Zanubrutinib looks promising on all fronts in ... - CLL Support

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Zanubrutinib looks promising on all fronts in first interim analysis of ALPINE Trial - Ibrutinib v Zanubrutinib in R/R CLL - report from EHA

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Jm954Administrator
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Dr Pete Hillmen (UK) reported on this at EHA on 11th June 2021

Background

First-generation BTK inhibitor ibrutinib is a standard of care in CLL/SLL around the world. Zanubrutinib is an irreversible, potent, next-generation BTK inhibitor designed to maximize BTK occupancy and minimize off-target inhibition of TEC- and EGFR-family kinases.

It was hypothesized that the increased specificity of zanubrutinib may minimize toxicities related to ibrutinib off-target inhibition (Coutre Blood Adv. 2019;3:1799-807) and more complete and sustained BTK occupancy may improve efficacy outcomes. Activity and tolerability of zanubrutinib in patients with CLL/SLL has been demonstrated in early phase trials (Tam Blood 2019;134:851-9; Tam Haematologica 2020;epub).

Aims

ALPINE (BGB-3111-305) is a global, randomized, phase 3 study comparing zanubrutinib vs ibrutinib in patients with relapsed/refractory (R/R) CLL/SLL. Here they present the results of a pre-planned interim analysis scheduled approximately 12 mo after the first 415 out of 652 patients were enrolled.

Methods

Patients with R/R CLL/SLL were randomly assigned 1:1 to receive zanubrutinib 160 mg twice daily or ibrutinib 420 mg once daily until disease progression. Randomization was stratified by age (<65 years vs ≥65 years), geographic region, refractory status, and del17p/TP53 mutation status.

The primary end point was overall response rate (ORR) as determined by investigators using the 2008 iwCLL guidelines for CLL and the Lugano criteria for SLL. Sample size was calculated to provide 90% power to demonstrate non-inferiority of zanubrutinib to ibrutinib response ratio at the non-inferiority margin of 0.8558.

A hierarchical testing approach was implemented to test the superiority of zanubrutinib over ibrutinib in ORR if non-inferiority was demonstrated.

Results

Between 5 Nov 2018 and 20 Dec 2019, 415 patients were randomized. Treatment groups were well balanced for demographic and disease characteristics: age ≥65 years 62.3% vs 61.5%, male 68.6% vs 75%, >3 prior lines of therapy 7.2% vs 10.1%, del17p 11.6% vs 12.5%, TP53 mutated without del17p 8.2% vs 5.8%, in zanubrutinib and ibrutinib arms, respectively.

At a median follow-up of 15 mo, ORR was significantly higher with zanubrutinib vs ibrutinib (78.3% vs 62.5%, 2-sided P=0.0006 compared with pre-specified alpha of 0.0099 for interim analysis). ORR was higher in patients with del11q (83.6% vs 69.1%) and del17p (83.3% vs 53.8%) with zanubrutinib, as were overall 12-mo PFS (94.9% vs 84.0%, Figure) and OS rates (97.0% vs 92.7%).

The rate of atrial fibrillation/flutter, a pre-specified safety endpoint, was significantly lower with zanubrutinib vs ibrutinib (2.5% vs 10.1%, 2-sided P=0.0014, compared with pre-specified alpha of 0.0099 for interim analysis).

Rates of major bleeding (2.9% vs 3.9%), and adverse events leading to discontinuation (7.8% vs 13.0%) or death (3.9% vs 5.8%) were also lower with zanubrutinib. Rate of neutropenia was higher with zanubrutinib (28.4% vs 21.7%), while grade ≥3 infections were lower with zanubrutinib (12.7% vs 17.9%).

Conclusion

In this interim analysis of a randomized, phase 3 ALPINE study in patients with R/R CLL/SLL, zanubrutinib was shown to have a superior response rate, an improved PFS and a lower rate of atrial fibrillation/flutter as compared with ibrutinib.

These data confirm that more selective BTK inhibition, with more complete and sustained BTK occupancy results in improved efficacy and safety outcomes. (Trial NCT03734016)

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13 Replies
DebKat999 profile image
DebKat999

Thank you Jackie, learning about these kinds of studies is always of great interest to me as I slowly get closer to treatment time. My CLL specialist has already spoken about Ibrutinib most likely being inappropriate for me, so I am very thankful to learn about each new subsequent drug treatment and any comparisons of the two.

Debbie

bennevisplace profile image
bennevisplace

This stuff is the fabled Medicinal Compound!

Thanks Jackie.

Milla15 profile image
Milla15 in reply tobennevisplace

"Most efficacious in (almost) every case"

CLLerinOz profile image
CLLerinOzAdministrator

Thanks, Jackie - it's good to see such promising data.

I've added this post to the ASCO & EHA 2021 summary post which lists the main abstracts from those two recent conferences. healthunlocked.com/cllsuppo...

Zanubrutinib Vs Ibrutinib Atrial Fibrillation
Phil4-13 profile image
Phil4-13

Sure wish those over 65 could have been in the trial, especially since it has been stated that average age of diagnosis is 72. Simply a wish, but accompanied with excitement for this continued research on our behalf. GO FORWARD RESEARCH!

Sandra 👍🙂

HopeME profile image
HopeME

Thanks Jackie. But how does it compare to acalabrutinib? I’m really confused now 😁. Lots of treatments but it makes choices incredibly difficult.

Jm954 profile image
Jm954Administrator in reply toHopeME

The answer is to look at the safety profile to know which one is right for you or at least not suitable for you

Heart issues? - not Ibrutinib

Joint issues, pre-existing arthralgia - probably not Ibrutinib

On PPIs - probably not Acalabrutinib

On Anticoagulants - probably not Ibrutinib

Head to head studies like this are unusual so I don't expect to see an Acalabrutinib v Zanubrutinib study any time soon but the newer BTKi's are cleaner with less off target effects which is good.

Jackie

wroxham-gb profile image
wroxham-gb in reply toJm954

Thanks Jackie.Sue

morepork profile image
morepork

Not all of us are fortunate enough to have a menu of 'brutinb' choices at hand.

Jm954 profile image
Jm954Administrator in reply tomorepork

Sadly, that's very true.

CCgroup profile image
CCgroup

Many thanks for the information - it is very positive. Great to see so much research on new products is being done. They are all steps towards and eventual cure.

Wetumpka profile image
Wetumpka

This is the first I have heard about this drug. Thank you for all you do .

Wetumpka profile image
Wetumpka

Thank you for all your very informative work to do on our behalf.

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