Impact of Major Trials on CLL Treatment

Susan M. O’Brien, MD: The RESONATE trial was the trial that led to the full approval, by the FDA, of ibrutinib for the treatment of relapsed CLL. And that was a randomized trial in relapsed patients where they received either ibrutinib or the anti-CD20 monoclonal antibody, ofatumumab. And it was very clear that ibrutinib produced higher response rates, longer progression-free survival, and, in fact, an improved survival also over ofatumumab. And that led to the approval for patients in first relapse. So, pretty much after that drug was approved for first relapse, we no longer had to use chemotherapy outside the frontline setting.

The RESONATE-2 trial was a trial in frontline patients who were all over the age of 65, so older patients who tend to tolerate chemotherapy less well. And the randomization there was to ibrutinib versus chlorambucil, the alkylating agent. And, again, the findings were that ibrutinib produced higher response rates and better progression-free survival. And even though that trial had a crossover design, we already see an improvement in survival with ibrutinib. That then changed the label, and the label now is also showing that ibrutinib is a treatment option for previously untreated patients with CLL.

One of the nice things about ibrutinib is that some of the high-risk groups that previously didn’t do as well with chemotherapy seemed to have quite high response rates to ibrutinib. So, for example, patients with 17p deletion who have very poor response to chemotherapy have excellent responses to ibrutinib. Now, interestingly, we would still consider them a high-risk subgroup, not because their response rate is inferior, but because they have a shorter progression-free survival than relapsed patients who do not have a 17p deletion. So, in the phase 2 trial, the median progression-free survival in the patients with a 17p deletion was 32 months. Now, just to put that in perspective, the best published frontline progression-free survival median in patients with 17p was 11 to 12 months. So, even in this relapsed/refractory group, we were getting almost triple progression-free survival compared to what we had previously seen in the frontline—so really phenomenal effectiveness in this subset. But for the patients who don’t have a 17p, in that group, we haven’t seen a median PFS yet. So, their remissions seem to be lasting longer. So, some of the high- risk subsets are still perhaps high-risk, perhaps not as high-risk as they were before.

The HELIOS trial was a randomized trial in relapsed CLL, where patients all received chemotherapy with bendamustine and rituximab. The randomization was actually to ibrutinib or placebo. So, during the chemotherapy, the patients received the chemotherapy plus either ibrutinib or placebo, and then after the chemotherapy was finished, they continued on either ibrutinib or placebo indefinitely. What that trial showed is that the patients who got ibrutinib plus bendamustine/rituximab did significantly longer with much better progression-free survival compared to bendamustine/rituximab alone. Now, when that trial was designed, bendamustine/rituximab was the most common regimen used for relapse. But, of course, now we have single-agent ibrutinib for relapse. There was no single-agent—ibrutinib arm in the trial at that time. So, the real question that people asked was well, do you even need the chemotherapy? Could you get just as good results with ibrutinib alone?

There actually is an abstract at ASCO this year showing that perhaps the chemotherapy is adding to the outcomes with longer follow-up. And the reason I say that is the complete response rate, over time, now in the BR/ibrutinib arm has gone up to 33%, whereas in the arm that only got BR, the CR rate hasn’t changed, of course, because they have no further therapy. And it’s less than 10%. So, it appears that the complete response rate is going up over time. The relevance of that is that 33% in the arm, where the patients received chemo with ibrutinib, is higher than any reported CR rate thus far for single-agent ibrutinib, including in the frontline setting. So, this now 2-year follow-up of the HELIOS data suggests that the chemo may be adding to the ibrutinib. And I think we’ll need longer follow-up to really know, because right now, it’s just so easy to give ibrutinib in relapsed as opposed to giving chemotherapy.