CAPTIVATE is a study that has been performed in order to assess the combination of two drugs, the BTK inhibitor ibrutinib in combination with a BCL2 inhibitor venetoclax. This study was based on some preclinical experiments that clearly showed that these two different drugs have a complementary mechanism of action that will allow to act in CLL in the different compartments of CLL, not only in peripheral blood but also in the lymph nodes and in the bone marrow. Therefore, this study was performed in combination with these two drugs, starting with three cycles of ibrutinib at the beginning and then followed by the combination of ibrutinib plus venetoclax given for twelve cycles and to stop therapy in these patients after 15 cycles in total after giving these two drugs.
What was the methodology of the study?
We included patients, previously untreated patients, with CLL younger than 70 and independent of if they had high risk features such as, for example unmutated IGHV genes or TP53 aberrations. So we have this population included in this trial.
This is a phase II trial in which in this fixed duration cohort by giving 15 cycles of therapy with this combination, we stop therapy and then we look at the primary endpoint of the study which was the rate of complete response achieved after giving this combination. There was another cohort in which that was performed according to the MRD status in which the patients were randomised according to their MRD status after these 15 cycles and, according to that, patients who had unconfirmed minimal residual disease undetectable or confirmed undetectable minimal residual disease, they were receiving different strategies.
But what we are focussing now today, and that has been presented at EHA this year, has been the fixed duration cohort in which we combined the two drugs given for a total of 15 cycles.
What were the key findings?
The key results of this study, if we look at the primary analysis that was published and that was presented last year with two years of follow-up, we observed that there was a high complete response rate by giving this combination which was near 60%, independent of the high risk features that the patients had, unmutated IGHV or TP53 aberrations. What we have confirmed with one more year of follow-up, which means two years after stopping this combination of therapy, is that the patients’ CR rate, the complete remission rate, improves a little bit and is independent of these high risk features that are present in patients with CLL such as unmutated IGHV and TP53 aberrations. What is more important is that the response was maintained even after one more year of follow up. This is translated into a longer progression free survival and clearly we can see that independent of the high risk features we are seeing that the PFS at 36 months is more than 85% of the patients are free of progression and even in patients with unmutated IGHV could do very well under this combination and slightly worse in those patients with TP53 aberrations.
So the main message is that with a time-limited therapy with these two drugs we are able to improve clearly the quality of the remission and that allows us to stop therapy in this population and we are seeing a maintained benefit after stopping the combination. After three years the patients are still, most of them, free of progression and obviously they are still alive.
How could these results affect the future treatment of CLL?
This combination is still not approved yet but once approved this is a great combination in the front line setting in order to treat CLL patients independent of the high risk features with a chemo-free regimen taking advantage of these two drugs which allows to act not only in the peripheral blood, as we have seen, but also at the lymph node sites and also in the bone marrow. So, all in all, this has given us a strategy, a time-limited therapy strategy for CLL patients in the front line setting in a young CLL population, including patients with high risk features such as those with unmutated IGHV and also the population with TP53 aberrations may also benefit from this combination given this treatment just only for a year.
What did you see in terms of safety?
In terms of the safety profile, I must say that this combination is very well tolerated since we are talking about stopping therapy so we are not seeing a high frequency of adverse events. Probably what is more important is that those patients who have already progressed after time-limited therapy with ibrutinib plus venetoclax, the option of retreating these patients with a BTK inhibitor seems to be very promising. Also there are a few patients who have already progressed under prior therapy and in this final analysis we have only 12 patients who were re-treated with ibrutinib. So what we are seeing, although the follow-up is still short, is that these patients respond again to a retreatment with the BTK inhibitor given as monotherapy.
So, all in all, this is giving us the view that by starting treating CLL patients with a time-limited therapy we probably can avoid mechanisms of resistance and then we have the option once they progress to retreat again with the same combination or with any of the drugs that we have used in the front line setting.