BTK Inhibitors in CLL: Ibrutinib

William Wierda, MD, PhD: Let's focus a little bit on BTK [Bruton tyrosine kinase] inhibitor-based therapy and have some discussion around that. Dr Shadman, we’ll start with you and maybe you can give us a summary. Ibrutinib has been around the longest, it was the initial BTK inhibitor that was available and studied. What are the data that we have available to review with ibrutinib in the frontline setting? Who does it work for? What are the expected responses that we see with ibrutinib-based therapy?

Mazyar Shadman, MD, MPH: The current era really started with ibrutinib, as you mentioned. As oncologists or hematologists, we're very interested in long-term data regarding how effective these drugs are and how safe they are. For example, we now have the phase 1b/2 study, PCYC-1102, for the initial study where ibrutinib was used in both frontline and relapsed settings. An 8-year follow-up of that specific study was recently published in 2020. There are a lot of studies using ibrutinib in combination or as monotherapy.

To briefly mention some of the take-home points from those studies, the 7-year progression-free survival rate in the first-line setting is 83% and the median was not reached. This is outstanding for a drug that has been around for that long. There are still patients taking it with such a great efficacy. Of course, as you mentioned, the numbers are lower, as expected, in the relapsed setting. For frontline, we are looking at an overall survival rate of more than 80%.

Interestingly, we are also getting more information about some of the adverse effects of ibrutinib. For example, the 5-year follow-up of the RESONATE-2 study, which was published last year, is telling us that most of the adverse effects of ibrutinib decline over time, with an exception of hypertension. So, the more we use ibrutinib, the adverse effects that will lead to drug discontinuation would basically disappear with the exception of hypertension.

More importantly, based on the long-term follow-up of the RESONATE-2 study, we are seeing that the quality of response improved over time. With the initial report of RESONATE-2, the CR [complete remission] rate was reported to be around 11% with 18-month follow-up, and 30% with 5-year follow-up. That, again, is an important message. What I gather from these 2 studies, and long-term follow-up of these studies, is that this is an effective drug. Ibrutinib works and if you take it longer, it works better and the quality of response improves.

Of the adverse events that patients may have issues with initially, most will go away, or there are interventions that may help with those symptoms, such as dose reduction or supportive care. More importantly, we're not seeing signals that the biology of the disease is changing in terms of transformation to more high-risk histology, as we’ve seen with other malignancies. I think it's important to continue to have follow-up studies from those initial studies, but this is really promising.

This is our first drug that really changed the landscape, and it's very reassuring to see that it remains to be effective and also safe, meaning no new safety signals or concerns. Of course, we then have a randomized study, the Alliance A041202 study, which was a very important 3-arm study that targeted patients who we would consider bendamustine or rituximab-type patients. In the study the patients either received bendamustine or rituximab or ibrutinib, or a combination of ibrutinib and rituximab.

The study tried to answer 2 important questions: ibrutinib-based therapy vs BR [bendamustine, rituximab], which is a very popular regimen for the frontline setting, or was at the time, and whether rituximab specifically added to ibrutinib would be beneficial. Now the study, as we know, was positive in terms of the end point in favor of ibrutinib-based therapy, and the primary end point being progression-free survival [PFS], with a 2-year PFS based on the original publication of 88%, which is outstanding.

With a longer follow-up of those patients, it sounds like this continues to be the case. What I mean by longer follow-up, we don't have a follow-up publication, but later in the course of treatment, it sounds like the benefit of ibrutinib-based therapy was seen in both mutated and unmutated IGHV for the primary end point of PFS, and I think that's very important. As Dr Burke mentioned, there is no overall survival [OS] benefit yet in favor of ibrutinib-based therapy.

So, if somebody really wants to go with BR, in my opinion, there are other reasons to convince them not to do it. From the OS standpoint, this study hasn't shown that ibrutinib-based therapy is better than bendamustine, rituximab. Again, a very important finding from this study was that rituximab really didn't add anything to ibrutinib therapy, so ibrutinib is used as monotherapy. Now, we can talk about other CD20 monoclonal antibodies and whether those could be beneficial, and other BTK inhibitors, but specific to rituximab and ibrutinib, there's really no point of using the combination.

Of course, the CLL [chronic lymphocytic leukemia] community became a little bit concerned when there were 7 sudden deaths reported on this study on the ibrutinib-based arms. That makes us look a little more closely at the other studies that use ibrutinib to see if this is something that is consistent. That’s basically the 3 major studies that use ibrutinib for the elderly and less fit population in the frontline setting.

John Burke, MD: There are a couple of interesting things that emerged from the longer-term follow-up that we didn't really know. Early on, it was getting good responses, but with the long-term follow-up data, you really see that the PFS is excellent. Even though the MRD [minimal residual disease] rates are not high and the CR rates are not high, the progression-free survival rate is outstanding. You can feel comfortable and your patients can feel comfortable, that when they start this drug, they are likely to have good control of their CLL for a long time.

The second point is we talked about initially when these drugs were coming out that they never achieved a CR. That’s not quite true. In fact, as you pointed out, with longer follow-up they are achieving CR in a higher percentage of patients. The third point is that the toxicities are a little higher than first reported. When we first heard about atrial fibrillation [AF] with ibrutinib in some of these studies, it was at that 3% to 5% range, and the grade 3 bleeding was at a 2% to 3% range. We are seeing with the longer follow-ups that they’re starting to parallel the real-world data. When I heard the 3% to 5% AF number, I said, that seems to be lower than what I see in my practice. Now, with the longer follow-up on these trials, it’s more like a 10% to 15% to 20% range of folks who are getting AF, and the actual grade 3 bleeding rate is about 10%, often in conjunction with other anticoagulants. I think the toxicities are a little higher than we heard about early on when these data were coming out.

Transcript Edited for Clarity