Paul M. Barr, MD, Wilmot Cancer Institute, University of Rochester Medical Center, New York, shares 7 years of follow-up results from the RESONATE-2 study of first-line ibrutinib treatment versus chlorambucil in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), the data of which were presented at the virtual 2021 American Society of Clinical Oncology (ASCO) Annual Meeting.

Transcript

I am Paul Barr from the University of Rochester in Rochester, New York. I am a lymphoma investigator. I am happy to present the results of the RESONATE-2 study at this year's ASCO meeting.

This study was designed and initiated many years ago. We are now presenting the long-term follow-up of this randomized trial. At the time the study was designed, we had early data that ibrutinib, a BTK inhibitor, was very effective for patients with relapsed/refractory disease. This study was conceived to better understand how well it worked in the first-line setting, and ultimately led to FDA approval for patients who were previously untreated with CLL.

We have presented periodic results of this study pretty much yearly since the initial results were released. The main impetus for this year's presentation is to understand the long-term outcomes.

The RESONATE-2 study enrolled patients with previously untreated chronic lymphocytic leukemia, randomized them to chlorambucil or ibrutinib. We previously observed a progression-free and overall survival benefit for the patients who received ibrutinib, but this again led to FDA approval years ago.

Now, we have more than 6 years of median follow-up, 6.2 years is the exact median follow-up of up to 7 years. What we can see at this point is that under half of patients still remain on ibrutinib taken daily, 47 percent to be exact. The primary reasons for stopping were primarily side effects in about a quarter of patients. Only a small amount have had disease progression, 12 percent so far.

Interestingly, we have not seen the median progression-free survival, meaning that half of patients have not progressed at this point. The PFS estimate at 6 and a half years is 61 percent. This tells us that patients continue to do well. It takes an awful long time to understand how well this therapy and some of the other novel agents work, which is a good problem to have. Patients continue to do very well.

Beyond that, we can see responses continue to deepen with time. About a third of patients have achieved a complete response. There are no new safety signals, meaning that we are not seeing cumulative toxicity this late. There have not been any leak surprises.

Interestingly, more than half of patients were able to receive gastric acid-reducing medications. This is important because some other agents that are in the same class have interactions with this category of medications.

Overall, obviously favorable outcomes. We are going to have to continue to monitor these patients even longer to understand what the real duration of benefit is.

I honestly think these results are directly applicable to clinical practice. Again, because this is such a long-running study, there have been many subsequent trials that are now investigating ibrutinib in combination with other novel agents, other BTK inhibitors, to understand what the toxicity profile and duration of benefit is.

We have many patients that are on single-agent ibrutinib. It comes up all the time in the clinic, the question being, "How long do we expect this agent to work? Might we encounter unforeseen toxicities?" I think we can safely say that patients, depending on the risk profile, can achieve many years of remission.

Again, we still have not gotten to the median PFS from this study. No new safety signals, so patients who are responding well to ibrutinib can be reassured that with continued use, they can continue to derive significant benefit and know that the agent continues to be safe long term.

As I mentioned previously, there are many next steps, to be [laughs] honest. Ibrutinib and other BTK inhibitors have completely changed how we treat chronic lymphocytic leukemia. This agent and others essentially relegated chemotherapy to the history books, so to say. We have completely changed our practice.

Ongoing next steps are investigating ibrutinib in combination with venetoclax and other novel agents to develop limited-duration treatment paradigms. Many of those studies are ongoing, and not surprisingly, the combinations look very effective.

In addition, there are a number of, so to speak, next-generation BTK inhibitors. To date, all of these agents look incredibly promising and have very favorable toxicity profiles. I do think that this study and the ones after it will continue to refine how we treat patients as the years to come.

Another comment I will make is that with the development and approval of ibrutinib, not only have we seen other classes of agents developed for chronic lymphocytic leukemia such as venetoclax, the approved BCL-2 inhibitor, other investigational BCL-2 inhibitors, the anti-CD20 antibodies, PI3K inhibitors.

We are also now seeing further development of additional BTK inhibitors. At times, for perhaps community practitioners, it can be confusing of, "With all these new agents, exactly how do we sequence them and fit them into the treatment paradigms?"

I would say, for patients, this is again, maybe a good way to put is, a good problem to have. Lots of new, very effective, well-tolerated agents that we continue to test further and develop new combinations.

With all of this in mind, I do think that we will continue to see changes year by year, study by study, as we learn more about how to apply these agents in the most effective and safest manner possible.