Nirogacestat success for desmoid tumours

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Published: 10 Sep 2022
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Dr Bernd Kasper - Universitätsmedizin Mannheim, Mannheim, Germany

Dr Bernd Kasper speaks to ecancer on his study of the DeFi trial’ a phase 3, randomised controlled trial of nirogacestat versus placebo for progressing desmoid tumours (DT).

DeFi is a global, Phase III, randomised, double-blind, placebo (pbo)-controlled trial in adults with progressing DT per RECIST v1.1

The results demonstrated significant PFS improvement of Niro compared with pbo. ORR was significantly improved with niro versus pbo, with a median time to response of 5.6 versus 11.1 months.

Niro demonstrated statistically and clinically significant improvements in PFS, ORR, symptom burden, physical/role functioning, and health-related quality of life and had a manageable safety profile in adults with progressing DT.

The background of my study is that we are actually testing a gamma-secretase inhibitor named nirogacestat in desmoid tumours. Desmoid tumours are, first of all, a rare disease; desmoid tumours are locally aggressive and invasive soft tissue tumours that are actually difficult to treat because they have a very different presentation, a very unpredictable clinical course often, and the problem is that we do not have any FDA or other health authority approved treatment for these tumours.

What was the methodology behind the study?

The trial is called the DeFi trial which stands actually for desmoid fibromatosis, which is another abbreviation for desmoid tumours. It is a large global randomised phase III placebo-controlled trial which actually tested the efficacy and, of course, also safety and tolerability in desmoid tumour patients who progressed, according to RECIST that means we had to have at least a 20% increase in their tumour size.

What were the key findings of the study?

The primary endpoint of that trial was progression free survival which was actually met. We saw an improved progression free survival with a statistically significant 71% reduction in the risk of disease progression. That was very clear and the median PFS in the placebo arm was 15.1 months and was not even reached with nirogacestat due to the very low number of events. If you look at the curves they separate very early and you can see the separation over the time. 

So that was the primary endpoint but, of course, we also had a couple of secondary endpoints. There was objective response rate – the confirmed objective response rate which was assessed by central blinded review was 41% with nirogacestat and 8% in the placebo arm. That was again highly statistically significant and we had 7% complete responses with nirogacestat.

Another important point is the time to response; that was 5.6 months with nirogacestat and about 11 months with placebo. Then there are even more results and maybe these results are even more important for the patients than the actual response rate or the PFS, these are the patient-reported outcomes. We did a lot of efforts in capturing patient-reported outcomes by using a variety of different patient-reported outcomes tools. We looked at pain, we looked at desmoid tumour-specific patient reported outcome tools – we used the EORTC QLQ-C30, which is, of course, very established. Interestingly, all these tools very consistently all showed an improvement, a statistically significant improvement for the patients who were on nirogacestat.

Can you explain the toxicity report for this study?

The toxicity, in terms of safety the drug was well tolerable overall. 95% of all the adverse events were grade 1 or 2 and most of these adverse events occurred very early, so during the first treatment cycle. The most frequent adverse events we had with nirogacestat were diarrhoea, rash, hypophosphatemia and stomatitis but that was usually very well manageable.

How do you think these results can impact future treatment of desmoid tumours?

The biggest thing about the trial is, of course, that it’s a clearly positive trial which forms the basis, actually, for a registration or an approval of a new drug in this entity. It’s actually the first trial that has been conducted so rigorously and straightforward, that we have a clear positive result for nirogacestat. So it can be the basis for a registration and for an approval by the FDA or by the EMA then. That would be the first approved drug in this indication.