NBTXR3, a first-in-class radioenhancer hafnium oxide nanoparticle, plus radiotherapy versus radiotherapy alone in patients with locally advanced soft-tissue sarcoma (Act.In.Sarc): a multicentre, phase 2-3, randomised, controlled trial
The primary report of Act.In.Sarc: a single injection of hafnium oxide nanoparticles before preoperative radiotherapy doubled the share of sarcomas with a pathological complete response, from 8 to 16 percent.
Overview
Phase 2-3 randomised, multicentre, international, open-label trial in adults with locally advanced soft-tissue sarcoma of the extremity or trunk wall requiring preoperative radiotherapy. Patients were randomised 1:1, stratified by histological subtype (myxoid liposarcoma versus others), to a single intratumoural administration of NBTXR3 (volume 10 percent of baseline tumour volume at 53.3 g/L) before external-beam radiotherapy of 50 Gy in 25 fractions, or radiotherapy alone, followed by surgery. The primary endpoint was pathological complete response by a central pathology review board under EORTC guidelines in the intention-to-treat full analysis set.
Between March 2015 and November 2017, 180 eligible patients were randomised and 179 started treatment (89 NBTXR3, 90 radiotherapy alone); 176 were analysed for the primary endpoint after three were found ineligible. Pathological complete response was noted in 14 of 87 (16 percent) in the NBTXR3 group and 7 of 89 (8 percent) with radiotherapy alone (p=0.044). Postoperative wound complication was the most common grade 3 to 4 event in both groups (9 percent each); serious adverse events occurred in 39 versus 30 percent, with no treatment-related deaths.
- Pathological complete response 14 of 87 (16%) with NBTXR3 plus radiotherapy vs 7 of 89 (8%) with radiotherapy alone (p=0.044).
- 180 patients randomised at international centres between March 2015 and November 2017; 176 analysed for the primary endpoint.
- Grade 3 to 4 events related to NBTXR3 administration: injection site pain 4%, hypotension 4%; serious adverse events 39% vs 30%; no treatment-related deaths.
This trial validated the radioenhancer mode of action and supported the 2019 European CE mark for NBTXR3 (Hensify) in soft-tissue sarcoma. Whether more pathological complete responses translate into fewer recurrences or longer survival was not shown here; the 2022 follow-up paper reported more R0 resections and no harm to quality of life.
- Open-label; pathological complete response is a surrogate, and the trial was not powered for recurrence or survival.
- The absolute difference is 8 percentage points with a p value of 0.044.
- Serious adverse events were more frequent with NBTXR3 (39% vs 30%).