Phase I study of duvelisib in patients with relapsed or refractory CLL
Dr Susan O’Brien – University of California, Irvine, California, USA
I presented on a new BCR inhibitor, BCR meaning the B-cell receptor. There are only two drugs approved in that class, ibrutinib and idelalisib, so this is the next generation PI3K inhibitor. Duvelisib is a PI3K delta and gamma inhibitor, so two of the isoforms. Those are the two that are the most relevant in haematologic malignancies. What we showed in this relapsed CLL trial is that the response rate using iwCLL criteria was quite good, was in the order of 58%, which is rather high given that the median number of prior regimens in the expansion cohort that we were looking at was five prior regimens. The expansion cohort was dosed at 25mg po bid because that dose clearly inhibits delta, a little bit less so gamma but the gamma is probably more important for lymphomas which are also being treated on that trial, my focus was on the CLL patients.
If we added in this other category of response that we now use for the B-cell receptor inhibitors which is called PRL, that’s a PR with lymphocytosis, because we know that all the B-cell receptor inhibitors have this pattern of activity where you get very rapid shrinkage of the lymph nodes initially but at the same time the lymphocyte count goes up because you get this egress of the lymphocytes into the peripheral blood. That peaks at 1-2 months with most drugs and then slowly comes down. The good news is that most patients with CLL can walk around with very high lymphocyte counts and be completely asymptomatic. It’s not usually something we worry about, it’s just important to monitor, but that is progressive disease.
Interestingly, with this drug we see a much more rapid resolution of the lymphocytosis. We did see patients with PRL and, in fact, if we added them to our true PRs and looked at the lymph node response, about 85% of patients had more than 50% shrinkage in their lymph nodes. There are some side effects with the drug, like there are with all drugs, but they’re generally mild. It can cause some transaminitis but that’s not such a bad side effect since patients don’t feel it so they’re not uncomfortable. We just have to monitor the transaminases and lower the dose if needs be. It can cause a little bit of diarrhoea colitis and pneumonitis, like other PI3K delta inhibitors but their incidence is pretty low and most of the patients tolerate the drug very well. So this is very impressive data for a single agent in a highly refractory population.
What plans have you got for future trials and future research?
There is a trial going on right now which is the pivotal trial which is a randomised trial in patients with relapsed CLL comparing duvelisib to ofatumumab. There is hope that if that is a successful trial then that could be the basis for an application for registration in the United States and in Europe. There are some investigator initiated trials looking at combinations also including with chemotherapy. There is also, importantly, a trial with duvelisib in patients who have failed ibrutinib. So this is a difficult group of patients because now they’ve had a good response to another B-cell receptor inhibitor but they’ve lost it. So that’s a difficult patient population to treat and so we’re looking at the activity specifically in that population of patients. That trial is also ongoing.
Is there a take home message?
I think it’s an exciting drug. If it gets approved it will join two other drugs that we already have. It’s a little bit different from idelalisib, the PI3K delta inhibitor, because of the delta gamma inhibition that we see with duvelisib but consistently producing high response rates with usually tolerable side effects. It will be very exciting to have another drug that we can use for patients with relapsed CLL.
