Expert Discusses Ibrutinib/Venetoclax Combo in MCL

Danielle Bucco
Published: Wednesday, Jun 14, 2017

Dr Constantine S. Tam

Constantine S. Tam, MBBS

The ongoing phase III PCYC-1143 trial is investigating the combination of ibrutinib (Imbruvica) and venetoclax (Venclexta) in patients with relapsed/refractory mantle cell lymphoma (MCL). Individually, both agents have achieved response rates of 67% to 75% in this patient population.

Patients will receive 560 mg of ibrutinib once daily and venetoclax daily starting at 20 mg on day 1 and gradually increasing to a target dose of 400 mg/daily. The primary endpoint is progression-free survival.

“The most important thing in the phase III study is to demonstrate that although we are seeing very high and deep responses [in phase II research], we would like to see patients staying in remission for longer with an increase in quality of life and ultimately living longer,” Constantine S. Tam, MD, said in an interview with OncLive at the 2017 International Conference on Malignant Lymphoma biennial meeting in Lugano, Switzerland.

Tam, associate professor, Peter MacCullum Cancer Centre, discussed the phase II results that led to the phase III trial, as well as the next steps with venetoclax /ibrutinib and other rational combinations in MCL.

OncLive: Please provide an overview of the phase II trial investigating the combination of ibrutinib and venetoclax in MCL and how this has led to the ongoing phase III trial?

Tam: As we know, ibrutinib and venetoclax are quite active in mantle cell lymphoma; however, patients typically have fairly low complete remission rates with these agents individually. As the 2 drugs don’t have overlapping toxicities, we undertook the phase II study to combine the 2 drugs in patients with MCL. This is an investigative initiated study. We’ve used the full dose of ibrutinib and venetoclax in all of our patients and we have finished accruing 24 patients with MCL. Of those 24 patients, 23 were heavily pretreated and only 1 was frontline.

The results demonstrate that the combination is quite tolerable. There were no unexpected toxicities or increases in the tumor lysis risk following the addition of ibrutinib to venetoclax. 

This study also demonstrates a very high response rate. The complete remission rate was 63% and of those patients, the majority—75%—were in fact minimal residual disease–negative on the bone marrow. We’re getting very high complete remission rates in combination and very deep remissions. 

Due to those results, Pharmacyclics has launched a phase III study investigating the combination versus ibrutinib alone in patients with MCL.

Can you discuss the toxicities that were observed?

We saw the toxicities that were expected from the 2 drugs individually. Ibrutinib had side effects in terms of bruising and bleeding. On the venetoclax side, we saw the usual reflux symptoms and neutropenia, which are both what we would expect to see with venetoclax. Importantly, neither one of these toxicities was higher when [these drugs were] given in combination [compared with monotherapy].

We did see a number of patients experience diarrhea, which led us to infer increased frequent bowel motions or an increase in reflux. This could be due to the fact that this treatment requires 8 tablets a day. However, none of the patients had to stop their treatment because of those side effects. In some of the patients who did find the side effects to be troublesome, we’ve decreased ibrutinib and venetoclax by 1 notch. Patients therefore only had to take compounded 3 tablets instead of 4 which usually takes care of the side effects.

What are the next steps?

The most important thing in the phase III study is to demonstrate that, although we are seeing very high and deep responses, we would like to see patients staying in remission for longer with an increase in quality of life and ultimately living longer. In my opinion, the phase III study should hopefully show us whether the encouraging signals that we see in response is translated through to better remission durations and better overall survival. 

Once we have that information, we need to start thinking about those patients who do not respond. Although we have a very high complete remission rates, about one-third of patients don’t respond and we need the ability to identify who those patients are. It would be great to be able to identify those patients in the frontline setting before we even subject them to these therapies in order to plan for alternative treatments for these patients. 

Ultimately, the other thing that we need to know is how durable the remission durations are. If the remission durations are very durable and patients experience very deep responses, then we may be able to overcome the need for allogeneic transplants for those patients. 

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