First-in-Class NBTXR3 Provides a New Option for Preoperative Treatment in Patients with Locally Advanced STS (Act-In-Sarc)

More patients with locally advanced soft tissue sarcoma (STS) of the extremity and trunk wall who received treatment with NBTXR3 hafnium oxide nanoparticles activated by radiotherapyshowed a pathological response than patients treated with radiotherapy alone, according to findings presented at the ESMO 2018 Congress in Munich, Germany.

Sylvie Bonvalot, Head of the sarcoma surgery, Institut Curie in Paris, France presented the results of an international, multicentre, randomised, open-label phase II/III trial (NCT02379845) of a novel agent, NBTXR3, which is a first-in-class Hafnium-Oxide nanoparticle in patients with locally advanced STS of the extremity and trunk wall.         

Professor Bonvalot explained that this trial stemmed from a phase I study in STS, which showed that a single NBTXR3 intratumoural injection at 10% of the baseline tumour volume administered together with preoperative radiotherapy was technically feasible, with both clinical activity and manageable toxicity being demonstrated. 

In study NBTXR3-301, 180 patients were randomised, and 179 started treatment either with a single intratumoural injection of NBTXR3 followed by radiotherapy or radiotherapy alone. Following the ITT-FAS principle, 176 patients were considered for efficacy analyses. 

Both treatment arms received subsequent surgical resection and the patients were stratified according to STS histological subtype. Radiotherapy comprised Intensity Modulated Radiotherapy or 3D-Radiotherapy of 2Gy/25 fractions to a total of 50 Gy. 

The primary endpoint was the pathological complete response rate (pCRR), which was defined as the percentage of patients presenting <5% of residual viable cancer cells (EORTC guidelines), as evaluated by a blind Central Review Board (BCRB). Key secondary endpoints included negative surgical margins (R0), and safety. 

Twice as many patients show a response with NBTXR3/radiotherapy than radiotherapy alone 

In the 176 patients of the ITT-FAS population, those treated with NBTXR3/radiotherapy demonstrated a response that was double that seen with radiotherapy alone; the pCRR was 16.1% with NBTXR3/radiotherapy compared to 7.9% with radiotherapy (p = 0.0448).

The R0 rate in the respective groups was 77.0% versus 64.0% (p = 0.0424). 

In total 13.5% patients experienced injection-site pain and NBTXR3 was associated with grade 3/4 acute immune reactions in 7.9% patients. These adverse events were of short duration, manageable, and resolved spontaneously in some cases. 

Aside from the injection site reactions, NBTXR3/radiotherapy was very well tolerated and demonstrated a safety profile that was comparable to radiotherapy alone. 

Conclusions 

The investigators noted that NBTXR3 can be intratumorally injected and, following activation by radiotherapy, it provides a higher energy deposit than radiotherapy alone and yields increased tumour cell death. 

In this trial, NBTXR3 activated by radiotherapy was significantly superior to radiotherapy alone. In addition, a positive safety profile was demonstrated. 

This trial met both primary and main secondary endpoints. 

NBTXR3 represents a new option for preoperative treatment in patients with locally advanced STS, as well as for other cancer patients with radiotherapy indication. 

Findings from this trial support currently ongoing studies investigating NBTXR3 in recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) or metastatic non-small cell lung cancer (NCT03589339),  HNSCC (NCT01946867; NCT02901483), prostate cancer (NCT02805894), liver  cancer (NCT02721056), and rectal cancer (NCT02465593), according to the authors.

Disclosure

This trial was sponsored by Nanobiotix. 

Reference

LBA66 – Bonvalot S, Rutkowski PL, Thariat J, et al. A phase II/III trial of hafnium oxide nanoparticles activated by radiotherapy in the treatment of locally advance soft tissue sarcoma of the extremity and trunk wall.