Second-Generation BTK Inhibitors Hit the Treatment Bullseye With Fewer Off-Target Effects

[Jm954]

August 16, 2020

Fewer off-target effects mean second-generation BTK inhibitors offer less cardiotoxicity, fewer AEs that result in stopping treatment and therefore allow patients to stay on them longer, increasing their efficacy.

Zanubrutinib is associated with less incidence of muscle spasm, peripheral edema, pneumonitis, and pneumonia. In essence, fewer overall AEs with second-generation BTK inhibitors means less of a need to reduce dosing and a greater likelihood of being able to stay on treatment longer. Tam noted that most AEs happen with zanubrutinib during the first year on treatment, before their incidence plateaus, whereas prolonged treatment with ibrutinib has a greater chance of inflicting cumulative damage to the vascular system. Compared with first-generation BTK inhibitors, the second-generation drugs are associated with fewer concerns about primary and acquired drug resistance.

These resistance mechanisms of action are 2-fold. They are molecular, in that they involve sustained distal B-cell receptor signaling through PIK3-AKT (protein kinase B) pathway activation, NFkB pathway activation, and cell cycle progression. They also are therapeutic, in that lines of therapy administered after BTK inhibitors do not produce prolonged responses or exceptional overall survival.

It’s a straightforward idea: When patients can tolerate treatment, it improves their chances of survival. “This is important,” Tam said during ASCO. “The longer you take the drug, the better your responses become.”

More here: ajmc.com/view/second-genera...

and here: jhoonline.biomedcentral.com...

Jackie

[Canuck901]

Interesting tney have been using Zanubrutnib for quite sometime In Europe and it’s just starting to trickle in the US not anywhere near close in Canada

[LeoPa]

That's really good. The more competition between manufacturers the better. It should help bring the astronomical prices down in the future.

[Agiledog in reply to LeoPa]

Not so sure competition has reduced drug prices in the U.S. Recently heard it cited on the topic that average markup in the nondrug retail market is about 50-100%. In pharma the average is 5,000%(50x). Wonder what the multiplier is for cancer drugs? Am I mistaken?

[LeoPa in reply to Agiledog]

The US is specific in this regard. I don't remember the details but there's some law passed by Congress that prevents the government from negotiating prices with the manufacturers or something similar. That's what I read somewhere. ABBV increased the price of Imbruvica twice this year. By substantial amounts.

[Agiledog in reply to LeoPa]

Yes, you are correct on the Abbvie point. So, just sayin’, competition has not proven friendly thus far. Pharma and the financial industry are the biggest contributors to those who make the laws. One big conundrum. Cheers. And best wishes,

Bud

[LeoPa in reply to Agiledog]

Thank you, likewise!

[NooNoo14]

Sounds good to me....

[bennevisplace]

Thanks for this useful update.

The various codes/ names of compounds and products by which these drugs are known can be confusing. Especially when the list of BTK inhibitors for CLL already exceeds a dozen. A good reference is AussieNeil's comprehensive review of 10 months ago, updated 20 Sept 2020.

healthunlocked.com/cllsuppo...

[SBMACLL]

I was on "Z" as part of a triple drug trial and had zero side effects.

[studebaker]

Thank you Jackie. This has been on my mind lately as I was questioning weather to stay on Acalabrutinib or maybe add Venetoclax.

I think that, I will stay on Acalabrutinib mono therapy as long as it works.

Stay safe Jackie

Dana

[Jm954 Administrator in reply to studebaker]

I think that's a good decision, cajunjeff has been wrestling with the same and I think pretty much decided the same with the support of his Dr.

Take care Dana,

Jackie

[Agiledog]

This is consistent with my experience which I was told to expect when I began the long term acalabrutinb dosing trial at NIH. ALC has improved steadily from 140 to 4 at last weeks labs, now 45 months in.

[Agiledog]

Jackie,

Could you expand a bit on the line from your post...........”in that lines of therapy administered after BTK inhibitors do not produce prolonged responses or exceptional overall survival.”

I am 45 months into acala NIH trial, continuously improving, now at ALC 4 from 140. So do I take the quote to mean that when I relapse on acalabrutinib(my first line was FCR), my outlook with Venetoclax or some combo is not so good?

Great post

Bud

[Jm954 Administrator in reply to Agiledog]

Agiledog, from the evidence we have at the moment, I'm afraid that appears to be true, even with Venetoclax. However, we can take solace in the fact that many people who had Ibrutinib as their first treatment, are now 8-9 years out and still going strong. Also, if we eventually develop a mutation that produces resistance then there are BTKi's that are being designed specifically to get around them.

I'm hoping and praying for many, many more years on our BTKi's.

Stay well, Jackie

[AdrianUK in reply to Jm954]

The data are not quite as clear cut since they are looking mainly at heavily pre treated patients. Some had 15 lines of therapy before venetoclax!

Also the statement about less durable responses only applied to those who developed resistance to ibrutinib not for those who were switched for other reasons. And also this wss a Trend towards less response not zero response. And finally most of these patients were not treated with combination with rituximab which does seem to add some benefit.

The data is not at all clear yet for what will happen for people who take Ibrutinib first or second line then progress and move to venetoclax. Or indeed what will happen the other way round for those who take venetcolax first or second line and then move to ibrutinib.

This might all also be complicated by the length of time someone has been unwell since CLL tends to evolve into more aggressive forms over time. Certainly we know that FCR seems to work best early in the disease and can lead in some comes to what is effectively a cure.

It may be that we would be wiser to consider a venetcolax combo relatively early in the disease wirh the hope of getting MRDU and a really long remission. And then moving to continuia jbrutinib or another inhibitor only when the CLL no longer fully responds to more aggressive treatment. Over the next few years theee may well be a trend towards adding venetcolax to those currrenyly on Ibrutinib to see if you can get off all treatments. I’m not currently aware of any clinical study run in that group, however.

Right now there is a lot of uncertainty. Time will tell what is the best strategy as will the various trials ongoing.

Here is a review paper talking about what predicts response to venetoclax ncbi.nlm.nih.gov/pmc/articl...

[Jm954 Administrator in reply to AdrianUK]

The paper you quote confirms exactly what I've already said.

Rituximab has not been shown to add significant benefit to Ibrutinib and Ibrutinib for relapsed CLL does not show long responses.

The charts from the paper you cite show a continual decline in PFS with Venetoclax, and, for those who do not achieve a CR or U-MRD that most will have progressive disease within 18-30 months. Even those that do have a CR or U-MRD are only estimated to have 36 months PFS at the most - a dismal picture.

"Fewer prior therapies were associated with higher CR rate, but not Duration of Response. Chromosome 17p deletion and/or TP53 mutation and NOTCH1 mutation were consistently associated with shorter DoR, but not probability of response. Thus, both pretreatment factors and depth of response correlated with DoR with venetoclax. Patients without bulky lymphadenopathy, BCRi-refractory CLL, or an adverse mutation profile had the most durable benefit."

What we need to know is that, if patients achieve a CR and come off Venetoclax, will they respond when re-challenged with it. As with all treatments, it's likely that, if they do respond, it will be for a shorter period.

Jackie

[Agiledog]

Thanks, Jackie. So far the second generation BTK’s are proving to be as robust as ibrutinib in the shorter duration of use. Hopefully that will be sustained. Mortality general statistics show that the longer one lives..........well, the longer one is expected to live. Forward, ho! Indeed.

Best,

Bud

[AussieNeil Partner Administrator]

Encouraging news regarding bleeding risk for those on 'blood thinners', with respect to third generation (non-covalent) bonding pirtobrutinib.

Research suggests Pirtobrutinib may provide a safe and manageable risk of bleeding in those requiring antithrombotic therapy

(People who require anti platelet or anticoagulant therapy)

healthunlocked.com/cllsuppo...

Neil