Combination Is Promising and Tolerable for MCL

There is currently no standard of care for patients with relapsed or refractory mantle cell lymphoma (MCL), but a recent phase 2 study proved that the combination of Imbruvica (ibrutinib) and Venclexta (venetoclax) may be a promising treatment strategy for this group of patients.
 
In an interview with CURE, Contantine Tam, associate professor, Department of Haematology, Peter MacCallum Cancer Centre and St. Vincent's Hospital, Melbourne, Australia, discussed the combination’s potential, as well as what more needs to be done in this treatment landscape — including a phase 3 trial that will dive deeper into this therapy.
 

Can you provide a little background information on the phase 2 study examining Imbruvica with Venclexta?

Both Imbruvica and Venclexta are active in MCL, so patients typically respond, but the response and complete remission rates are fairly low when the agents are used individually. Since the two drugs don't have overlapping toxicities, we began an investigative initiative phase 2 study to combine the two drugs in patients with MCL. We used the full dose of Imbruvica and Venclexta in all our patients and we'll finish it with 24 patients with MCL, of which 23 were heavily pretreated, and one was a first-line. 
 
The results will show that the combination is quite tolerable. So, there were no unexpected toxicities and, importantly, there were no unexpected increase in the tumor lysis risk with the addition of Imbruvica to Venclexta. We also showed that there was a very high response rate. The complete remission rate was 63 percent, and of those patients, the majority — more than 75 percent — were minimal residual disease negative on the bone marrow as tested. So, we can verify the remission rate in the combination as very deep remissions. 
 
On that basis, a phase 3 study has been launched with the combination.
 

Earlier, you mentioned toxicities, can you talk about what kind of toxicities were seen with the combination?

We saw the types of toxicities that were expected with the two drugs individually. So, we saw Imbruvica-type side effects in terms of bruising and bleeding, and we also saw a small number of patients with atrial fibrillation — irregular heartbeat. On the Venclexta side, we saw the usual reflux symptoms and neutropenia. Importantly, none of these rank as higher than we'd expect when given individually than when we gave the two agents together. 
 
However, a number of patients had increased diarrhea and bowel movements of reflux. We think that was from pill burden because they're taking eight pills a day. None of the patients had to stop the drugs because of those side effects, but we do find some of the side effects to be troublesome in some patients. We chose to decrease Imbruvica and Venclexta by one notch. So, Venclexta is now given in three tablets instead of four, and that usually takes care of the side effects. 

What is being done to better understand why some patients don't respond?

The advantage of our particular phase 2 study is that all 24 patients were treated at our site. We actually have gotten very comprehensive sample sets of these patients. We have baseline tumor, bone marrow, blood plasma and we also have a sample of when they've relapsed. So, the work is being done to determine why they responded or why they didn't respond. Hopefully, based on our preliminary data, we'll be able to generate a signal to open a larger phase 3 study to confirm what we found.

What are the next steps following this phase 3 trial?

I think the most important thing to show in a phase 3 study is that, although we gained a very high response and very deep responses, ultimately what we'd like to see is patients staying in remission longer with very good quality of life and living longer. I think that's what the phase 3 study will hopefully show for us, whether the encouraging signals that we see in response are translated through to better remission durations and better overall survival. 
 
Once we get that then we need to start thinking about those patients who don't respond. Although we have a very high complete remission rate, about a third of patients don't respond and we need to know who they are. It would be great to be able to identify those patients frontline, before we even subject them to this therapy so that we can plan for alternate 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 get very deep responses, then, firstly, we may be able to overcome the need for allogeneic transplants for those patients, and some patients may even be able to come off drug therapy and may be able to restart the drug if it comes back. 
 
Those are all unanswered questions. I think the first step is to determine if the combination of the two drugs gives us better quality of remission and longer remission compared to the single agent. 

What are the main takeaways from this study?

Although Imbruvica and Venclexta have made a big step in patients with MCL, they are not permanent solutions. I think we're taking steps to make rational combinations with these drugs to improve therapy. 
 
And, what we're learning from this combination in MCL is probably also applicable to other diseases like chronic lymphocytic leukemia that could be sensitive to these drugs. So, we're developing new combinations. 
 
I think it's important to stress that we see the results of phase 3 studies before we confirm that this combination should be given routinely in the clinic. 

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