Phase II study of idelalisib monotherapy in older CLL patients

Dr Andrew Zelenetz – Memorial Sloan Kettering Cancer Center, New York, USA

Today I presented data on the role of idelalisib, a delta-specific PI3 kinase inhibitor for the treatment of CLL in patients who have never received prior therapy. We originally had done an earlier study which we reported with a combination of idelalisib and rituximab and in that study there was an extremely high overall response rate of 97% with a complete response rate of 19%. There was very little lymphocytosis and, other than the management of lymphocytosis, the question was was the rituximab doing anything. So we proceeded to a second cohort of patients, this cohort was 41 patients, where we looked at, again in the same group of patients, older patients over the age of 65, never received treatment for CLL before, and asked what was the role of single agent idelalisib in the outcome of patients with CLL. What we found is, again, a very high response rate, not quite as high as the combination. The overall response rate was 87% but, interestingly, the complete response rate was zero. We actually saw no complete responses in this second cohort of patients compared to the first cohort.

We, interestingly, saw a little bit less toxicity in this cohort of patients, somewhat less grade 3 diarrhoea, which is a common toxicity with idelalisib, but I’m not sure that that’s because of more limited exposure or that we have shorter follow-up on the second cohort or if we’re simply better at managing the diarrhoea, which we are. We know when to stop, when to use steroids, whether it’s prednisone or budesonide, we know we’re better at managing the toxicity. There were toxicities with respect to pneumonitis and pneumonia, they were grouped together, and they represented a group of patients but, again, these are toxicities we’ve seen before with idelalisib.

So when we take it all in sum this was a very active single agent but my interpretation in a non-randomised sequential cohort study was that rituximab probably did add a little bit to single agent idelalisib seeing the difference in the complete response rate. Obviously this could really only be definitively answered in a prospective randomised trial but this is the closest we have and this is a sequential cohort study in very similar patients.

So are you planning a randomised controlled trial down the track?

Well, the question is is it worth doing that study or should we be asking other questions. One of the things about idelalisib, ibrutinib, venetoclax, right now these are being approved as single agents that are meant to be given continuously. Exceedingly expensive drugs, average cost is about $100,000 a year and that’s US, not Australian, dollars. So we’re talking a significant sum of money. I think that there’s good rationale to take these novel agents and combine them in ways that could potentially cause early complete responses and allow us to have a limited course of therapy rather than continuous therapy instead of asking every single phase III question – idelalisib versus rituximab plus idelalisib. I think it makes sense to do a series of phase II studies, find combinations that truly have high complete molecular remission rates and then compare them to standard therapy.