Paul Barr, MD, Wilmot Cancer Institute, University of Rochester Medical Center, New York, shares 6-year follow-up data from patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) treated with ibrutinib on the RESONATE study.

Transcript

This is Paul Barr. I work at the University of Rochester and the Wilmot Cancer Institute. I'm an Associate Professor of Medicine. I'm reporting on the final analysis of the RESONATE trial 6-year follow-up, a randomized clinical trial comparing Ibrutinib and ofatumumab in previously treated CLL (chronic lymphocytic leukemia) and SLL patients. This data was presented at the 2019 ASCO meeting.

The first question, "What existing data led you and your investigators to study Ibrutinib in patients with CLL or SLL?"

Well, this clinical trial was designed several years ago. At the time, there were phase 1 and phase 2 preliminary data sets that suggested in patients with CLL, who had been previously treated, that ibrutinib was safe and very effective. We had learned at that time, that it was best to administer ibrutinib when used as a single agent until disease progression on a daily basis.

Also, at that time, we saw there really wasn't any severe toxicity that was happening frequently. So, it looked very promising, to say the least. This clinical trial, again, was called the RESONATE study. The initial intent was 2-fold really to justify approval of ibrutinib in relapsed/refractory CLL patients. And to compare it against, at that time, arguably a standard of care, ofatumumab.

The clinical trial initially enrolled 391 patients with previously treated CLL or SLL, they had received greater than one prior therapy and were not candidates for other chemotherapy options at that time. Patients were randomized to oral ibrutinib or IV ofatumumab over 24 weeks. When patients ultimately progressed later on in the study, they were allowed to cross over to ibrutinib and about 68% of patients ultimately did that.

Very early on, you could see a dramatic difference between ibrutinib and ofatumumab. Ibrutinib provided a much higher response rate in progression free survival and to speak bluntly, that's kind of old news. I think everyone… that's very well appreciated.

The major intent of this data cut presented at ASCO was to look at the long-term follow up. To appreciate how long the ibrutinib-treated patients are responding, and to ensure that there isn't any additional toxicity.

At this data cut, the median treatment duration was 41 months for the ibrutinib-treated patients. Median follow up was 65 months, so pretty mature data. Again, cut to the chase: there was a markedly better progression free survival for the Ibrutinib-treated patients. Again, that's expected. The median PFS was 44 months.

This is in a group of patients that are very high risk. More than half of these patients had TP53 aberrations, either a deletion 17P or an actual mutation. So very high-risk group, median PFS 44 months. A similar PFS was seen in the high-risk patients when you focus on those with deletion 17p, 11q or unmutated Immunoglobulin heavy-chain genes. They seem to do equally as well. As we previously demonstrated, those that have mutated or unmutated heavy-chain genes, they seem to have equally durable remissions.

Beyond that, we showed that at this later time point, the complete remission rate continues to go up and is at about 11%. Again, not the depth of remission that we're seeing with combinations, but it is interesting to see that even with single agent ibrutinib, some patients can achieve a complete remission. Nonetheless, about 91 percent of patients responded either a partial or complete remission.

The overall survival, the median, at this point is 67 months with Ibrutinib. Again, that's pretty remarkable in such a high-risk group, this is much more dramatic than -- much better I should say -- than what we would expect in the days prior to targeted agents.

Lastly, it's reassuring to see that there isn't cumulative toxicity over time for the most part. Without a doubt, patients on ibrutinib still have a risk of atrial fibrillation. It's in the 10% range roughly over many years. There certainly is a risk of bleeding, but that rate remains fairly low as well. One side effect that seems to continue to increase over time is hypertension. For the most part, this is pretty manageable and easy to monitor for.

In summary, I think the data we presented at ASCO really demonstrates that with 6 years follow up, we now have a good understanding of the durability of responses with ibrutinib in this patient population, that we're also seeing the same thing in the high-risk patients, and that the safety profile remains very acceptable.

The last question, "What are the possible real-world applications of these findings in clinical practice, and how will they affect the treatment landscape?"

Well, this trial supported the approval of ibrutinib in the relapsed refractory setting. That obviously changed our standard of care.

Since that time, subsequent studies have supported its approval and further use in the first-line setting. Most recently, we've demonstrated superiority over chemoimmunotherapy regimens. So ibrutinib and the other targeted agents, small molecule inhibitors, are really starting to dominate the treatment landscape, really replacing chemotherapy across the board.

I think going forward, what we will see is more and more novel combinations, combining BTK inhibitors, with BCL-2 inhibitors and anti-CD20 agents. Attempting to achieve deep remissions with these combinations and hopefully give patient treatment breaks.

Coming back to this data set that we presented, I think one take-home that I keep in mind is that some patients are served very well with long-term use of single agent ibrutinib. So, I think this has been very clinically relevant and remains very clinically relevant.