Summary

Background and purpose: Pancreatic ductal adenocarcinoma (PDAC) remains one of the leading causes of cancer-related deaths in the world. For patients with PDAC who are not eligible for surgery, radiation therapy improves local disease control, yet safely delivering therapeutic doses of radiation remains challenging due to off-target toxicities in surrounding normal tissues. NBTXR3, a novel radioenhancer composed of functionalized hafnium oxide crystalline nanoparticles, has recently shown clinical activity in soft tissue sarcoma, hepatocellular carcinoma, head and neck squamous cell carcinoma, and advanced solid malignancies with lung or liver metastases. Here we report the first patient with pancreatic cancer treated with NBTXR3.

Materials and methods: A 66-year-old male with unresectable locally advanced PDAC was enrolled on our clinical trial to receive NBTXR3 activated by radiation therapy. Local endoscopic delivery of NBTXR3 was followed by intensity modulated radiation therapy (IMRT). Follow-up assessment consisted of physical examination, laboratory studies including CA19-9, and CT of the chest, abdomen, and pelvis.

Results: The patient received NBTXR3 by local endoscopic delivery without any acute adverse events. Radiation treatment consisted of 45 Gy in 15 daily fractions using IMRT. The patient began radiation twelve days after NBTXR3 injection. Daily CT-on-rails imaging demonstrated retention of NBTXR3 within the tumor for the duration of treatment. At initial follow-up evaluation, the lesion remained radiographically stable and the patient did not demonstrate treatment-related toxicity.

Conclusion: This report demonstrates initial feasibility of local endoscopic delivery of NBTXR3 activated by radiation therapy for patients with pancreatic cancer who are not eligible for surgery.

Summary

Purpose of review: The current review focuses on the therapeutic use of nanoparticles in head and neck cancer (HNC), highlighting nanoparticles at the most advanced clinical development stages.

Recent findings: Literature review covers the three main approaches for therapeutic use of nanoparticles in HNC: first, enhancing radiotherapy effect; second, performing targeted delivery of chemotherapy, immunotherapy, or genome editing molecules; third, photothermal therapy.

Summary: Nanoparticles are spherical nanoscale objects that have application in cancer therapies. Nanoparticles have diverse and often composite structure composition to ensure their function, increase their bioavailability in tumor tissues, and decrease off-target effects, sometimes by means of activating internal or external stimuli. Hafnium oxide nanoparticles are being tested in phase I to III trials for radiotherapy enhancement. Nanoparticle-based delivery of paclitaxel, cisplatin, and of the immune activator CpG-A DNA is being evaluated in phase II trials. No nanoparticle is currently approved for HNC treatment.

Summary

Background: Combining radiotherapy with PD1 blockade has had impressive antitumor effects in preclinical models of metastatic lung cancer, although anti-PD1 resistance remains problematic. Here, we report results from a triple-combination therapy in which NBTXR3, a clinically approved nanoparticle radioenhancer, is combined with high-dose radiation (HDXRT) to a primary tumor plus low-dose radiation (LDXRT) to a secondary tumor along with checkpoint blockade in a mouse model of anti-PD1-resistant metastatic lung cancer.

Methods: Mice were inoculated with 344SQR cells in the right legs on day 0 (primary tumor) and the left legs on day 3 (secondary tumor). Immune checkpoint inhibitors (ICIs), including anti-PD1 (200 μg) and anti-CTLA4 (100 μg) were given intraperitoneally. Primary tumors were injected with NBTXR3 on day 6 and irradiated with 12-Gy (HDXRT) on days 7, 8, and 9; secondary tumors were irradiated with 1-Gy (LDXRT) on days 12 and 13. The survivor mice at day 178 were rechallenged with 344SQR cells and tumor growth monitored thereafter.

Results: NBTXR3 + HDXRT + LDXRT + ICIs had significant antitumor effects against both primary and secondary tumors, improving the survival rate from 0 to 50%. Immune profiling of the secondary tumors revealed that NBTXR3 + HDXRT + LDXRT increased CD8 T-cell infiltration and decreased the number of regulatory T (Treg) cells. Finally, none of the re-challenged mice developed tumors, and they had higher percentages of CD4 memory T cells and CD4 and CD8 T cells in both blood and spleen relative to untreated mice.

Conclusions: NBTXR3 nanoparticle in combination with radioimmunotherapy significantly improves anti-PD1 resistant lung tumor control via promoting antitumor immune response.

Summary

Purpose: Radiation combined with PD1 blockade offers significant treatment benefits in several tumor types; however, anti-PD1 resistance precludes such benefits in many cases. Here we attempted to overcome anti-PD1 resistance by combining localized radiation with a radioenhancing nanoparticle (NBTXR3) and systemic anti-PD1 treatment to achieve abscopal effects in an anti-PD1–resistant mouse model of lung cancer.

Methods and Materials: Female 129Sv/Ev mice were inoculated with 344SQ anti-PD1–resistant (344SQR) or anti-PD1–sensitive (344SQP) metastatic lung cancer cells in the right leg on day 0 (“primary” tumor) and the left leg on day 4 (“secondary” tumor). Primary tumors were injected intratumorally with NBTXR3 on day 7 and were irradiated with 12 Gy on days 8, 9, and 10. Mice were given 6 intraperitoneal injections of anti-PD1. T cell receptor repertoire was analyzed in tumor samples with RNA sequencing, infiltration of CD8 T cells with immunohistochemical staining, and activities of various immune pathways with NanoString analysis.

Results: The triple combination of NBTXR3 with localized radiation and systemic anti-PD1 significantly delayed the growth of both irradiated and unirradiated tumors in both 344SQP and 344SQR tumor models. NBTXR3 remodeled the immune microenvironment of unirradiated tumors by triggering the activation of various immune pathways, increasing the number of CD8+ T cells, and modifying the T cell receptor repertoire in the 344SQR tumor model.

Conclusions: The ability of NBTXR3 to evoke significant abscopal effects in both anti-PD1–sensitive and anti-PD1–resistant lung cancers could open the possibility of its use for treating patients with metastatic lung cancer regardless of sensitivity (or resistance) to immunotherapies.

Summary

Purpose: The side effects of radiotherapy induced on healthy tissue limit its use. To overcome this issue and fully exploit the potential of radiotherapy to treat cancers, the first-in-class radioenhancer NBTXR3 (functionalized hafnium oxide nanoparticles) has been designed to amplify the effects of radiotherapy.

Patients and methods: Thanks to its physical mode of action, NBTXR3 has the potential to be used to treat any type of solid tumor. Here we demonstrate that NBTXR3 can be used to treat a wide variety of solid cancers. For this, we evaluated different parameters on a large panel of human cancer models, such as nanoparticle endocytosis, in vitro cell death induction, dispersion, and retention of NBTXR3 in the tumor tissue and tumor growth control.

Results: Whatever the model considered, we show that NBTXR3 was internalized by cancer cells and persisted within the tumors throughout radiotherapy treatment. NBTXR3 activated by radiotherapy was also more effective in destroying cancer cells and in controlling tumor growth than radiotherapy alone. Beyond the effects of NBTXR3 as single agent, we show that the antitumor efficacy of cisplatin-based chemoradiotherapy treatment was improved when combined with NBTXR3.

Conclusion: These data support that NBTXR3 could be universally used to treat solid cancers when radiotherapy is indicated, opening promising new therapeutic perspectives of treatment for the benefit of many patients.

Summary

Introduction: Non-surgical standard of care (SOC) for locally advanced head and neck squamous cell carcinoma (LA HNSCC) patients is chemoradiation with cisplatin/cetuximab. Elderly patients, and those with poor performance status, comorbidities, and/or intolerance, may not benefit from current SOC, representing a high unmet need. NBTXR3, a novel radioenhancer composed of functionalized hafnium oxide nanoparticles, is activated by radiotherapy (RT). NBTXR3 increases RT energy deposit in tumor cells and subsequent tumor cell death, while sparing healthy tissues compared to RT alone. NBTXR3 subsequently primes an adaptive immune response.

Objectives: The phase I dose expansion study aims to evaluate safety and efficacy of NBTXR3 + RT in patients with stage III–IVA or T3/T4 (TNM-8) HNSCC of the oropharynx or oral cavity, ineligible to cisplatin or cetuximab and amenable for RT.

Methods: Patients received a single intratumoral injection of NBTXR3 + RT (70 Gy, 35 fractions/7 weeks). A 3 + 3 dose escalation design tested four NBTXR3 doses: 5, 10, 15, and 22% of baseline theoretical tumor volume; and established RP2D as 22%. Primary endpoints of the dose expansion part are objective response rate (ORR) and complete response rate (CRR) of the primary tumor (RECIST 1.1).

Results and Conclusion: As of March 26, 2021, 52 patients were treated in the dose expansion part. Median age and tumor volume were 71.6 years and 60.6 mL respectively. ORR of the primary lesion was 82.5% and CRR was 62.5% (N = 40) at a median of 8.1 months after NBTXR3 injection. RT-related toxicity was as expected. Six patients experienced at least one G3–4 serious adverse event (AE) related to injection procedure and/or NBTXR3 (< 1% of all AEs). Four deaths related to RT were observed, also one death from sepsis possibly related to NBTXR3, RT, and cancer disease was reported. NBTXR3 + RT showed promising efficacy, supporting further evaluation in a phase III randomized trial.

Summary

Background: The non-surgical standard of care (SOC) for the treatment of locally advanced head and neck squamous cell carcinoma (LA HNSCC) patients is concurrent chemoradiation with high dose cisplatin or cetuximab in case of contra-indication to cisplatin. However elderly patients, and those with poor performance status, comorbidities, and/or intolerance, may not benefit from these SOC treatments and represent a high unmet need. New approaches are thus needed to improve clinical outcomes without adding toxicity. NBTXR3, a novel radioenhancer, composed of functionalized hafnium oxide nanoparticles, is injected once intratumorally and activated by radiotherapy (RT).NBTXR3 increases the RT energy deposit inside tumor cells and subsequently increases tumor cell death compared to RT alone, while sparing healthy tissues. We present here the results of the dose expansion part of the phase I study evaluating NBTXR3 plus intensity modulated radiation therapy (IMRT) in this population.

Methods: Patients with stage III-IVA or T3/T4 (AJCC/UICC TNM staging system 8th ed.) HNSCC of the oropharynx or oral cavity, ineligible to cisplatin or cetuximab and amenable for RT, received a single intratumoral injection of NBTXR3 and IMRT (70 Gy in 35 fractions /7 weeks). A classical 3 + 3 dose escalation design has tested four doses of NBTXR3, equivalent to 5, 10, 15, and 22% of baseline theoretical tumor volume. The RP2D established as 22% of baseline tumor volume is further tested in the dose expansion part. The primary endpoints of the dose expansion part are objective response rate (ORR) and complete response rate (CRR) of the primary tumor, by imaging according to RECIST 1.1. Safety is also evaluated.

Results: As of August 13, 2020, 43 patients have been treated in the phase I dose expansion part. The median age was 70.7 years old (range: 50.7- 89.9), 70% of patients had cardiac disorder risk, 44% had gastrointestinal disorder risk and 44% metabolic and nutrition disorder risk. The median tumor volume was 42.8 mL (range: 1.3 – 222.3). At a median time of 7.8 months after NBTXR3 injection, the ORR of the primary lesion was 83.9% and the CRR 67.7% in the evaluable population for efficacy (N = 31). Three patients (7%) experienced at least one serious adverse event (AE) related to the injection procedure and/or NBTXR3 which represented less than 1% of all reported AEs. RT-related toxicity was as expected with IMRT. Three deaths due to AEs related to RT and other causes were reported. The recruitment is ongoing and updated efficacy and safety results will be presented.

Conclusions: NBTXR3 intratumoral administration followed by IMRT may represent an option in elderly patients or patients with multiple comorbidities with LA-HNSCC who have limited therapeutic options. NBTXR3 activated by RT showed promising anti-tumor efficacy, supporting further evaluation in a phase III randomized trial. Clinical trial information: NCT01946867.

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

Purpose or Objective: Concurrent radiotherapy (RT) with high-dose cisplatin, or cetuximab in case of intolerance to cisplatin, are the non-surgical standard treatment for locally advanced head and neck squamous cell carcinoma (LA HNSCC). However, elderly patients, patients with poor performance status, comorbidities, and/or intolerance may not benefit from these treatments and represent a high unmet medical need. New approaches are thus needed to improve patient clinical outcomes without adding toxicity. NBTXR3, composed of functionalized hafnium oxide nanoparticles, is injected intratumorally and activated by RT. NBTXR3 increases the RT energy deposit inside tumor cells and subsequently increases tumor cell death compared to RT alone, without adding toxicity to healthy tissues. Here we present current results of the dose expansion part of the phase I study evaluating NBTXR3 plus intensity modulated radiation therapy (IMRT) in this population.

Materials and Methods: Patients with stage III-VA or T3/T4 (AJCC/UICC TNM staging system 8th ed.) HNSCC of the oropharynx or oral cavity, ineligible to cisplatin or cetuximab and amenable for RT, received a single intratumoral injection of NBTXR3 and IMRT (70 Gy in 35 fractions /7 weeks) [ NCT01946867]. A classical 3 + 3 dose escalation design has tested four doses of NBTXR3, equivalent to 5, 10, 15, and 22% of baseline theoretical tumor volume. The RP2D established as 22% of baseline tumor volume is further tested in the dose expansion part of the study. The primary endpoints of the dose expansion part are objective response rate (ORR) and complete response rate (CRR) of the primary tumor, by imaging according to RECIST v1.1. Safety is also evaluated.

Results: As of August 13, 2020, 43 patients have been treated in the dose expansion part of the study. The median age was 70.7 years old (range: 50.7- 89.9), 70% of patients had cardiac disorder risk, 44% had gastrointestinal disorder risk and 44% metabolic and nutrition disorder risk. The median tumor volume was 42.8 mL (range: 1.3 – 222.3). In the evaluable population for efficacy (N=31), the ORR of the primary lesion was 83.9% and the CRR 67.7% at a median time of 7.8 months after NBTXR3 injection. Three patients (7%) experienced at least one serious adverse event (AE) related to the injection procedure and/or NBTXR3 which represented less than 1% of all reported AEs. RT-related toxicity was as expected with IMRT. Three deaths due to AEs related to RT and other causes were reported. Recruitment is ongoing and updated efficacy and safety results will be presented.

Conclusion: NBTXR3 intratumoral administration followed by IMRT may represent an option in elderly in elderly patients or patients with multiple comorbidities with LA-HNSCC who have limited therapeutic options. NBTXR3 activated by RT showed promising anti-tumor efficacy, supporting further evaluation in a phase III randomized trial.