Nanobiotix is claiming a victory for its nanoparticle therapy NBTXR3 in soft tissue sarcoma in the Act.In.Sarc study, which it hopes could pave the way for a European CE mark. And the company has its eye on a bigger prize – in yet another approach to turn “cold” tumours “hot”, the project will soon be combined with anti-PD-1 antibodies in the US.
However, there are major doubts about whether Act.In.Sarc was in fact a success. The study only just reached nominal statistical significance on its primary endpoint, and question marks over patients excluded from the final analysis, and the robustness of the threshold used to meet that significance, should give pause to investors who sent the French company’s stock up 50% today.
The group's backers are taking a punt on the theory that NBTXR3, which comprises nanoparticles made of hafnium oxide, could enhance the effect of radiotherapy, either alone or in combination with other agents such as PD-(L)1 antibodies or Parp inhibitors.
According to Nanobiotix, the Act.In.Sarc study results suggest that this approach has legs. The open-label trial compared NBTXR3 plus radiotherapy versus radiotherapy alone in 180 patients with locally advanced soft tissue sarcoma (STS) of the extremity and trunk wall. NBTXR3 was given as an intratumoural injection 24 hours before the start of a five-week course of radiotherapy.
Nanobiotix said the trial met its primary endpoint in an intent-to-treat analysis, with 16% of the NBTXR3-treated group achieving pathological complete response versus 8% in the control arm.
However, this only just met the nominal margin for statistical significance, with a p value of 0.0448 barely squeezing under the adjusted threshold of 0.04575 – and there were questions over how Nanobiotix had achieved even this narrow victory.
For a start, the company appears to have excluded some patients from its supposed intent-to-treat analysis: on a conference call today the group said its intent-to-treat population comprised 176 patients. However, it also confirmed that 180 had been enrolled, but did not explain what happened to the missing four patients.
With a p value that barely meets its threshold, these four patients could have made all the difference between failure and success. Nanobiotix called the primary endpoint effect "significant" in its press release, and "statistical" on the call, but stopped short of saying it was "statistically significant".
Even more worryingly, the company confirmed that the p value it tested for here was one sided, again without giving reasons for this.
Using two-sided p values is standard practice unless there are strong scientific arguments to the contrary. A threshold of 0.05 can still be set for a one-sided p value, but this makes statistical significance twice as likely to be hit than if applying a two-sided p value threshold of 0.05.
Enough for the EU?
These results might be enough to support a CE mark for the project – this regulatory pathway, used for medical devices, usually only requires products to demonstrate safety. Still, Nanobiotix has been waiting a long time to reach this milestone – it first applied for the CE mark in 2016.
But presumably FDA approval, particularly alongside immuno-oncology agents, would be a tougher task.
Nanobiotix is soon to start a phase I/II trial combining NBTXR3 with either Opdivo or Keytruda, with the aim of turning checkpoint inhibitor non-responders into responders. This study, NBTXR3-1100, will include patients with relapsed head and neck cancer or NSCLC.
The company also has various other trials of NBTXR3 ongoing, mainly looking at NBTXR3 and radiotherapy alone; however, some have added chemotherapy to the mix.
For now, investors appear to have taken Nanobiotix’s claims of victory at face value. With more studies reading out in the near future the validity of these could soon be put to the test.
|Indication||Study details||Trial ID||Primary completion|
|Soft tissue sarcoma||Phase II/III trial in Europe/Asia (Act.In.Sarc)||NCT02379845||Reported|
|Liver cancer||European phase I/II trial||NCT02721056||Jun 2017|
|Head & neck cancer||European phase I trial||NCT01946867||Aug 2017|
|Rectal cancer||Asia phase I/II trial, plus chemo||NCT02465593||Dec 2017|
|Head & neck cancer||US phase I/II trial, plus chemo||NCT02901483||Nov 2018|
|Prostate cancer||US phase I/II trial, +/- brachytherapy||NCT02805894||Nov 2020|
|Note: All trials evaluate NBTXR3/radiotherapy combo. Source: Clinicaltrials.gov.|