beigenemedical.com/Congress...
This is a combo trial, sonrotoclax and Zanubrutinib on treatment naive patients. Zanubrutinib given for 8-12 weeks prior I would think to lessen the chance of TLS, and there were 0 reports of TLS, so seems like a good strategy
1) 100% ORR
2) 100% PFS
3) 10x the potency over venetoclax
4) 4 hour half-life -- this is a very short half life compared to 26 hours of venetoclax. Would love to hear any thoughts on the short half-life: should that reduce toxicity?
As a grateful participant in this trial, I can endorse the promising results so far:Rapid improvement in symptoms after first few months.
No significant side effects and reached MRD after 12 months.
Due to complete 2yr trial in 6 months.Hopefully this new treatment opportunity will be readily available soon.
Awesome, so glad to hear this. Thanks for sharing.
Thanks for sharing these slides. Very promising results, although the short follow up time of 10 months and low sample size have to be taken into account.I hope to start a phase 3 trial with one arm SonroZa and one VenO soon. The dosage will be 320mg as determined superior by this study.
I just whish we knew more about the chances of developing a resistance to Bcell2 and BTK inhibitors after the first line of treatment.
Resistance!
Yes, this is what scares me.
My original post in this site was an idea to address resistance and adverse reactions.
The idea is not to treat to uMRD but rather use a short term intermittent low dose therapy that just keeps the disease in check
In this way, you can dramatically reduce resistance and AE, keep the micro environment intact, and reduce costs.
There have been excellent papers on this that people were so kind to provide on this site.
i still remain hopeful that a pulsed therapy protocol will turn out to be a better strategy for treatment.
Reducing resistance seems nice but I havent seen any recent papers prproposing intermittent therapy over MRD guided therapy.In the meantime there are more novel therapies each year which offer options post BTKi resistance.
- Non covalent BTKis like Pirtobrutinib have great results
- Bi specific CD20 therapy with the (very) novel Epcoritimab drug looks promising
- Some evidence shows retreatment with BCell2 inhibitors and BTKi inhibitors is possible if resistance was not yet developed in the previous treatment line.
These all do feel a bit too novel to bet your life on in the long run. Maybe I'm being overly optimistic.
Here's some links, images, and a write up on the pulsed therapy. I thought it was a new idea, but it looks like there's been considerable work already done on it.
"Robert Gatenby, Matias Casás-Selves & James DeGregori published several papers making the argument not to reduce the disease to uMRD, but rather, limit therapy to simply control the disease, thereby reducing the chance of resistant mutations and adverse reactions. See their fascinating papers, trial results, and write up in Scientific American:
Great overview of their work published in Scientific American
scientificamerican.com/arti...
Paper on the importance of the tumor microenvironment
link.springer.com/content/p...
Actual trial of the pulsed therapy technique published in Nature for prostate cancer that showed promising results (of course, prostate cancer is not CLL, but conceptually their rationale seems plausibly transferrable)
nature.com/articles/s41467-...
The graphic (below, upper portion) from the Springer paper shows the course of the disease when attempting to achieve uMRD. When the drug therapy is used long term, it creates a small but homogenous population that is likely to have become selectively resistant to the drug. And when the population inevitably returns, it will need to be treated with an alternative drug, provided one is available.
On the other hand (graphic below, lower portion), by just treating the disease enough to keep it in check, the population never becomes homogeneous, selective resistance is minimized, and competition from the microenvironment keeps replication rates in check. I noticed in the CLL14 study supplement, post-treatment doubling times ranged from roughly 45-90 days which seems to support an undesirable rate increase from pre-treatment levels.
I became interested in creating a model for this behavior and found a breakthrough paper from 2017 (I'm sure you know it) where the researchers used heavy water to quantitatively determine the CLL cell replication and CLL cell apoptosis rates both without treatment and with ibrutinib. Here's their results:
Untreated
replication rate 0.39% ± 0.21% per day
apoptosis rate 0.18% ± 0.18% per day
net increase in CLL cells .21% per day (which very reasonably comes to an annual doubling rate)
Treatment with Ibrutinib
replication rate 0.05% ± 0.09% per day
apoptosis rate 1.5% ± 0.83% per day
net decrease in CLL cells 1.45% per day
Using these results, I was able to model the increase in CLL cells (+.21%/day) during the untreated period and the decrease in CLL cells (-1.45%/day) in the treatment period and found a protocol of 2 weeks on and 4 months off achieved a stable CLL count (see figure below).
I suspect a combination therapy of ibrutinib or one of the newer BTK inhibitors plus venetoclax would achieve an even longer treatment to non-treatment ratio. While there is no definitive study of this actual treatment regimen for CLL, it does make a compelling case for the reasonable likelihood of beneficial outcomes: less adverse reactions, reduced risk of selective resistance, less disruption of the microenvironment, and hopefully longer survival times, as well as lower drug treatment costs."
Thanks for sharing these slides which, I think, were released to coincide with the presentation of data from this study at the ASH 2023 conference late last year.
Constantine Tam, MD, who's been involved in this research, gave an interview for VJHemOnc at the conference and, in it, he explained that it's hoped that sonrotoclax + zanubrutinib will have a better side effect profile than, say, ibrutinib plus venetoclax. The video is linked in this post: healthunlocked.com/cllsuppo...
A couple of months ago, AussieNeil also provided some additional information about sonrotoclax in this post: healthunlocked.com/cllsuppo...
More recently, the ASCO 2023 meeting included an abstract about sonrotoclax + zanubrutinib vs ven + obinutuzumab (obi) in patients with TN (treatment naive) CLL (A phase 3 trial is ongoing) healthunlocked.com/cllsuppo... (Scroll down to ABSTRACT #TPS7087)
CLLerinOz
Also, there are a number of papers on sonrotoclax that were presented at the 2024 European Hematology Association (EHA2024) that ended a couple of days ago:
library.ehaweb.org/eha/#!*s...
Thanks. I didn't know this was so widely known. I tried to search here on it, and nothing came up, so I figured I'd spread the word on it. Seems like I'm late to the game. This forum is good.
PulsedTherapy, I am glad that you posted! Please continue to do so!
A comment on "potency" of medications. A "more potent" med doesn't work better than another in the same class. Potency refers to the "mg strength" needed to obtain the same effect. A "more potent" medication is a problem when someone accidentally or purposely takes an overdose; 50 pills of a more potent medication can cause more problems than 50 pills of a less potent medication.
"Efficacy" is the thing we are looking for. If one drug is more effective than another at the same relative dose, everything else being equal, the more efficacious drug is likely to be used before a less efficacious one.
"Half life" may affect side effects, or it may not. Something that has 10 times the potency may have a corresponding side effect increase, mg per mg. Half life is only one of a number of factors involved in how well a drug works. The problems surrounding long half life versus short half life are also affected by something called a drugs Volume of Distribution, and whether or not it is fat soluble. If a drug stays mainly in the bloodstream but doesn't penetrate lymph nodes or spleen well, its usefulness in CLL may be limited, regardless of potency. Short half life medications may need to be taken multiple times a day, which annoys/is difficult for some patients. (Not all medication can be formulated in an extended dose form.) But too long of a half life, means if one is getting adverse effects, it will take longer to get out of the body. If a drug is highly fat soluble, patients who have a higher body fat percentage may take longer to reach the effective "blood concentration" as the drug is slowly getting into fat cells, as well as taking longer to clear the system when discontinued. In addition, there is a concept called "therapeutic index" of a drug, which refers to the range a drug concentration can change such that it is effective without being toxic. A larger theraputic index, without side effects, is more desirable. Smaller therapeutic index agents generally need careful monitoring, since the blood level needed for effectiveness is closer to the blood level where toxic effects occur. A classic low therapeutic index drug is lithium. If you look at the therapeutic range example of Table 1.1 in the link below, you can see how small the differences are for lithium, compared to the other drugs listed.
And this also is affected by absorption elimination, excretion, interaction with other diseases/drugs issues.
ashp.org/-/media/store%20fi...
Sofia,
Wow! That was as comprehensive an answer that I have ever read here.
Jeff
Regarding drug half-life and toxicity, the measured plasma levels alone can sometimes predict toxicity and this information is essential in phase I clinical trials and beyond in drug development. However, other pharmacokinetic measures such as total exposure over time after a dose, a.k.a. area under the plasma concentration vs time curve or "AUC" and/or steady state levels after multiple doses may correlate better than drug half life alone. Also, more frequent dosing e.g., once vs twice vs....etc. may be chosen for some, but not all drugs with a short half life. Eventually, a steady state level of the drug results that is aimed to be sufficient to inhibit the target, such as BCL-2 or BTK. Others factors affect drug toxicity such as off-target effects of the drug, or so-called specificity. If the drug inhibits other targets, then more toxicity may occur, like gastrointestinal, cardiac, dermatologic etc. toxicity. Finally, if the drug effect on the target protein (s) are more complete and longer lasting even while the measured drug half-life in plasma is short, then this may also affect toxicity. Combine all of this with individual variably on how the drug is metabolized and variations in the pharmacokinetics, and you can see why phase I studies and continued study of how the drug is handled in the body are so important in predicting therapeutic efficacy and toxicity.
I’m getting ready to start this trial at Moffitt Cancer Center. Sounds like it went pretty well for you! My lymph nodes are what’s causing a lot of problems. My bloodwork isn’t the best but pretty stable right now.
My onocologist thinks this combo would be good for me due to enlarged lymph node situation.
I'm in the Phase 1 trial on this drug combination. There are several other board participants in that trial as well, though several don't post much because they reached uMRD and have happily moved on. I'm not in that boat, but it's been going OK. CLL symptoms have mostly improved. ALC reduction from problematic levels was immediate and rapid. Side effects are there but mostly manageable. Immune system effect has been non-zero but I have not required IVIG treatments. I'd recommend Phase 3 to the right patients (those with more aggressive CLL and/or unfavorable genetic profiles).
Shorter half-life and higher potency, as SofiaDeo and Bluesintheknight post above, don't necessarily correlate to outcome. They do however give practitioners some different options in terms of dosing and frequency of medication.
The whole idea of immunotherapy requires a consistent level of the medication in your bloodstream and bone marrow where it can do its work against the cancer cells, but not build up in places where it can cause unwanted side effects. If half-life is too long, then the drug could accumulate in your body over time. If it's too short, it could drop to low levels and give the cancer a chance to recover. But these must be matched to dosing frequency and amount.
Pharmacokinetics is complicated. Much of the Phase 1 work was designed to sort that out - I had 4 blood draws a day intermittently for quite some time early in the trial. But the Phase 3 won't have to do as much of that.
Keep in mind, though... it's early still. They did not do a phase 2, and phase 1 administered Sonrotoclax to I think <1000 patients across all trial arms. There's some evidence it works, but across all CLL cases and for a long time? That's still being figured out.
Great update from "the trenches", thanks for sharing.
Long, but much needed post about calquence vs venetoclax
What happens IF you break a venetoclax tablet before you swallow it?
Treatment time, hard choice!
Cost Effective Venetoclax from India or elsewhere
Venetoclax before Gazyva 
