The CAPTIVATE study is a frontline study for patients with chronic lymphocytic leukaemia younger than 70 where patients received three months of ibrutinib single agent and then twelve cycles of combination therapy. They were evaluated for their MRD status at the end of the twelve cycles of combination therapy. Patients who were confirmed as undetectable MRD, and confirmed undetectable MRD required two determinations to be undetectable separated by three cycles, and undetectable MRD in blood and bone marrow at 10-4 sensitivity which was evaluated by 8-colour flow cytometry. Patients who were confirmed undetectable were randomised to receive continued single agent ibrutinib versus placebo. Patients who were not confirmed as undetectable MRD were randomised to continued combination therapy with ibrutinib plus venetoclax versus ibrutinib single agent.
The primary endpoint of the study and the primary endpoint that I’ll be presenting is the one year disease free survival for the confirmed undetectable cohort comparing the patients who received placebo versus continued ibrutinib single agent.
Patients were stratified in the randomisation in both arms by IGHV mutation status. Disease free survival was defined as patients who did not relapse with regard to their MRD and MRD relapse in this definition required a rise in their MRD measurement to 1% or higher from undetectable or clinical progression of disease or death by any cause.
The primary results confirmed that there was not a difference in one year disease free survival between the placebo arm versus patients who continued ibrutinib single agent at the one year disease free survival follow-up. There are additional analyses that we’ll be presenting, for example, the MRD status for the unconfirmed group between the two treatment arms and safety data as well. We did not identify any safety signals with this study. We do see with the unconfirmed MRD arm there are patients who continue on treatment and there are patients who have improved their response with the continued treatment.
Can you explain some of the key results?
The key results are for the confirmed undetectable MRD arm. Patients were randomised to receive either placebo or continued ibrutinib monotherapy. The one year disease free survival was not statistically significantly different between the two treatment arms. The placebo arm had a one year disease free survival rate of 95%; the one year disease free survival rate for the continued ibrutinib single agent was 100%. Again, one year disease free survival was defined as patients who did not relapse with regard to their MRD to a level of greater than 1% in the blood and did not have progressive disease and patients needed to be alive at that one year time point.
That is the primary endpoint of the study and, again, other endpoints will be presented such as safety as well as reduction in tumour lysis risk with the three cycle lead-in of ibrutinib single agent, particularly reduction in the high risk for TLS with venetoclax initiation going significantly down with ibrutinib, three cycles of monotherapy or single agent, prior to venetoclax initiation. Other endpoints will be MRD rate in the unconfirmed MRD cohort between the two treatment arms, those being ibrutinib monotherapy continued versus ibrutinib plus venetoclax.
How can these results impact the future treatment of CLL?
Targeted therapy, having significantly changed the landscape of how we manage patients. This trial is a multicentre study, actually an international study with combination therapy which demonstrates a very high rate of undetectable MRD in patients who received the one year of combination therapy or twelve cycles of combination therapy.
The take-home message from this study is that for those patients who have confirmed undetectable MRD if we stop treatment and give a fixed duration of treatment, at least the one year disease free survival as we’ve defined it in this study, is not different for patients who continued ibrutinib single agent versus placebo. So we have data now that supports a rationale for giving fixed duration treatment with an expectation of a reasonably long duration of response with discontinuation of treatment.
So this is a large study that’s a multicentre study that has demonstrated activity with combined targeted therapy with very deep remissions and a disease free survival, as we’ve defined it, which is significant, including for patients who are discontinuing treatment.