Case 1: Targeted Therapy: Ibrutinib for Newly Diagnosed CLL

EXPERT PERSPECTIVE VIRTUAL TUMOR BOARD

William Wierda, MD, PhD:Moving on to the small molecule inhibitor options for this patient, there’s a trial that was reported relatively recently, referred to as the RESONATE-2 trial. This was a frontline trial that studied patients over 65 years of age. These patients were randomized to ibrutinib versus chlorambucil. Matt, you could highlight, for us, the outcomes of that trial? What important features of that trial are particularly related to the management of this patient?

Matthew S. Davids, MD, MMSc:The 2 standards that we might consider for a patient like this would be bendamustine and rituximab or chlorambucil in combination with a CD20 antibody like obinutuzumab. In the RESONATE-2 study, we see a comparison with chlorambucil monotherapy, which we’re not typically using as a standard approach. When this study was designed, that was still a standard approach, particularly in Europe where a lot of patients were put on this study. So, I think it makes it a little bit challenging to compare, across this population, RESONATE-2 with some of the other data sets that we just saw. But nonetheless, I do think RESONATE-2 is a very valuable data set. It was a large randomized phase III trial of over 265 patients. In total, there were 269 patients. These patients were randomized (1:1) to ibrutinib or chlorambucil, with a primary endpoint of progression-free survival.

There are several important findings from this trial. In particular, looking at the ibrutinib arm, we saw a very nice progression-free survival at 24 months. It was in the range of 85% or so, which I think is very encouraging for this population. As expected, chlorambucil had a much shorter progression-free survival. That’s not a major surprise to us. One of the things that I took away from the RESONATE-2 study was that patients with some of the higher-risk markers, in particular those with deletion 11q and the unmutated IGHV, had very nice progression-free survivals.

William Wierda, MD, PhD:So, the presence of deletion 11q and the unmutated V gene, in terms of chemoimmunotherapy-based treatment, puts this patient at higher risk for shorter progression-free survival, relapse, and the need for re-treatment. How does that factor in, in terms of small molecule inhibitor-based therapy? What’s the relevance of deletion 11q and the unmutated V gene, in terms of ibrutinib-based therapy?

Matthew S. Davids, MD, MMSc:For unmutated IGHV, we’re seeing equivalence (in terms of the progression-free survival in patients treated on ibrutinib), irrespective of unmutated versus mutatedIGHVstatus. It’s important to note that this has historically been very different with chemoimmunotherapy-based regimens, where we’ve always seen a shorter progression-free survival with patients with unmutatedIGHV. So, I think this is a very encouraging development in the field—with ibrutinib.

Now, I think the deletion 11q story is also very interesting. We had seen, from the relapsed/refractory studies—the PCYC-1102 study, for example—that there was a hint of a shorter progression-free survival in patients with deletion 11q. In the RESONATE-2 study, this is a little different. We’re actually seeing, perhaps, a slightly better progression-free survival in patients who have deletion 11q—or at least equivalence. That was specifically seen in the RESONATE-2 study. Tom Kipps and colleagues put together an integrated analysis, where they looked at several different studies pooled together. In that population, there was a significant improvement in progression-free survival at 24 months in the patients with deletion 11q compared with patients without. I think this suggests that ibrutinib, and perhaps drugs like it, may help to overcome some of these traditional poor prognostic factors.

William Wierda, MD, PhD:Maybe you can comment on the quality of remission with small molecule-based therapy as monotherapy? What does this mean, in terms of duration of treatment, etc?

Matthew S. Davids, MD, MMSc:So far, these studies, that we’ve been discussing, have been designed with ongoing continuous therapy. They require this ongoing therapy to achieve the progression-free survival numbers that we’ve seen. We don’t know what would happen if patients were to stop, but we have a sense that they would likely progress because most of these patients are not achieving a complete remission, let alone without MRD detectability. If patients are in a partial remission and they stop a kinase inhibitor, we’re probably not very confident that they’re going to have a durable response. That’s why, as we’ll discuss, some of the future regimens are combinations that try to achieve deeper responses and allow for time-limited therapy.

William Wierda, MD, PhD:CD20 antibodies are highly important in chemoimmunotherapy regimens. Clearly, the addition of a CD20 antibody has improved overall survival in the FCR (fludarabine/cyclophosphamide/rituximab) regimen. In terms of the small molecule inhibitors, particularly ibrutinib, looking first at the frontline setting, do we think about a CD20 antibody with ibrutinib, for example? Are there data that gives us some insight into that combination?

Matthew S. Davids, MD, MMSc:We have thought about this question—looking at the combination of ibrutinib and rituximab versus ibrutinib alone. A study was led by Jan Burger and colleagues, MD Anderson Cancer Center. In this randomized study, we certainly did see a more rapid improvement in lymphocytosis, as we see with ibrutinib, but this did not translate into improved progression-free survival at this point. Certainly, there are cosmetic benefits to adding the antibody. But whether that’s going to actually benefit the patients, I think, remains unclear. There are some ongoing randomized studies that may help to answer this question, including the ALLIANCE study, in the frontline setting. In addition to comparing ibrutinib-based regimens to chemoimmunotherapy with BR, there is also a comparison of ibrutinib versus ibrutinib/rituximab. I think that’s going to be an important study to look out for.

Transcript edited for clarity.