ASH 2023 | FLAIR trial: improved outcomes with MRD-guided ibrutinib plus venetoclax in CLL compared to FCR

So, at ASH this year we’re going to see the first results of the MRD-directed treatment of ibrutinib plus venetoclax versus FCR. So, an important randomization from the UK NCRI FLAIR trial. So to update you about the FLAIR trial, this is an adaptive trial design with multiple experimental arms in this study. And the control arm, the initial control arm, was FCR, a regimen we’re very used to using historically over many years in CLL. 

The investigation arm ibrutinib plus venetoclax is given in an MRD-guided fashion, so the therapy length of the ibrutinib plus venetoclax is defined by the time it takes somebody to reach MRD-negativity. And this is a very different phenomenon to what we’ve been used to with ibrutinib plus venetoclax where the licensed and approved therapy is ibrutinib plus venetoclax in combination for a total of 15 months -three months of ibrutinib, 12 months of the combination. Whereas the ibrutinib plus venetoclax in this study, it’s delivered and MRD is tested as time goes by and if patients were, MRD-negative, by the time they reach MRD-negativity effectively their time on I plus V is double the time it takes them to reach formal MRD-negativity approximately. So, that is a novel approach to giving BCL2/BTK combinations. 

Now, the primary endpoint of this study has read out and at ASH this year, we’re going to see data showing that ibrutinib plus venetoclax given in this mode of therapy, so MRD-directed, results in extremely good outcomes. The four year progression-free survival is nearly 94% and that’s as good as anything we’ve ever seen, really, in frontline CLL in terms of disease control at four years, versus FCR four year progression-free survival of about 65%. And that’s consistent with historical data with FCR. There’s an overall survival advantage for the I plus V arm given in this fashion, 95% OS at four years versus 87% with the FCR arm, hazard ratio of 0.31 and that’s strongly statistically significant. So the importance here is that on a national basis, on a national scale, in a big randomized clinical trial, MRD-guided therapy was possible and proved superior to chemoimmunotherapy and, you know, it has the potential to be superior to fixed-duration therapy. And so this will, I’m sure, cause a great deal of discussion at ASH. Very exciting data and I look forward to seeing the formal presentation.