Expert Perspective on RESONATE-2 Findings and the Value of Long-term Data for Single-Agent BTK Inhibitors

For roughly the past 10 years, Bruton tyrosine kinase (BTK) inhibitors have played a central role in the treatment of chronic lymphocytic leukemia (CLL), both as single-agent therapies and in combination with other mechanisms. As the utilization of BTK inhibitors expands, it is important to continue to investigate the long-term safety and efficacy of these agents.

Up to 7 years of follow-up data from the RESONATE-2 trial were presented at the American Society of Clinical Oncology (ASCO) 57th Annual Meeting, Virtual Edition. The findings, representing the longest to date for a BTK inhibitor, showed that single-agent ibrutinib conferred sustained benefits in overall survival (OS) and progression-free survival (PFS).

Ahead, Paul M. Barr, MD, associate professor of Medicine and director of the Clinical Trials Office for the Wilmot Cancer Institute at the University of Rochester Medical Center in Rochester, New York, discusses key takeaways from the follow-up data and reflects on the clinical and practical implications of the 7-year findings.

Targeted Oncology™: Could you share your perspective on the evolution of the BTK class, and the role of these agents in the treatment of CLL?

Barr: BTK inhibitors have revolutionized how we take care of patients with CLL. I think every investigator would agree with that. This was the first class of agents that were approved since predominantly using chemoimmunotherapy, and we quickly saw patients without treatment options responding very well with little toxicity. Over time, this class of agents has become a standard of care in the relapsed and front-line settings starting with ibrutinib. There are subsequent, more specific second-generation BTK inhibitors including acalabrutinib, now approved for CLL as well. Zanubrutinib as well as pirtobrutinib, a non-covalently binding BTK inhibitor, are showing promise as well. Without a doubt, the class is here to stay, and I think it's a fair statement that nearly all CLL patients requiring therapy receive BTK inhibitors at one stage or another.

Targeted Oncology: Can you talk about the results of the 7-year follow-up on the RESONATE-2 trial, and what these findings convey about long-term survival and progression in patients treated with ibrutinib?

Barr: The RESONATE-2 study was a randomized trial comparing first-line ibrutinib to chlorambucil in 269 patients who were either younger than 65 or had comorbidities that prevented the use of chemoimmunotherapy. After a median of 6.2 years of follow-up, more than half of patients continue to receive single-agent ibrutinib, and 47% continue treatment at current follow-up.

The PFS estimate at 6.5 years is 61%, and we see similar outcomes for ibrutinib treated patients with certain high-risk markers—including deletion 11q and those with unmutated immunoglobulin heavy chain genes. Additionally, the OS benefit over chlorambucil remains.

Regarding adverse events (AEs), there were no new concerns. If you look at the events of clinical interest—such as hypertension, arrhythmias, major hemorrhage—the rates in year 6 and 7 remain low overall. Another important point to make is that over half of patients received acid-reducing agents, and in most cases, these were proton pump inhibitors.

Overall, I think the study is important because it has the longest follow-up of all first-line BTK studies, and it continues to show the sustained PFS benefit [associated with ibrutinib]. The duration of disease control is really unprecedented compared to what we were used to with chemoimmunotherapy. Also, ibrutinib remains well tolerated, with no new safety signals observed.

Targeted Oncology: One of the notable findings of the follow up data is depth of response, with an increase in complete response. Can you talk about the relevance of these findings and their implications for treatment?

Barr: The response rate at this time point is 92%, with 34% of patients having achieved a complete response. I think most investigators feel that response rate with single-agent ibrutinib isn't the most critical measure of the drug's efficacy. Even though we're not achieving very deep responses, the duration of benefit, the PFS is very prolonged. This data is particularly relevant as we think about combinations. If we were to use BTK inhibitors in a fixed-duration treatment model, they have to be combined with other agents, given the lack of response depth alone.

Targeted Oncology: Given that this is the first BTK inhibitor to have such long-term data, what's the importance of the safety tolerability findings of this follow-up data?

Barr: It's critical to show that ibrutinib is well-tolerated long-term. Given prolonged use when being used as a single agent, demonstrating a lack of long-term or cumulative toxicity is important. This is obviously what limited many of our cytotoxic agents, so to see an agent like this being well-tolerated many years out is gratifying.

The other thing to keep in mind is that while the AEs are low, it's important to know what to watch for and what to inform patients about. We need to monitor for hypertension and help primary care physicians manage it. We should inform patients about the bleeding risk, especially to hold ibrutinib prior to invasive procedures, and we have to think about patients’ cardiovascular risks given the potential for atrial fibrillation.

Targeted Oncology: As more BTK agents enter this landscape, what is the value of durability of safety and efficacy when it comes to the use of targeted therapies such as BTK inhibitors, and what can we learn about these agents and CLL more broadly by studying them long-term?

Barr: The long-term data show us that the degree of immunosuppression is fairly minimal with BTK inhibitors. We do not see—as you might expect from the drug's mechanism—a long-term increase in infectious complications, especially in patients who are already prone to such events. It's also important as we think about investigating new combinations. Ibrutinib and the other BTK inhibitors lend themselves well to combining with other classes of drugs, like BCL-2 inhibitors and anti-CD20 agents.

Targeted Oncology: As the BTK landscape continues to evolve, can you discuss the challenges and opportunities that remain, and what you would like to see emphasized in the continued study of ibrutinib and BTK inhibitors more broadly?

Barr: We've seen a sea change in how we treat CLL patients, not only with BTK inhibitors, but with venetoclax, the only BCL-2 inhibitor approved, the anti-CD20 agents, as well as other investigational strategies like chimeric antigen receptor T-cell therapy. Many challenges remain. It still is difficult to treat the highest risk patients. Even though we have these great agents, some of these patients fail our standard treatment options, so that certainly is an unmet need. We would like to keep moving towards a cure for this disease, so we need to continue studying combinations, ideally of fixed duration, so that we can achieve very deep remissions. I think that that's really what the emphasis should be, understanding how best to use these agents, and what combinations are most useful for our patients.