Safety and Efficacy Considerations in CLL

Steven Coutre, MD: I think with diseases like CLL we had forgotten that we needed better therapies. Certainly, we were looking at a drug like single-agent chlorambucil as initial therapy, where you don’t get good depths of responses and, therefore you don’t get long durations of responses, but that’s all we had. We added drugs. We got our monoclonal antibodies and they’ve certainly added benefit, but still for most patients, you eventually come to a point where you’ve exhausted the reasonable treatment options that you would have confidence that would be effective for a patient.

Now, of course, it’s all different. We have fundamentally different drugs that work by different mechanisms that are very well tolerated. And so, yes, we should focus on efficacy. Tolerability is important in the equation, especially for our typical older patients, but these drugs are tolerable, too. So, what’s wrong with giving a more effective drug? There’s nothing wrong with that. What’s wrong with giving a drug that’s better tolerated? That sounds pretty good to me. And, fortunately, we’ve demonstrated in trials that we can get dramatically improved efficacy in many settings compared to our standard therapies, whether it’s progression-free survival or, in some cases, overall survival. And, from a tolerability standpoint, ibrutinib has been very well tolerated.

Some would argue, “Well, we haven’t really seen comparisons to our best therapies: our BRs, our FCRs,” and that is true, except to say that those trials have been done. They’ve very recently completed direct randomized trials. And so, it will be very helpful to see the results of those as well.

Sometimes when we do clinical trials that focus all on the initial results—say one therapy versus another, who does better—there’s different ways of measuring what ‘better’ is. But, one of the other advantages in many situations is really learning how patients do as they continue on a therapy, or after they’ve received a therapy and are followed over time. We all want to know how patients, who receive FCR, do. And so, for example, recently, there are a lot of data on long-term follow-up from FCR studies, how do patients do 10 years later. And, that’s definitely true with drugs like ibrutinib.

We’re still following those patients from our very first trial in CLL after the first-in-man trials. Those patients are still enrolled in those trials that began over 6 years ago. And those trials are invaluable in terms of not only learning whether patients still benefit, whether their disease is still controlled, but also how well it’s tolerated. Can they stay on the therapy? And that’s especially important, because this is a therapy that we have dosed continuously.

So, the RESONATE 2 trial, for example, one could say, “Well, that’s a comparison to chlorambucil, that doesn’t really matter. Of course, it’s going to show an efficacy advantage.” I think the great advantage of that trial is going to be following that large group of patients who have received ibrutinib as initial therapy, to answer the continued efficacy standpoint, and also safety. It’s nice that we have the availability of continuing to monitor these patients in order to really educate ourselves and educate our colleagues in the community about what to expect longer term.