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

Doubling complete histological response in sarcomas with radiation therapy using nanoparticles (Hafnium oxide, NBTXR3), a phase III trial

Summary

Background: Pathological complete response to preoperative treatment in adults with soft-tissue sarcoma can be achieved in only a few patients receiving radiotherapy. This phase 2–3 trial evaluated the safety and efficacy of the hafnium oxide (HfO2) nanoparticle NBTXR3 activated by radiotherapy versus radiotherapy alone as a pre-operative treatment in patients with locally advanced soft-tissue sarcoma.

Methods: Act.In.Sarc is a phase 2–3 randomised, multicentre, international trial. Adults (aged ≥18 years) with locally advanced soft-tissue sarcoma of the extremity or trunk wall, of any histological grade, and requiring preoperative radiotherapy were included. Patients had to have a WHO performance status of 0–2 and a life expectancy of at least 6 months. Patients were randomly assigned (1:1) by an interactive web response system to receive either NBTXR3 (volume corresponding to 10% of baseline tumour volume at a fixed concentration of 53·3g/L) as a single intratumoural administration before preoperative external-beam radiotherapy (50 Gy in 25 fractions) or radiotherapy alone, followed by surgery. Randomisation was stratified by histological subtype (myxoid liposarcoma vs others). This was an open-label study. The primary endpoint was the proportion of patients with a pathological complete response, assessed by a central pathology review board following European Organisation for Research and Treatment of Cancer guidelines in the intention-to-treat population full analysis set. Safety analyses were done in all patients who received at least one puncture and injection of NBTXR3 or at least one dose of radiotherapy. This study is registered with ClinicalTrials.gov, number NCT02379845, and is ongoing for long-term follow-up, but recruitment is complete.

Findings: Between March 3, 2015, and Nov 21, 2017, 180 eligible patients were enrolled and randomly assigned and 179 started treatment: 89 in the NBTXR3 plus radiotherapy group and 90 in the radiotherapy alone group.Two patients
in the NBTXR3 group and one patient in the radiotherapy group were excluded from the efficacy analysis because they were subsequently discovered to be ineligible; thus, a total of 176 patients were analysed for the primary endpoint in the intention-to-treat full analysis set (87 in the NBTXR3 group and 89 in the radiotherapy alone group). A pathological complete response was noted in 14 (16%) of 87 patients in the NBTXR3 group and seven (8%) of 89 in the radiotherapy alone group (p=0·044). In both treatment groups, the most common grade 3–4 reatment-emergent adverse event was postoperative wound complication (eight [9%] of 89 patients in the NBTXR3 group and eight [9%] of 90 in the radiotherapy alone group). The most common grade 3–4 adverse events related to NBTXR3 administration were
injection site pain (four [4%] of 89) and hypotension (four [4%]) and the most common grade 3–4 radiotherapy-related adverse event was radiation skin injury in both groups (five [6%] of 89 in the NBTXR3 group and four [4%] of 90 in the radiotherapy alone group). The most common treatment-emergent grade 3–4 adverse event related to NBTXR3 was hypotension (six [7%] of 89 patients). Serious adverse events were observed in 35 (39%) of 89 patients in the NBTXR3 group and 27 (30%) of 90 patients in the radiotherapy alone group. No treatment-related deaths occurred.

Interpretation: This trial validates the mode of action of this new class of radioenhancer, which potentially opens a large field of clinical applications in soft-tissue sarcoma and possibly other cancers.