The phase III RESONATE trial was a randomisation between ofatumumab and ibrutinib, which is the new agent, in patients who had had prior treatment for CLL. It showed excellent results. These have already been published last year and what I was doing today was updating some of those results with longer follow-up. Essentially ibrutinib resulted in an improved overall response rate, so the overall response rate for ibrutinib was 90% compared with only 25% for ofatumumab, and an improvement in progression free survival. So at a year, 84% of patients who received ibrutinib were still in remission against 18% of patients with ofatumumab who remained in remission, so significant difference between the two. In fact, at the interim analysis on the trial the data monitoring committee found such a significant improvement for patients receiving ibrutinib that they recommended crossover for those patients who were on ofatumumab so that when their disease progressed they were able to go on and then receive ibrutinib. To date, out of 195 patients randomised to ofatumumab 122 of them have crossed over to receive ibrutinib. So the majority of the patients now on the RESONATE study are on on-going treatment with ibrutinib.
How many patients are there in the trial?
In the trial altogether it was 391 with a randomised 195 in each arm, 195, 196 in the ofatumumab arm. So it’s a large study and what I was showing today as well was subset data. So it’s data by analysis of different subsets of patients according to prognostic markers, genetics. Regardless of any of those factors, some of the factors that we associate with poorer outcome in CLL, didn’t have any negative impact for the patients who received ibrutinib. So all of them benefitted from it and there was no difference whether they had an abnormality of 17p, for example, or not, they still derived the same level of benefit.
What’s next?
There are several unanswered questions, clearly. The first unanswered question is we don’t know how long patients need to stay on this type of treatment. This was a relapsed refractory study and the expectation in that group of patients is a fairly short survival. Nobody expected 90% overall survival at a year for this particular group of patients. So it was designed to allow patients to remain on treatment until either they couldn’t tolerate the treatment or their disease progressed. As yet, that hasn’t happened for many so at the median follow-up of 16 months on this study 76%, so three-quarters of patients, remain on treatment. A recent longer follow-up on an earlier trial with ibrutinib at the three year median follow-up a similar number, three-quarters of patients, are remaining on treatment. So at the moment people are staying on this drug for really long periods of time, years. So we don’t know how long that might be, so in the UK we have a front line study incorporating this drug in one of the arms where we actually have a time limit. We’re going to stop at six years, but whether it’s possible to stop earlier or whether the disease comes back if you stop the treatment, we don’t yet know.
The other issue is whether these drugs can be combined well with other small molecule inhibitors, so other oral therapies that are non-chemotherapy, because this is one of the attractions about the drug is that it’s not chemotherapy, it’s a targeted agent. It’s given orally so it’s very easy to administer and has a very good toxicity profile so people tolerate the treatment very well and they don’t get many side effects. So whether one can combine it with something similar that doesn’t add to the toxicity or side effects that patients might get but improves the response and maybe allows a shortening of the total treatment period, that might be an advantage.
Thirdly, we don’t know whether there are going to be any long-term side effects. So far the side effect profile has been very good and in fact it seems to be mostly early when patients start the treatment and it diminishes over time but we don’t know whether there might be some unexpected late side effects that emerge after patients have been on treatment for several years.
Is there a message you would like to end on?
It’s inspiring for clinicians but most of all it’s a real hope for patients because this is not the only drug in a whole class of new therapies that are going to be easy to deliver but have huge efficacy. It’s astonishing to see 90% response rates in a group of refractory or relapsed patients, often with high risk features. So that’s the most exciting thing is that we’ve got our hands now on some drugs that have extraordinary potential. CLL is a disease that plays out over years, often decades, and I think what we’re seeing now is that patients really only have to stay one drug ahead of their disease and they’ll be alright and they may be able to go on and have almost normal life expectancy with sequential treatments like this that are able to deliver such good results.
