Idelalisib and Ibrutinib Continue to Advance CLL Treatment

Susan M. O’Brien, MD

Since the approvals of idelalisib (Zydelig) and ibrutinib (Imbruvica) in July 2014 and November 2013, respectively, the treatment of chronic lymphocytic leukemia (CLL) has advanced rapidly.

Encouraging data have been presented demonstrating the promise of the two therapies, both as single agents and in combination with other drugs.

The recent phase III HELIOS study, which examined ibrutinib in combination with bendamustine and rituximab (BR) in relapsed/refractory CLL, was hailed as practice changing, with median progression-free survival (PFS) not yet reached after a median follow-up of 17.2 months in the ibrutinib arm compared with 13.3 months with BR alone (HR, 0.203; 95% CI, 0.150-0.276; P <.0001).

Multiple other clinical trials evaluating ibrutinib in combination with a range of therapeutic strategies in CLL are underway and, as a monotherapy, ibrutinib has demonstrated response rates ranging from approximately 43% to nearly 66%.

Idelalisib has also been gaining prominence in CLL. Between the first and second quarters of 2015, sales for the PI3K-delta inhibitor rose 15%.

Gilead Sciences, the developer of idelalisib, recently filed an application with the FDA to expand the indication of idelalisib to include use in combination with ofatumumab (Arzerra) for patients with relapsed CLL. This new application is based on findings from the phase III Study 119 trial.

Study 119 randomized 261 patients with CLL who progressed within 24 months from their last therapy to idelalisib plus ofatumumab (n = 174) or single-agent ofatumumab (n = 87). Patients were stratified based on relapsed versus refractory status, 17p deletion (del17p) and/or TP53 mutation status, and whether they harbored an IGHV mutation.

The combination resulted in PFS of 16.3 versus 8.0 months with ofatumumab alone (HR, 0.27; P <.0001). In patients with del17p or TP53 mutations, the median PFS was 13.7 versus 5.8 months, respectively (HR, 0.33; P <.0001).

The overall response rate was 75.3% in the combination arm versus 18.4% in the ofatumumab alone arm (odds ratio = 15.9; P <.0001).

OncLive: What new agents have made the biggest difference in the treatment of CLL?

To better understand the impact and the future outlook for idelalisib and ibrutinib in CLL, OncLive spoke with Susan M. O’Brien, MD, associate director for Clinical Science for the Chao Family Comprehensive Cancer Center and medical director of the Sue and Ralph Stern Center for Cancer Clinical Trials and Research at UC Irvine Health.Dr O’Brien: The two drugs that are now approved in the United States and Europe are ibrutinib, which targets Bruton tyrosine kinase (BTK) and idelalisib, which targets PI3K-delta. The dosing strategy for both right now is continuous either until patients lose their response or they have a toxicity that necessitates them coming off the drug.

What are the biggest advantages of treatment with idelalisib or ibrutinib for patients with CLL?

What are the similarities and differences between idelalisib and ibrutinib?

Both of these drugs have been approved for relapsed/refractory CLL, and ibrutinib is also approved as initial treatment for patients with CLL and a 17p deletion. That is actually based on relapsed/refractory data with very little frontline data. Because the relapsed/refractory data for 17p deletion was so much better than any frontline data, I think it is reasonable that the authorities gave the approval for this drug in the frontline setting. Upfront patients with 17p deletion constitute only about 5% to 10% of the previously untreated. We see it frequently in the relapsed/refractory population.In terms of the duration of response with these agents, results have been very positive. Response has lasted for multiple years for some patients. In ibrutinib, the only group for which the median PFS has been reached within the relapsed/refractory population are those with 17p deletion where it was 28 months. If you look at the best data for frontline 17p deletion, PFS is only 11 months. If, in the relapsed/refractory patient setting, it is 28 months, then that is a very impressive result.Both of those therapies are approved in the relapsed/refractory setting. Ibrutinib is approved as a single agent; it is given at approximately 420 mg once daily for patients with CLL. There are a couple of similar qualities between the two drugs. They both cause extremely rapid reduction in lymph nodes. When you look at both of these as single agents, you see a very interesting pattern of response. You see a very rapid reduction in lymph node size, but the lymphocyte count initially goes up. Research has shown that these drugs markedly decrease the chemokines that cause the cells to adhere to the stroma and there is an initial flux of the cells into the peripheral blood. The good news is that most people with CLL can walk around with lymphocyte counts and have no symptoms. For the most part, we do not worry about it. We see less of it with idelalisib because when you add in a monoclonal antibody you slow down that lymphocytosis and response happens more quickly.

What challenges exist for oncologists who are unfamiliar with these drugs?

With idelalisib and ibrutinib, one of the biggest advantages is that they do not cause myelosuppression. The biggest disadvantage to giving chemotherapy-based regimens to patients with CLL is myelosuppression and infection. In a population that is already often immunosuppressed by their disease, this is concerning. With idelalisib and ibrutinib, that complication virtually goes away.These drugs are very good at improving cytopenia. We see that improvement in baseline platelet and hemoglobin counts very early. This is very interesting because we are also seeing lymphocyte counts in the hundreds of thousands and, at the same time, the platelets and the hemoglobin are improving. This can be challenging to some doctors because they believe that, because their patient has a baseline cytopenia, they should start them on a reduced dose. This is an understandable assumption for those who only have experience with treating CLL. However, it is an incorrect assumption. You want to give the full dose because you want this very rapid improvement in the cytopenia that you see when the full dose is given.