Steven Coutre, MD: After our initial trial experience and then the RESONATE trial with relapsed/refractory patients, there was a lot of interest in looking at it earlier in treatment. In fact, the trial before RESONATE, our very first trial in CLL, after we had enrolled relapsed/refractory patients and saw dramatic efficacy, we included a cohort of treatment-naïve patients over 65. There were 31 patients where we used it as initial therapy. So, we have data from that trial, and we have a longer-term experience now to have confidence that it’s effective in that group. That was really the genesis of the RESONATE 2 trial, which is a randomized trial for previously untreated patients, comparing single-agent ibrutinib with chlorambucil. That trial was recently reported within the last year, and it really is what led to the approval of ibrutinib as initial therapy in CLL. It, again, demonstrated superiority in terms of progression-free survival, as well as overall survival, compared to, in this case, single-agent chlorambucil.
We’re fortunate that we have a body of experience now from our trials, where we’ve used ibrutinib in a variety of clinical settings for CLL; heavily pretreated, refractory patients. We have trials in the up-front setting. For example, we have nice randomized trials, not just single-agent trials. And so, we’ve gained a lot of experience, and what we’ve learned is that you see efficacy across a broad range of patients. In fact, I can’t think of a subgroup who doesn’t benefit from treatment. It’s not like we have to exclude a group because of some characteristics that they have. We’ve also learned that it’s very well tolerable across many different types of patients; patients who are fit, patients who are unfit. We have a fair amount of long-term follow-up now to understand the safety profile.
We’ve learned that most of the adverse events you might see happen within the first year; they actually decline. So, that speaks to two things. It speaks to the continued efficacy of the drug, and it also speaks to the fact that it continues to be well tolerated, and we’re not seeing, say, cumulative side effects from staying on the therapy. Those are important considerations, especially for ibrutinib, where we’re using the drug continuously. We want to know that patients will continue to tolerate it just as much as we want to know that they’re going to continue to benefit from it. And so, I think the trials that we’ve had, the different scenarios, and the different patient populations have been very helpful in getting this information.
The HELIOS trial was also a randomized clinical trial. This, again, was for patients who’ve had prior treatment, not treatment-naïve patients, and it was a very simple design. In this case, it was a standard regimen: bendamustine/rituximab (BR) versus ibrutinib/bendamustine/rituximab. So, it wasn’t a single-agent ibrutinib comparison. This trial also showed a significant benefit, a longer progression-free survival if one added ibrutinib to bendamustine/rituximab. The results we saw with the bendamustine/rituximab arm alone were very comparable to prior clinical experience, prior trials in the relapsed setting. There wasn’t anything different about that. Adding ibrutinib not only increased the efficacy, but also was tolerable. We learned that you can get a better result and patients will tolerate it. One criticism, however, is that you’re still using chemoimmunotherapy, and it’s not a direct comparison of, say, ibrutinib to bendamustine/rituximab.
In my view, at least, in my practice, that’s really the crux of the issue. If I wanted to know the value of bendamustine/rituximab, I would want to know its value compared to ibrutinib. I’m not really interested in adding a novel drug to chemoimmunotherapy, I’m interested in avoiding chemoimmunotherapy. But, to be fair, if you’re comfortable using the BR regimen, and you want to use it, then you know you can safely add ibrutinib and likely get a better result.