Time-Limited Triplet Emerges as a Potential Standard in Relapsed/Refractory CLL

[Jm954]

Oncology live May 06, 2020

The time-limited triplet of umbralisib, ublituximab, and venetoclax (Venclexta) could potentially become a standard of care for patients with relapsed/refractory chronic lymphocytic leukemia (CLL) who have progressed on frontline BTK inhibition, according to Paul M. Barr, MD.

In a phase 1/2 dose-escalation trial, the regimen led to a high rate of undetectable minimal residual disease (uMRD) and complete responses (CRs) in patients with relapsed/refractory CLL.

Results showed that the objective response rate (ORR) was 100%, and the CR rate was 44% at the end of 1 year of treatment. All patients had uMRD in the peripheral blood, and 78% had MRD negativity in the bone marrow. At a median follow-up of 6.4 months (range, 0.7-19.0+), no patients had progressed.

Umbralisib and ublituximab are relative new comers to the CLL treatment scene so it will be interesting to see how the safety profile develops. In the meantime, this study offers more hope for CLL patients.

More here: onclive.com/web-exclusives/...

Jackie

[HopeME]

Hi Jackie:

Why would this triplet only be considered for patients who have failed a BTK inhibitor? Is it that a BTK inhibitor would likely be part of a second line therapy if a patient hadn’t received it before or is there another reason? The number of approaches in the second line seems mind numbing.

Thank you,

Mark

[Jm954 Administrator in reply to HopeME]

I agree Mark and I don't think this should necessarily be just for those who have failed a BTK inhibitor but, personally, I would need more safety data on Umbralisib before I would venture there. Most previously treated people still have not yet had a BTK inhibitor and that would be the natural follow on from CIT, with or without venetoclax.

Jackie

[Hidden]

the problem for me with these triplet trials is they all depend on venetoclax to do the heavy hitting.

are there any new bcl-2 drugs? coming out At least umbralasib is a p13k inhibitor-some what different than imbruvica

[HopeME in reply to Hidden]

Agreed. The big V is always surrounded by rotating supporting actors.

[cajunjeff in reply to Hidden]

I would not discount the role umbralisib and ublituximab play in this combo. The results of this trail so far are nothing less than astounding, over 70% mrd negative in a relapsed population. Imagine what the results would be in a treatment naive group.

Umbralisib is a second generation P13 k inhibitor and has been engineered to reduce side effect profile of idelalisib, a drug that is effective but intolerable for a lot of people. It works like ibrutinib, it just inhibits a different part of the chain.

Ublituximab is like other cd 20 monoclonal antibodies p, but perhaps as much as 50 times or more powerful than other cd 20 antibody drugs. It’s a glycoengineered drug, a process where sugar is taken out of the antibody allowing it to bind more effectively and kill more Cll cells.

I don’t know what the stats are for venetoclax alone in a Cll relapsed group, but I doubt it’s 100% mrd negativity in the blood and 78% in the marrow.

This triple features 3 hard hitting drugs with 3 different mechanisms of action. I do think venetoclax is likely the best of the three, but it’s still likely that the future of Cll treatment will be combination therapy.

I think the acalabrutinib, obinituzimab and venetoclax combination is the rock star group. Now I am not so sure. A trial comparing AVO and UVU would be a heavyweight matchup. Exciting times.

[Hidden in reply to cajunjeff]

my point is the drug that does NOT get replaced is venclexta. what we need is next generation bcl-2 drugs. would make me feel better.

[Hidden in reply to Hidden]

and i found the next generation bcl-2 inhibitor

biospace.com/article/releas...

[AussieNeil Partner Administrator in reply to Hidden]

I'm maintaining a list of newer CLL drugs here, which is not exhaustive, but I had included APG-2575 as a new BCL-2 drug:

healthunlocked.com/cllsuppo...

[Canuck901]

Amazing phase 1 trial they have a ways to go in trials though yet , looks promising

Looks like a any thing. Combined with Venetoclax is having outstanding results

[AdrianUK in reply to Canuck901]

Yes you are right. Basically we are reinventing a new FCR. Remember F and C were originally used alone, then together, and then with R. Similarly it makes total sense that even though V is fantastic on its own if you add it to other drugs you will hopefully find that you are more likely to get to MRDU and hopefully more likely that if you do relapse you won't be resistant to any of the treatments since a new clone would have to be resistant to all of them to have a survival benefit.

[cartwheels]

Wow this sounds exciting and for those of us on btk inhibitors reassurance that another great option is out there when our current one fails. I like the sound of this if i have read it correctly then there would be treatment break once MDR is achieved which is very appealing

[Jm954 Administrator in reply to cartwheels]

Yep, you read it right