs. Upon activation, the high energy radiation physically kills the tumor cells by triggering DNA damage and cell destruction improving clinical outcomes.

Since its first successful clinical evaluation in a completed phase I trial in patients with locally advanced soft tissue sarcoma, NBTXR3 is currently evaluated in numerous indications worldwide (EU, Asia, US).

NBTXR3 have shown promising results in non-clinical studies with marked antitumor efficacy and in clinical development in terms of safety and preliminary evaluations of efficacy. Considering the preliminary results of the 145 patients injected across all clinical trials, these first-in-class nanoparticles have already proven to be an encouraging innovative treatment in various types of tumors. The last patient of the phase II/III trial in STS was included and the results of this study regarding efficacy and safety will soon be disclosed.

Summary

NBTXR3 is a first-in-class Hafnium-Oxide nanoparticle intratumorally (IT) injected. When activated by radiotherapy (RT), it allows for a higher energy deposit than RT alone, yielding an increased tumoral cell death.

A phase I study in soft tissue sarcoma (STS) showed that a single NBTXR3 IT injection at 10% of the baseline tumor volume with preoperative RT was technically feasible with manageable toxicity and clinical activity was observed.

In this international, multicenter, randomized, open-label phase II/III study, patients (pts) with locally advanced STS of the extremity and trunk wall received either a single IT injection of NBTXR3 followed by RT or RT alone (1:1 ratio), both followed by surgical resection. RT was by Intensity Modulated RT or 3D-RT of 2Gy/25 fractions (total 50 Gy). The primary endpoint was the pathological Complete Response Rate (pCRR) defined as the percentage of pts presenting ≤5% of residual viable cancer cells (EORTC guidelines) evaluated by a blind Central Review Board. Key secondary endpoints included negative surgical margins (R0) and safety.

In the intent-to-treat full analysis set population (n=179), which included all pts who were randomized and stratified by STS histological subtype, the pCRR was 16.1% vs 7.9 (p=0.0448) and the R0 rate was 77.0% vs 64.0% (p=0.0424) for NBTXR3+RT and RT alone respectively. NBTXR3 caused injection-site pain in 12 (13.5%) pts. It was also associated with grade 3-4 acute immune reactions in 7 (7.9%) pts, but these adverse events were of short duration, manageable, and resolved spontaneously in some cases. Outside the injection, NBTXR3 was very well tolerated and its safety profile was comparable to RT alone.

NBTXR3 activated by RT was signicantly superior to RT alone and this trial met both primary and secondary endpoint with a positive safety profile. NBTXR3 represents a new option for preoperative treatment for locally advanced STS.