Summary

Purpose/Objective(s): Immune checkpoint inhibitors (ICIs) have led to improved treatment outcomes in a variety of cancers; however, the majority of patients exhibit resistance to ICIs. Overcoming this resistance is a major challenge in immune-oncology. Radiation therapy (RT) has emerged as a promising combination with ICIs since it may act synergistically with ICIs by producing an immunomodulatory effect. NBTXR3, composed of functionalized hafnium oxide nanoparticles, is injected intratumorally and activated by RT. NBTXR3 increases RT energy deposit inside tumor cells and subsequent tumor cell death, without adding toxicity to healthy tissues. Preclinical data demonstrate NBTXR3/RT can trigger a local and systemic anti-tumor immune response and overcome anti-PD-1 resistance. NBTXR3/RT combined with anti-PD-1 may prime the immune system to increase the proportion of ICI responders or convert ICI non-responders to responders.

Materials/Methods: This multicenter, open-label, phase I trial [NCT03589339] is evaluating NBTXR3/RT/anti-PD-1 in 3 cohorts: (1) Locoregional recurrent or recurrent and metastatic head and neck squamous cell carcinoma (HNSCC) amenable to HN re-irradiation and (2) lung or (3) liver metastases from any primary cancer eligible for anti-PD-1. Stereotactic body RT (SBRT) is delivered at tumor-site selective doses per standard practice. The primary objective is to determine the NBTXR3/RT/anti-PD-1 recommended phase 2 dose in each cohort. Secondary objectives are anti-tumor response (objective response rate), safety, and feasibility of NBTXR3 injection.

Results: Nine patients have been treated: 3 HNSCC, 4 lung, 2 liver. Overall tumor regression was observed in 8/9 patients of which 7 were anti-PD-1 non-responders. A complete response lasting over 1 year was observed in the injected lymph node in 1 anti-PD-1 naïve patient. 2 SAEs related to anti-PD-1 and possibly related to NBTXR3 (G5 pneumonitis, G4 hyperglycemia) were observed in 1 anti-PD-1 naïve HNSCC patient and considered DLTs. This patient also experienced 2 other G4 SAEs related to anti-PD-1 (diabetic ketoacidosis, acute kidney injury). SBRT-related safety profile was as expected. Updated safety and efficacy results with additional patients and longer follow-up will be presented.

Conclusion: Safety data from this first-in-human phase I trial evaluating NBTXR3/RT/anti-PD-1 in patients with advanced cancers, show NBTXR3 intratumoral injection is feasible and well-tolerated in HNSCC, lung, and liver. NBTXR3/RT/anti-PD-1 demonstrated promising signs of efficacy and led to tumor regression in patients having progressed on prior anti-PD-1. These data support further development of NBTXR3 in combination with anti-PD-1 as well as other ICIs.

Summary

Purpose/Objective(s): Immune checkpoint inhibitors (ICIs) have led to improved treatment outcomes in a variety of cancers; however, the majority of patients exhibit resistance to ICIs. Overcoming this resistance is a major challenge in immune-oncology. Radiation therapy (RT) has emerged as a promising combination with ICIs since it may act synergistically with ICIs by producing an immunomodulatory effect. NBTXR3, composed of functionalized hafnium oxide nanoparticles, is injected intratumorally and activated by RT. NBTXR3 increases RT energy deposit inside tumor cells and subsequent tumor cell death, without adding toxicity to healthy tissues. Preclinical data demonstrate NBTXR3/RT can trigger a local and systemic anti-tumor immune response and overcome anti-PD-1 resistance. NBTXR3/RT combined with anti-PD-1 may prime the immune system to increase the proportion of ICI responders or convert ICI non-responders to responders.

Materials/Methods: This multicenter, open-label, phase I trial [NCT03589339] is evaluating NBTXR3/RT/anti-PD-1 in 3 cohorts: (1) Locoregional recurrent or recurrent and metastatic head and neck squamous cell carcinoma (HNSCC) amenable to HN re-irradiation and (2) lung or (3) liver metastases from any primary cancer eligible for anti-PD-1. Stereotactic body RT (SBRT) is delivered at tumor-site selective doses per standard practice. The primary objective is to determine the NBTXR3/RT/anti-PD-1 recommended phase 2 dose in each cohort. Secondary objectives are anti-tumor response (objective response rate), safety, and feasibility of NBTXR3 injection.

Results: Nine patients have been treated: 3 HNSCC, 4 lung, 2 liver. Overall tumor regression was observed in 8/9 patients of which 7 were anti-PD-1 non-responders. A complete response lasting over 1 year was observed in the injected lymph node in 1 anti-PD-1 naïve patient. 2 SAEs related to anti-PD-1 and possibly related to NBTXR3 (G5 pneumonitis, G4 hyperglycemia) were observed in 1 anti-PD-1 naïve HNSCC patient and considered DLTs. This patient also experienced 2 other G4 SAEs related to anti-PD-1 (diabetic ketoacidosis, acute kidney injury). SBRT-related safety profile was as expected. Updated safety and efficacy results with additional patients and longer follow-up will be presented.

Conclusion: Safety data from this first-in-human phase I trial evaluating NBTXR3/RT/anti-PD-1 in patients with advanced cancers, show NBTXR3 intratumoral injection is feasible and well-tolerated in HNSCC, lung, and liver. NBTXR3/RT/anti-PD-1 demonstrated promising signs of efficacy and led to tumor regression in patients having progressed on prior anti-PD-1. These data support further development of NBTXR3 in combination with anti-PD-1 as well as other ICIs.

Summary

Introduction: Immune checkpoint inhibitors (ICIs) have improved treatment outcomes in a variety of cancers; however the majority of patients (pts) exhibit resistance. Emerging evidence suggests radiation therapy (RT) can enhance response to ICIs by producing an immunomodulatory effect. NBTXR3, composed of functionalized hafnium oxide nanoparticles, is injected intratumorally and activated by RT. NBTXR3 increases RT energy deposition inside tumor cells and subsequent tumor cell death, without adding toxicity to healthy tissues. Preclinical data demonstrate NBTXR3/RT can trigger a local and systemic anti-tumor immune response and overcome anti-PD-1 resistance. NBTXR3/RT combined with anti-PD-1 may prime the immune system to increase the proportion of ICI responders or convert ICI non-responders to responders.

Materials and Methods: A multicenter, open-label, phase I trial [NCT03589339] evaluating NBTXR3/SBRT/anti-PD-1 (nivolumab or pembrolizumab) in 3 cohorts (1) Locoregional recurrent or recurrent and metastatic HNSCC amenable to HN re-irradiation, (2) lung or (3) liver metastases from any primary cancer eligible for anti-PD-1. Stereotactic body RT (SBRT) is delivered at tumor-site specific doses per standard practice. Primary objective is to determine the NBTXR3/SBRT/anti-PD-1 recommended phase 2 dose in each cohort. Secondary objectives are anti-tumor response (objective response rate), safety, and feasibility of NBTXR3 injection.

Results: Nine pts have been treated, 3 HNSCC, 4 lung and 2 liver. HNSCC was the primary cancer in 2 pts in the lung and 1 pt in the liver cohort. 7/9 pts were anti-PD-1 non-responders. Overall tumor regression was observed in 8/9 pts. NBTXR3/SBRT/anti-PD-1 resulted in tumor regression in 6/7 pts who had progressed on prior anti-PD-1. One anti-PD-1 naïve HNSCC pt achieved a complete response lasting over a year in the injected lymph node. 2 SAEs related to anti-PD-1 and possibly related to NBTXR3 (G5 pneumonitis, G4 hyperglycemia) were observed in 1 anti-PD-1 naïve HNSCC pt and considered DLTs. This pt also experienced 2 other SAEs (G4 diabetic ketoacidosis, G4 acute kidney injury) related to anti-PD-1. SBRT-related safety profile was as expected.

Conclusions: Safety data from this first-in-human phase I trial evaluating NBTXR3/SBRT/anti-PD-1 in pts with advanced cancers show NBTXR3 intratumoral injection is feasible and well-tolerated in HNSCC, lung, and liver metastases. NBTXR3/SBRT/anti-PD-1 demonstrated promising signs of efficacy and led to tumor regression in pts having progressed on prior anti-PD-1. These data support further development of NBTXR3/SBRT in combination with anti-PD-1 as well as other ICIs.

Summary

Background: Cancer immunotherapies have shown promising clinical outcomes; however, the majority of patients are non-responders or will develop resistance during the course of treatment. One of the current challenges is to increase the response rate to immune checkpoint inhibitors (ICIs). Combining immunotherapy with radiation therapy (RT) is emerging as a valuable strategy to prime the immune response. However, RT dose and ultimate efficacy are limited by toxicity related to exposure of healthy tissues. First-in-class radioenhancer NBTXR3, administered by one-time direct intratumoral injection, is designed at the nanoscale to increase RT dose deposit with subsequent increase in tumor cell killing, without increasing toxicity to normal tissue. Preclinical and early clinical data suggest NBTXR3/RT can prime the immune system and act as an in situ vaccine leading to an anti-tumor immune response, producing both local and systemic (abscopal) effects. We hypothesize NBTXR3/RT in combination with anti-PD-1 (NBTXR3/RT/PD-1), will act synergistically to increase the proportion of ICI responders or convert ICI non-responders to responders.

Methods: A multicenter, open-label, phase I trial [NCT03589339] evaluating safety and tolerability of NBTXR3/RT/PD-1 in three cohorts: (1; H&N) Locoregional recurrent or recurrent and metastatic head and neck squamous cell carcinoma (HNSCC) amenable to re-irradiation of the HN field, (2; lung) lung or (3; liver) liver metastases from any primary cancer eligible for approved anti-PD-1 treatment. NBTXR3 injected volume is based on a percentage of baseline tumor volume. Stereotactic body RT (SBRT) is delivered as per standard practice. The primary objective is to determine NBTXR3/RT/PD-1 recommended phase II dose in each cohort. Secondary objectives are to evaluate anti-tumor response (objective response rate), safety and feasibility of NBTXR3 injection, and NBTXR3 body kinetic profile.

Results: To date 6 patients have been treated: 3 in H&N (2 anti-PD-1 naïve) and 3 in lung (all anti-PD-1 non-responders. No DLT or SAE has been observed. Grade 2 nausea related to NBTXR3 or injection procedure was observed in H&N. 2 H&N patients and 3 lung patients have completed RT and initiated anti-PD-1 treatment. RT-related safety profile was as expected. Tumor shrinkage was observed in 1 anti-PD-1 naive and 2 anti-PD-1 non-responders and additional preliminary efficacy and updated safety results will be presented.

Conclusions: To date, NBTXR3 administration activated by SBRT in combination with anti-PD-1 treatment has been safe and well tolerated in patients with advanced cancers. Promising early signs of efficacy in anti-PD-1 naïve, as well as in patients having progressed on previous anti-PD-1 therapy will be presented.

Summary

Purpose: First in class hafnium oxide nanoparticles (NBTXR3) activated by radiotherapy (RT) increase radiation dose deposit within cancer cells compared to RT alone. Given that RT can prime an anti-tumor immune response we hypothesized that this response could be enhanced by NBTXR3+RT in both animals and humans.

Method & Materials: Different abscopal assays in mice were conducted. Immunocompetent mice were injected in both flanks with murine tumor cells. Intratumoral injection of NBTXR3 (or vehicle) was performed in right flank tumors, followed by RT of right flank tumors only. Tumor growth was followed and immune cell infiltrates were analyzed by immunohistochemistry (IHC). Some mice received anti-PD-1 injections and tumor growth was monitored. Pts with locally advanced soft tissue sarcoma (STS) [NCT02379845] received either NBTXR3+RT or RT alone. Pts pre- and post-treatment tumor tissues were analyzed by IHC and Digital Pathology for immune biomarkers.

Results: Animal studies demonstrated that NBTXR3+RT induces an immune response which was not observed with RT alone. IHC showed significantly more CD8+ cells present in NBTXR3+RT treated and untreated tumors. Furthermore, NBTXR3+RT improved the effect of anti-PD-1. Similarly, increased CD8+ T cell infiltration pre- vs post-treatment was observed in tumor tissues from STS pts treated with NBTXR3+RT. An increase in biomarkers, including CD8, following NBTXR3+RT was also observed by IHC in tumor samples from STS pts compared to RT alone.

Conclusion: These results demonstrate that NBTXR3+RT induces a specific adaptive immune profile in both mice and STS pts. NBTXR3+RT also improved response to anti-PD-1 in mice, opening the potential for combination with immunotherapeutic agents in humans. We have therefore sought to investigate the safety and systemic effect of NBTXR3 activated by stereotactic ablative radiotherapy (SABR) in combination with anti-PD-1 in pts with locoregionally recurrent or metastatic (lung or liver) head and neck squamous cell carcinoma, as well as in metastatic non-small cell lung cancer and liver metastasis pts [NCT03589339].

Clinical Relevance & Application: The results of this study highlight the potential of NBTXR3 to be used in combination with immune checkpoint inhibitors in order to improve patient outcomes.

Summary

Purpose/Objective(s): Hafnium oxide nanoparticles (NBTXR3) activated by radiotherapy (RT) increase radiation dose deposit within cancer cells compared to RT alone. Currently 7 clinical trials are underway to evaluate NBTXR3+RT. To date, no dose limiting toxicities (DLTs) have been observed. Given that RT can prime an anti-tumor immune response we hypothesized that this response could be enhanced by NBTXR3+RT in both animals and humans.

Materials/Methods: Immunocompetent mice were injected in both flanks with CT26 cells. An intratumoral injection of NBTXR3 (or vehicle) was performed in right flank tumors, followed by RT (3x4Gy). Tumor growth was followed, and animals sacrificed when tumors reached 800mm3. Alternatively, tumors were collected 3 days after last RT fraction and immune cell infiltrates analyzed by immunohistochemistry (IHC). Pts with locally advanced soft tissue sarcoma (STS) [NCT02379845] received
either NBTXR3+RT or RT alone. Pre- and post-treatment tumor tissues (biopsy and tumor resection respectively) from pts were analyzed by IHC
and Digital Pathology for immune biomarkers (>16 pts per arm).

Results: Animal studies demonstrated that NBTXR3+RT can induce an immune response which was not observed with RT alone. IHC analyses showed that significantly more CD8+ cells were present in NBTXR3+RT treated and untreated tumors, compared to tumors from mice treated with RT alone. Similarly, increased CD8+ T cell infiltration pre- vs post-treatment was observed in tumor tissues from STS pts treated with NBTXR3+RT. An increase in biomarkers, including CD8 and PD1, following NBTXR3 +RT was also observed by IHC in tumor samples from STS pts compared to RT alone.

Conclusion: These results demonstrate that NBTXR3+RT induces a specific adaptive immune profile in both mice and STS pts. As such, it may convert immunologically “cold” tumors into “hot” tumors, opening the potential for combination with immunotherapeutic agents. We have therefore sought to investigate the safety and systemic effect of NBTXR3 activated by stereotactic ablative radiotherapy (SABR) in combination with anti-PD-1 antibody in pts with locoregionally recurrent or metastatic (to lung or liver) head and neck squamous cell carcinoma (HNSCC), as well as in metastatic non-small cell lung cancer (NSCLC) and liver metastasis patients [NCT03589339].

Summary

Background: Radiotherapy (RT) can prime an anti-tumor immune response. Unfortunately, this response rarely generates total tumor destruction and abscopal effect. When activated by RT, intratumorally (IT) administered hafnium oxide nanoparticles (NBTXR3) locally increase radiation dose deposit and tumor cell death compared to RT alone. We hypothesized that NBTXR3 + RT could enhance the anti-tumor immune response, both in mice and humans.

Methods: Murine CT26 cells were injected in both flanks of immunocompetent mice. When tumor volume reached 50-120mm3, NBTXR3 (or vehicle) was injected IT in right flank tumors only, then irradiated (3x4Gy). Mice were sacrificed when tumors reached 800mm3. Alternatively, tumors were collected 3 days after last RT fraction and immune cell infiltrates analyzed by immunohistochemistry (IHC). Patients (pts) with locally advanced Soft Tissue Sarcoma (STS) (NCT02379845) received NBTXR3 + RT or RT alone. Pre- and post-treatment (biopsy and resection, respectively) tumor tissues from pts were analyzed by IHC and Digital Pathology for immune biomarkers ( > 16 pts per arm).

Results: In mice, IHC analyses showed an increase of CD8+ T cells infiltrates in both flanks of mice treated with NBTXR3+RT, while this was not observed in animals treated with RT alone. Furthermore, ICH analysis of post- vs pre-treatment samples from STS pts showed a marked increase of CD8+ and PD1 biomarkers for pts treated with NBTXR3 + RT, while no differences were seen for pts treated with RT alone.

Conclusions: NBTXR3 + RT markedly changes the tumor immune profile in a similar manner in mice and pts with STS. We hypothesize that this adaptive immune response could help convert a local tumor microenvironment to a “hot” phenotype and thus improve the efficacy of immune checkpoint inhibitors. These results led us to investigate the safety and systemic effect of NBTXR3 activated by stereotactic ablative RT (SABR) in combination with anti-PD-1 antibody in pts with locoregionally recurrent or metastatic (to lung or liver) Head and Neck squamous cell carcinoma HNSCC, as well as in metastatic non-small cell lung cancer (NSCLC) and liver metastasis patients [NCT03589339].

Summary

Hafnium oxide nanoparticles (NBTXR3) activated by radiotherapy (RT) increase radiation dose deposit within cancer cells compared to RT alone. There are currently 7 clinical trials underway to evaluate NBTRX3 activated by RT, including a phase I/II study in elderly frail patients with locally advanced head and neck squamous cell carcinoma (HNSCC) [NCT01946867]. To date, no dose limiting toxicities (DLTs) have been observed. Studies in animals showed that NBTXR3 + RT can induce an immunogenic cell death-mediated abscopal effect which was not observed with RT alone. Furthermore, the immune cell infiltration profiles pre-treatment (biopsy) vs post-treatment (tumor resection) in patients with locally advanced Soft Tissue Sarcoma were modified in patients who received NBTXR3 + RT, compared to RT alone, as measured by immunohistochemistry. These results have led us to investigate the safety and systemic effect of NBTXR3 activated by stereotactic ablative radiotherapy (SABR) in combination with anti-PD-1 antibody in patients with more advanced disease: locoregionally recurrent or metastatic (to lung or liver) HNSCC, as well as in metastatic non-small cell lung cancer (NSCLC) and liver metastasis patients [NCT03589339].

Recent clinical studies have demonstrated the efficacy of anti-PD-1 in recurrent/metastatic HNSCC and metastatic NSCLC patients. However, only a subset of these patients benefits from this treatment, while most patients with recurrent/metastatic HNSCC and metastatic NSCLC demonstrate innate (primary) resistance to checkpoint inhibition and do not respond to initial therapy. There is thus an important unmet medical need of a curative treatment for this checkpoint inhibition-resistant population. We hypothesize that intra-tumoral/intralesional injection of NBXTR3 in the primary tumor or in one of the liver or lung metastases, followed by SABR may be a powerful mechanism to convert the local immune microenvironment to a “hot” phenotype and thus help to overcome resistance to immune checkpoint inhibition.

We have therefore designed an open label phase I/II, non-randomized clinical study of NBTXR3 activated by SABR in combination with PD-1 blockade in patients with recurrent or metastatic HNSCC, metastatic NSCLC , or liver metastasis*. The phase I primary objective is to determine the maximum tolerated dose(s), the early DLTs and the recommended dose(s) of NBTXR3. The Phase II primary objectives are Complete Response Rate of target lesion/s by RECIST v1.1 for the locoregional recurrent group, Objective Response Rate by RECIST v1.1 for the metastatic group, and safety and tolerability of SABR activated NBTXR3 in combination with anti-PD-1 at the recommended dose(s) in both groups.

The mode of action of first-in-class NBTXR3 has already been demonstrated in a phase II/III randomized trial in locally advanced soft tissue sarcoma patients. NBTXR3 activated by RT met both primary and main secondary endpoints and demonstrated a significant superiority in terms of clinical benefits compared to RT alone [NCT02379845]. The combination of NBTXR3 activated by SABR and PD-1 inhibition may therefore be able to improve patient response in advanced HNSCC and NSCLC.

*Metastatic patients must have received an approved anti-PD1 with SD for at least for 12 weeks or with confirmed PD at 12 weeks.

Summary

Background: Despite proven efficacy, a limited number of patients (pts) with recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) or metastatic non-small cell lung cancer (NSCLC) benefit from anti-PD-1 treatment. Indeed, most pts do not respond to initial therapy due to intrinsic re-sistance to checkpoint inhibition. There is thus an important unmet medical need for a curative treatment in these pts and converting the local immune microenvironment to a “hot” phenotype may help to overcome therapeutic resistance.

Hafnium oxide nanoparticles (NBTXR3) activated by radiotherapy (RT) increase radiation dose de-posit within cancer cells compared to RT alone. Recently, a phase II/III randomized trial of NBTXR3 in locally advanced soft tissue sarcoma (STS) met primary and main secondary endpoints with sig-nificant superiority compared to RT alone [NCT02379845]. Furthermore NBTXR3+RT demonstrated an immunogenic cell death-mediated abscopal effect in a pre-clinical setting, and immune cell infil-tration was observed in some tumors from STS pts treated with NBTXR3+RT but not in tumors from pts treated with RT alone. NBTXR3 is currently being evaluated in 7 clinical trials, including a phase I/II study in elderly frail patients with locally advanced HNSCC [NCT01946867]. To date, no early dose limiting toxicities (DLTs) have been observed.

Methods: Overall, these results have led us to evaluate NBTXR3 activated by stereotactic ablative radiothera-py (SABR) in combination with an approved anti-PD-1 antibody in an open label phase I/II, non-randomized clinical trial in pts with more advanced diseases: locoregionally recurrent or metastatic HNSCC, metastatic NSCLC, and liver metastasis pts [NCT03589339].

The phase I primary objectives are to determine NBTXR3 maximum tolerated dose(s), incidence of early DLTs and recommended dose(s). The phase II primary objectives are Complete Response Rate of target lesions and Objective Response Rate for the locoregional recurrent and the metastatic group respectively by RECIST 1.1, and safety/tolerability of treatment at the recommended dose(s).