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Ibrutinib Plus Venetoclax Provide High Rates of Undetectable MRD in CLL

Most patients with previously untreated chronic lymphocytic leukemia (CLL) who received a combination of ibrutinib and venetoclax achieved undetectable residual disease, according to partial results from the phase II CAPTIVATE trial presented at the recent 2019 American Society of Hematology meeting in Orlando.

In this exclusive MedPage Today video, contributing author Ryan Jacobs, MD, of Atrium Health in Charlotte, North Carolina, and Javier Pinilla-Ibarz, MD, PhD, of H. Lee Moffitt Cancer Center in Tampa, Florida, discuss the findings.

Following is a transcript of their remarks:

Ryan Jacobs: This is a study looking at a very now exciting combination of treatments in the CLL field, which is looking at taking two of our best treatments and putting them together. This is a study looking at ibrutinib, which is a BTK inhibitor, combined with venetoclax, which is, of course, a BCL2 inhibitor. Although there were a few different oral presentations looking at this combination this morning at the session, what was unique about CAPTIVATE is it was looking at frontline patients and it was treatment given the combination specifically over the course of a year, whereas other studies looked specifically at high-risk patients and had smaller numbers, treatment was given over longer periods of time, or perhaps an alternative BTK was used.

At CAPTIVATE, specifically, it looked at about 150 patients, so it was the largest study presented in terms of numbers. All had reached the time-specific point of followup where MRD [minimal residual disease] was assessed after a year of the combination. It was fully mature in that aspect, so that was also a unique aspect of the study. After three months of ibrutinib lead in, all patients got a year of the combination, and the data that was reported today specifically was the response data at that one-year point of combined therapy.

Javier Pinilla-Ibarz: What is the importance on this combination? These two drugs represent the two more important mechanisms of action or mechanisms of disease of CLL. One is BCR inhibition and the second one is BCL2 inhibition. The two are quite complimentary. In the trial, you have a lead on three months of ibrutinib at standard doses of 420 milligrams, followed by 12 months of venetoclax. As we know from the data of venetoclax, venetoclax is a very, very powerful agent to really eradicate many matters of disease in the bone marrow of a patient. But even in combination with ibrutinib, obviously, the nodal reduction is quite dramatic. Responses are extremely high in the sense of overall responses as well as complete responses, but what is something that’s coming up of this trial as happened in the CLL14 trial combination venetoclax/obinutuzumab is the high proportion of MRD-negative patients that people can obtain.

Jacobs: In addition to this all-oral, chemo-free combination that has proven to be more effective in our IV cytotoxic chemoimmunotherapy combination, another exciting point is how in addition to being easily administered, being oral, it’s very well tolerated. The discontinuation rates on the study were low at only around 5% to 7%, so less than 10% discontinuation rates with really no alarming safety signals. The drugs seem to complement each other in terms of their mechanism of action, but don’t seem to add a whole lot in terms of toxicity when taken together. Some increase in nausea was seen, some increase in diarrhea, but not to alarming levels. The discontinuation rates were around what you would expect for either of the drugs taken individually.

Pinilla-Ibarz: Also, the more important thing is adding to the classical obinutuzumab/venetoclax, this ibrutinib/venetoclax is adding to the fixed duration of therapy. Something that in the last years has been a subject to multiple investigations and discussions between the CLL world. Now that ibrutinib is a drug that can be given until disease progression and a set of all toxicity, now that the venetoclax combination with obinutuzumab is one year in frontline, two years in the second line. Ibrutinib and venetoclax is really bringing, once again, a time limit of therapy with a very, very high likelihood to produce durable responses with an MRD negative that is really, really translated in prolonged PFS. We still don’t know really the follow up of these patients. However, we think we are very, very excited to see how this data is going to mature mainly in the high-risk population of patients.

Jacobs: Still a lot of work to be done, but very exciting for CLL patients, mostly importantly, to have this effective combination that’s well tolerated on the horizon.