Efforts Continue to Optimize Ibrutinib in CLL

Jennifer R. Brown, MD, PhD

Despite the RESONATE-2 trial having demonstrated the efficacy of ibrutinib (Imbruvica) in treatment-naïve elderly patients with chronic lymphocytic leukemia (CLL), Jennifer Brown, MD, explains that oncologists should carefully select patients to receive the drug depending on their age, comorbidities, and risk.

The RESONATE-2 trial was the basis for the FDA’s March 2016 approval of ibrutinib for the treatment of patients with CLL in the first-line setting.

In May 2016, the FDA expanded the label of ibrutinib to include overall survival results in treatment-naïve patients with CLL, as well as outcomes with the BTK inhibitor when combined with bendamustine and rituximab (BR) in relapsed/refractory patients with CLL.

OncLive: What is the role of ibrutinib in the frontline setting for elderly patients?

In an interview with OncLive, Brown, director of the Chronic Lymphocytic Leukemia Center, senior physician, associate professor of Medicine at Harvard Medical School and Dana-Farber Cancer Institute, discusses the findings and impact of the RESONATE and RESONATE-2 trials, as well as the role of ibrutinib in older and younger patients in both the frontline and relapsed settings.Brown: Ibrutinib actually got a broad approval for frontline CLL in March 2016. This was based on the RESONATE-2 trial, which was a randomized trial that enrolled CLL patients previously untreated over the age of 65 and assigned them to either ibrutinib or chlorambucil. In that setting—unsurprisingly, since chlorambucil is not a very good comparator—ibrutinib did improve progression-free and also overall survival (OS), with about 85% to 90% of patients still on ibrutinib at the 18-month follow-up.

These were low-risk patients—no 17p deleted patients. Generally, despite their older age, they did not have comorbidities. Approximately 30% of them had comorbidities.

Ibrutinib is now a frontline option, but I would tend to restrict it to patients over 70. In general, we think it could be applicable to patients with comorbidities, though it actually hasn't been studied that extensively in patients with comorbidities. That would be reasonable, except in cases where we should avoid it, such as anti-coagulation.

How does that compare to other frontline options for that patient population?

I tend to avoid ibrutinib for patients with significant cardiac disease because of the arrhythmia risks, as well as for patients with significant renal failure.Other treatment options in this older patient population include BR, which, as a chemoimmunotherapy, has a median progression-free survival (PFS) of 3 or 4 years; however, you receive it for 6 months and you're done. Then, obinutuzumab and chlorambucil have been shown to be better than chlorambucil, and also better than rituximab and chlorambucil in an older patient population, where the patients did, in fact, have higher comorbidity levels.

What about younger patients? What are their options in the frontline setting?

There is some evidence that ibrutinib is not well tolerated in older patients who have comorbidities. Therefore, for people who have many comorbidities, the obinutuzumab/chlorambucil regimen can be quite well tolerated. Recent updates on that data showed a time to next treatment of 51 months, equating to over 4 years for a short-duration, relatively well-tolerated therapy.The standard treatment option for younger patients has been fludarabine, cyclophosphamide, and rituximab, or FCR, and that's based on a couple of German CLL study groups starting with CLL8, where rituximab prolonged OS when added to FCR.

Then, there was CLL10 where FCR beat BR. The importance of the significant benefit of FCR over BR was brought home recently, because we now have 3 long-term follow-up trials of FCR.

We know that, in a subset of patients, they remain progression-free at 12 years. Approximately 60% of patients with mutated IGH, the favorable IGH, are alive and progression-free 12 years after FCR. That means that many of them are probably cured. Therefore, it is very important to emphasize this with this subgroup of patients—they have the opportunity to do 6 months of therapy, be done, and possibly be cured.

In the higher-risk, unmutated group, they do show continuous relapse. They have a median PFS of about 5 years with FCR. Ibrutinib has actually been approved in this setting but, for a young, fit patient, it means going on a drug for possibly the rest of their lives. There are some toxicities associated with that, such as atrial fibrillation, bleeding, muscle spasms, and edema. Therefore, it is very important that your mutated patients stick with FCR and not BR. There is no evidence that BR results in any prolonged PFS in any subgroup.

For the unmutated patients, FCR remains a very good standard option. You can also have a conversation about ibrutinib with the patient.

How is ibrutinib applied in the relapsed/refractory setting?

RESONATE was the first designed registration trial for ibrutinib. It turns out that ibrutinib actually was registered based on the phase Ib/II data that showed remarkable efficacy, but then RESONATE became the confirmatory registration trial where patients with relapsed/refractory CLL were randomized to receive ibrutinib or ofatumumab. That study showed, even in early follow-up, a significant PFS and OS benefit, and about an 80% reduction in the risk of progression or death with ibrutinib compared with ofatumumab.

We have reported on an 18-month follow-up of that trial, which is still relatively early. In the ibrutinib arm, 76% of patients remain progression-free. Furthermore, we've looked at some of the high-risk features, such as 17p deletion, 11q deletion, and some of the novel somatic mutations that have been defined in CLL.

What do you take away from this study?

Within the ibrutinib arm there is currently no difference in the PFS response rates, based on the presence or absence of those high-risk features.Ibrutinib is a highly effective therapy in relapsed/refractory CLL. It's generally well tolerated, and about 20% of patients have gone off it for various reasons, but many patients stay on and have extended disease control. The interesting feature is that most do not have complete remissions. The complete remission rate is low, but the partial remissions that they have remains stable for extended periods. They do tend to improve over time in many of the patients, with progressively less disease remaining.