Expert Discusses Ibrutinib/Venetoclax Combo in MCL

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.

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, 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.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.

Can you discuss the toxicities that were observed?

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

What are the next steps?

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.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.

Additionally, some patients may even be able to come off of drug therapy and restart the drug if the disease comes back.

How do you determine who will respond to this treatment?

Those are all unanswered questions, but the first step is to determine if the combination of the 2 drugs gives us better quality of remissions and longer remissions compared to the single agents. The advantage of our phase II study is that all 24 patients were treated at our site. Due to this, we have very comprehensive sample sets on these patients. We’ve got the baseline tumor, bone marrow, blood and plasma information in these patients, in addition to the sample when they relapsed, as well. The work is being done in order to determine why certain patients responded over others.

What are the main takeaways from this that you hope the audience will take with them?

Hopefully, based on our preliminary data, we will be able to generate a signal to open a larger phase III study to confirm what we have found.The main takeaway is that although ibrutinib and venetoclax have made a big step in the treatment of patients with refractory MCL, they are not permanent solutions. We’re taking steps to make rationale combinations with these drugs to improve therapy. What we’ve learned is that this combination in MCL might also be applicable to chronic lymphocytic leukemia, Waldenström macroglobulinemia, and other diseases. We’re also developing new combinations.

It’s important to note that we need to see the results of the phase III studies before we can confirm that these are combinations that should be given routinely in the clinic.

Tam CS, Rule S, Le Gouill S, et al. Phase 3 study of ibrutinib in combination with venetoclax in patients with relapsed/refractory mantle cell lymphoma. Hematological Oncology. 2017, 35: 421-422. doi: 10.1002/hon.2440_4.