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Ibrutinib and Idelalisib Continue to Impress in CLL, May Eventually Replace Chemotherapy for Some Patients

Gina Columbus @ginacolumbusonc
Published: Tuesday, Apr 28, 2015

Dr. Steven E. Coutre

Steven Coutre, MD

The efficacy of ibrutinib (Imbruvica) and idelalisib (Zydelig) in chronic lymphocytic leukemia (CLL) suggests the drugs could potentially replace chemoimmunotherapy completely for some patients, according to Steven Coutre, MD, a professor of Medicine (Hematology) at Stanford University Medical Center.

Phase III studies have shown higher overall response rates with idelalisib plus rituximab (77%) versus what has been traditionally seen with rituximab plus chemotherapy for patients with previously treated CLL (54%). Additionally, ibrutinib as a single-agent has shown response rates (58.3%) that are similar to the combination of rituximab and chemotherapy in previously treated CLL. These observations have led researchers to believe that chemotherapy can be omitted altogether, making room for less toxic, orally administered novel agents.

Currently, ibrutinib is indicated for treatment of patients with CLL receiving one prior therapy and for patients with a 17p deletion. Idelalisib is approved for use in combination with rituximab in patients with relapsed CLL who are good candidates for single-agent rituximab due to comorbidities.

Coutre, who has conducted research with ibrutinib and idelalisib, recently presented results from an ibrutinib trial at the 2015 AACR Annual Meeting. The study demonstrated durable responses, including complete responses, with long-term use of the drug.

To gain further insight into the impact of ibrutinib and idelalisib, as well as other emerging therapies and treatment strategies in CLL, OncLive sat down with Coutre at the AACR meeting, which took place from April 18 to 22 in Philadelphia.

OncLive: Ibrutinib has been approved for CLL since early 2014. What is its impact on clinical practice so far and how do you see its use evolving?

Dr Coutre: The drug has had a significant impact already. It is a very well tolerated therapy, so that gives you an option for patients who might not tolerate standard chemoimmunotherapy. Also, for patients who no longer respond to standard therapy, it is a great alternative. It also meets an unmet need in CLL, specifically those patients who have the 17p deletion. In fact, it has a specific approval as initial therapy for those patients.

Can you discuss the development of ibrutinib resistance and, specifically, a recent study from Ohio State University researchers published in JAMA Oncology on ibrutinib resistance mechanisms?

The study published from Ohio State University really details their experience with a large number of patients, including patients from our study. It really tells us two things. First, we see patients who progress because of a transformation, such as Richter’s transformation, which, fortunately, is a minority of individuals. It may simply reflect the advanced nature of the patients’ disease in these trials. Secondly, it tells us that the reason the majority of patients who progress for other reasons is likely due to mutation—a mutation that leads to specific resistance to ibrutinib.

You have also been involved in research with another CLL drug, idelalisib. What are the latest developments with this agent?

Idelalisib is another FDA-approved drug. It is also an oral therapeutic, but it is a different target. It is a PI3K-delta inhibitor, so it is really the first-in-class of those drugs. Idelalisib is also a very effective agent for relapsed/refractory disease. It was approved in CLL in combination with rituximab, including patients who were not fit for standard chemoimmunotherapy. From an efficacy standpoint, it is also a terrific drug, as is ibrutinib.

The side-effect profile is a bit different. You can see early transaminitis, which is generally reversible, and it usually does not limit subsequent use of the drug. However, later side effects include a diarrheal illness, likely colitis, and perhaps an inflammatory insult to the colon. That has led to problems with being able to continuously dose the drug. I think we will need to see further studies that really tell us how best to use this particular drug. Regarding the 2015 AACR Annual Meeting, I’m not aware that there are any new findings being presented on idelalisib.

What impact has idelalisib had on patient treatment since its approval for CLL in 2014? Have there been any findings in terms of acquired resistance mechanisms with the drug?

Idelalisib’s impact has been less than ibrutinib, primarily because of the side-effect issues, not from an efficacy standpoint. I think physicians have much more of a limited experience with it to date.

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