Zanubrutinib-Gazyva Shows Promise for CLL/SLL

[Jm954]

June 25, 2019

Zanubrutinib (BGB-3111) is an investigational small molecule inhibitor of Bruton’s tyrosine kinase (BTK). Gazyva is a monoclonal antibody designed to bind to CD20, a protein found on the surface of certain types of B cells, including malignant CLL or SLL cells.

The safety and efficacy of the combination therapy of zanubrutinib and Gazyva in patients with different types of B-cell malignancies are currently being assessed in an open-label Phase 1b trial (NCT02569476) taking place in the U.S., Australia, and South Korea.

81 people had enrolled in the trial, 45 CLL/SLL patients — either treatment-naïve or who had failed prior treatments — and 36 follicular lymphoma patients who had failed prior lines of therapy.

Key findings presented at the conference showed that:

- Among the 20 previously untreated CLL/SLL patients, 100% responded to treatment, including 30% who achieved a complete response (complete tumor eradication);

- Among the 25 CLL/SLL patients who had failed prior therapies, 92% achieved a response, including 28% complete responses;

- Of the 36 follicular lymphoma patients, responses were observed in 72.2%, with 38.9% of the patients attaining a complete response;

- Of the six CLL/SLL patients with complete responses who were tested, half were negative for minimal residual disease (MRD, had less than one malignant cancer cell found among 10,000 white blood cells);

- Progression-free survival (PFS, the time patients lived without their disease worsening) had not been reached for either group of CLL/SLL patients, with 73.3% of the patients remaining on treatment;

- Most treatment-emergent adverse events were either mild or moderate but one patient with CLL/SLL experienced a treatment-emergent adverse event that resulted in death.

More here: lymphomanewstoday.com/2019/...

Jackie

[Indolent]

Great news! More options is always better! Chemo seems to be fading away!

[Jonquiljo]

Zanabrutinib? Wow! There seems to be a lot of BTK inhibitors out there. Has it yet been tested (even short term) against other BTK inhibitors?

Since I joined this forum over a year ago - there have been SO many new options for treatment (not just BTK inhibitors) that it is amazing! It seems that the limiting step is to test them all. Thats a good place to be in.

If the laws of economics hold true, prices should eventually come down as the competition is fierce among pharma companies.

[Jm954 Administrator in reply to Jonquiljo]

No head to head testing that I am aware, just undergoing phase 1 and 2 trials.

Yes, lots of great new drugs

Jackie

[cajunjeff in reply to Jonquiljo]

Like acalabrutinib, zanabrutinib is a more targeted btk inhibitor which means in theory less side effects than ibrutinib.

Ibrutinib dos not appear to have any synergy with monoclonal antibodies (mabs) like Gazyva and Rituximab. For reasons that are over my head, they think zanabrutinib will have synergy with the mabs, hence this trial.

So it sounds like on a couple levels zanabrutinib could be a better btk mousetrap than ibrutinib.

[Jonquiljo in reply to cajunjeff]

Makes sense. It must be that a good deal of these BTK inhibitors bind different sites, and therefore act differently. The people that develop them probably know where they precisely bind, but do not yet know what their clinical profile will be.

Ideally (in reality) a good BTK inhibitor would be synergistic with Mabs. This would lead to the possibility of using a lower inhibitor dose and (hopefully) reducing side effects. The same would be with the Mab - possibly even more than one Mab! Either way, the use of combos would likely be far more effective than a single drug.

I just see so many advances in such a short time for a disease that is not that common - it's very encouraging. Now, many of these drugs may target multiple diseases - but the more the merrier.

[Jm954 Administrator in reply to cajunjeff]

Interesting that some of the patients were MRD negative (their words) in a short time after starting treatment. If that is replicated in other studies it shows a lot of promise over Ibrutinib.

Jackie

[Jm954 Administrator in reply to cajunjeff]

Newdawn and I would love to be rid of the terrible joint pain side effects we suffer from 😞

[Justasheet1 in reply to cajunjeff]

Jeff,

I think Dr Davids from Sloan Kettering addresses this,

“I think an important thing to note is that we learned from ALLIANCE that ibrutinib and rituximab are not better than ibrutinib alone, but we can’t extrapolate this finding to other BTK [Bruton tyrosine kinase] inhibitors, for example acalabrutinib, which doesn’t have the same degree of off-target effects on natural killer cells. It also doesn’t say anything about obinutuzumab, which can kill CLL cells directly, without these immune effector cells. We’re going to need clinical trial data with these different agents before we know that. Fortunately, several ongoing studies will be able to address these questions.”

More targeted might mean synergy 🙏🏻

Jeff (from Georgia)

[HopeME in reply to Justasheet1]

What year was this quote from? It must be old since Dr. Davids has been at Dana Farber for quite a few years? He was at Sloan Kettering some time ago.

Thanks,

Mark

[Justasheet1 in reply to HopeME]

June 17, 2019

You’re right.

onclive.com/publications/sp...

[HopeME in reply to Justasheet1]

Jeff:

Thanks for posting the article. It’s great to see the increase in options available but it is also confusing trying to evaluate them all.

[Smakwater in reply to cajunjeff]

Although the MABs are as you say "does not appear to show synergy", they are relevant in giving benefit by expediting apoptosis where needed in some cases.

Kind of the equivalent of heavy artillery prior to a boots on the ground invasion.

JM

[cartwheels]

Sounds very promising Jackie thanks for the post

[country76]

Thank you this sounds very promising. I have a bright cd20.

[Wroxham]

Seems there are improvements all the time.

Thanks Jackie.

[Smakwater]

Jackie,

Considering the number of enrollees that were from failed prior treatments, this is better than just good news.

JM