Chronic Lymphocytic Leukemia Treatment Demonstrates Long-term Efficacy

Jim Dean, MD, PhD, Imbruvica global development lead and executive medical director, AbbVie, discusses data from the RESONATE-2 study showing that single-agent ibrutinib (Imbruvica) improved progression-free and overall survival for up to seven years in patients with chronic lymphocytic leukemia, compared to the standard of care.

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Welcome back to PopHealth Perspectives, a conversation with the Population Health Learning Network where we combine expert commentary and exclusive insight into key issues in population health management and more.

Today, we are joined by Dr Jim Dean, Imbruvica global development lead and executive medical director at AbbVie.

He discusses data from the RESONATE-2 study showing that single-agent ibrutinib improved progression-free and overall survival for up to seven years in patients with chronic lymphocytic leukemia, compared to the standard of care.

Dr Dean?

Hi. My name is Jim Dean. I am an executive medical director and the global development lead for Imbruvica and pediatrics with Pharmacyclics and AbbVie oncology development. I trained as a medical oncologist, I have an MD and a PhD, and I have experience in both clinical and laboratory research in the oncology space.

Can you talk a bit about the previous data that led investigators to conduct the RESONATE-2 study?

The RESONATE-2 study was initiated on the basis of early-phase studies and a large phase 3 study in the relapsed refractory setting for patients with CLL. In these studies of patients with CLL and other indications, the activity of ibrutinib was really groundbreaking.

The substantial benefit led the team to believe that ibrutinib could potentially provide benefit to patients who had not had prior treatments for their CLL. This was the existing data that led to the initiation of RESONATE-2.

Can you briefly describe the study itself, including any outcomes that stood out?

Yeah, I'm happy to. RESONATE-2 was the initial and pivotal study of ibrutinib demonstrating benefit for Imbruvica as a single agent in patients with previously untreated CLL.

The study was designed as a comparison with chlorambucil single-agent. It was primarily tested in older patients for whom, at the time, chlorambucil was one of the standards of care.

Initial results with about 18 months of follow up demonstrated highly significant progression-free survival and, in fact, also demonstrated an overall survival benefit for patients receiving Imbruvica compared to chlorambucil.

With the current report of RESONATE-2, we provided updates to both efficacy and safety. At this report, with up to seven years of follow up, the median progression-free survival has not yet been reached for these patients with previously untreated CLL who were randomized to Imbruvica.

More than half of these patients are alive and without relapse of their CLL, and complete response rates continue to increase.

One thing that's very exciting is that this PFS benefit is actually very similar across patients with different ages, clinical stages, and risk factors, notably including patients with the increased genomic risk factors of unmutated IGHV, which was 58% of enrolled patients, and deletion 11q present in 22% of patients.

These patients, in particular, with unmutated IGHV and deletion 11q, were able to benefit from 89% and 97% reductions in the risk of progression or death with treatment with Imbruvica compared to chlorambucil.

This is also the longest survival follow up available for any BTK inhibitor, and at this time with an average of about six and a half years of treatment, 78% of patients treated with Imbruvica are still alive.

One unique aspect to this current report is that we evaluated the frequency of the use of proton-pump inhibitors and other supportive important medications. Proton-pump inhibitors were used in about 56% of patients on ibrutinib and 36% of patients on the chlorambucil arm.

The report also includes information about the use of antithrombotic medications that are used to treat and prevent blood clots, as well as antihypertensive medications.

Finally, we always need to address safety. The adverse events in this follow up remain similar to those reported previously. Fortunately, no new safety signals have been identified.

We also looked at how adjustments of Imbruvica dosing with active dose management holds or reductions help to address adverse events and enable most patients to continue benefiting from Imbruvica treatment.

How might this data possibly impact future clinical practice?

These findings are of immediate application to the many thousands of patients with CLL who are being treated with Imbruvica worldwide. Providing the results that we have seen with long-term treatment help them understand what results they might experience and helps to support patients with their Imbruvica treatment pathway.

It also helps to inform the physicians that are helping to treat those patients, and the things that they should watch out for so that they can fully support their patients during this treatment.

Do you plan on expanding upon this research?

The research in this study led to follow-on studies evaluating Imbruvica-based regimens versus the chemoimmunotherapy standards of GC, BR, and FCR, and more recently, has led directly to the clinical studies of the fixed-duration combination of Imbruvica with venetoclax in the front-line setting.

These are the CAPTIVATE and GLOW studies, which together have explored this combination in broad patient populations, including those with increased genomic risk factors like deletion 17p and unmutated IGHV.

Is there anything else you would like to add about the RESONATE-2 study today?

We are excited by these important results for patients with CLL as they get treated in various places around the world.

We are excited to be able to continue our work to explore how ibrutinib can benefit patients, both as single-agent treatments as in RESONATE-2, as well as in exciting new combinations such as the Imbruvica plus venetoclax fixed-duration regimens explored in CAPTIVATE and GLOW.

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