More Promising BCL-2's and a Trial opportunity

[Smakwater]

Fresh off the press from cllsociety.org, an insight about a new study with a BCL-2 drug called sonrotoclax in combination with zanubrutinib.

cllsociety.org/2024/03/recr...

[Sushibruno]

good to know🙌 thanks.

[DriedSeaweed]

I would like to know if there is evidence sonrotoclax is successfully used on those resistant to venetoclax. Does it bind the same way or should we consider it a different generation like pirtobrutinib is to ibrutinib.

I’ll try to remember to ask during my next doctor’s visit in late May.

If anyone has already found out please share.

[DriedSeaweed in reply to DriedSeaweed]

Okay. They think it will work but needs confirmation.

“In summary, sonrotoclax emerges as a potential second-generation BCL2 inhibitor for the treatment of hematologic malignancies with the potential to overcome BCL2 mutation-induced venetoclax resistance. Sonrotoclax is currently under investigation in multiple clinical trials.“

pubmed.ncbi.nlm.nih.gov/382...

“In conclusion, sonrotoclax is a promising next-generation BCL2 inhibitor that is effective against both WT BCL2 and several mutants. It has potential for treating treatment-naïve patients as well as those resistant to venetoclax due to BCL2 mutations. Furthermore, combining sonrotoclax with other anticancer drugs that utilize different mechanism of action presents a therapeutic landscape for hematologic malignancies. Sonrotoclax as a monotherapy or in combination with other anti-cancer agents for the treatment of various cancers is under clinical investigation (NCT04277637, NCT04771130, NCT04883957, NCT05471843, and NCT05479994).”

[Smakwater in reply to DriedSeaweed]

Thank You for the citations.

[scryer99 in reply to DriedSeaweed]

I can't speak to the binding mechanism covalency/non-covalency, but I do know they told me in sonrotoclax trial prep that it was estimated at 10x the potency of venetoclax. The rampup was extremely slow - only 1-2 milligrams the first week - to ensure it didn't work too well and kick off tumor lysis syndrome.

The links DriedSeaweed provided, and the move to an immediate Phase III trial against the current standard of care, would certainly indicate confidence on BeiGene's part that they have a winner here in sonrotoclax. That kind of trial is not cheap. They also make zanubrutinib, and I'm sure hope to corner the market on treatment for CLL (and other leukemias as well).

I haven't had quite as smooth a ride as Foyks and some other posters, but side effects have been manageable and the medicine clearly is working to some level.

They are doing a ton of combination therapy trials so if you are comfortable going that route, there may be options for both treatment-naive and R&R patients. The pro is you hit CLL with a strong combination quickly, and it's fixed-duration so you may reduce your long-term CLL mutation risk. The con is you are using multiple treatments at once, and there are only so many arrows in the CLL medications quiver. I do know anecdotally that several Phase I participants have reached uMRD, particularly in the sonrotoclax + obinutuzumab arm. There's a number of papers reporting results; search for BGB-11417 which was the drug's tag prior to the sonrotoclax naming. One relevant to the CLL audience is here:

ashpublications.org/blood/a...

It's worth checking out. Trials are definitely more work as a patient, but the tradeoffs of high levels of monitoring/care and the drug cost sponsorship can work out.

[Smakwater in reply to scryer99]

Your post has brought an intensity to the conversation.

Both exciting and encouraging.

I am headed over to the link you provided.

Thanks scryer99

[DriedSeaweed in reply to scryer99]

I wonder if all trial participants should be checked for CHIP or some sort of predisposition of MDS before starting sonrotoclax. If there is a risk with using venetoclax for an extended period of time then if a drug is 10x stronger I would wonder if using it for less time could have an impact. Then we will know in a decade if there is a subpopulation of patients at risk.

I would still use sonrotoclax but it would be good to know.

This must have crossed someone’s mind at the company but I guess it is another expense and it risks bad press.

I will ask my doctor about it in May…

[Smakwater in reply to DriedSeaweed]

Those are some good questions to consider.

[bennevisplace]

Thanks. A v promising combination.

[Kiwidi]

Recruiting here in Aotearoa NZ too which is a real lifesaver for those wanting more ‘up to date’ treatment. Chemo is the only first line treatment available (apart from those who are TP53 and 17p deleted) I know of several CLLers who have been able to take advantage of it.

[Smakwater in reply to Kiwidi]

I am interested to see the follow up data.

[Foyks]

As a trial participant for over a year under first line treatment, I can attest to the effectiveness and lack of side effects for the combo of Zanabrutinib + Sonrotoclax.Hopefully it will become readily available in the near future.

[Smakwater in reply to Foyks]

Thank You for participating in the search for curative cause and a efficacious management for CLL patients.

I hope your effort provides you with a durable quality of life.

Thanks Again Foyks. Keep us posted

JM

[Steffi50]

Look forward to following this trial. Thx for posting

[Chi-town_Girl]

Hello. I am a participant in the Phase I clinical trial for "BGB-11417" now known as Sonrotoclax plus Obinutuzumab. This was my first treatment for CLL. I started my treatment almost one year ago on May 2, 2023 and am winding down the last few cycles of treatment. I have had an extremely favorable response. I needed to start blood pressure meds and have gained about 7 lbs, but I am anticipating losing the weight and getting off the blood pressure meds when I stop taking Sonrotoclax in early July.

I have been MRD-4 negative (since cycle 5 back in October 2023 and again when tested in Dec 2023). I was not considered "CR" (complete response) in Dec after CT scans because I have one lymph node that measured 18 mm which is above the 15 mm cut off for CR. They ran a pre-treatment ClonoSeq panel prior to treatment and will also test at that level MRD at some point in the future. I am scheduled for a bone marrow biopsy in June.

All my best to everyone in this trial!! Would love to hear other updates.

[Smakwater in reply to Chi-town_Girl]

Another sincere thanks to you for being a trial participant. These novel treatments would be very slow in coming if not for patients like you.

Thank you for sharing your experience and please keep us updated.

Wish you a long quality of life reward for the effort.

JM

[Msupsych in reply to Chi-town_Girl]

My doc discussed this trial with me earlier this week - so happy to hear from someone who has tried it! My numbers are doubling, but so far I don't have any physical symptoms so he didn't feel the need to start treatment, although I suspect it's quickly approaching.

[AussieNeil Partner Administrator in reply to Chi-town_Girl]

Thank you so much for participating in this trial and for your encouraging sharing of your trial experience.

Based on my experience on a similar combination therapy (acalabrutinib + obinutuzumab + venetoclax), be patient about your body getting back to normal after finishing treatment. It took me about 3 months.

Neil

[AussieNeil Partner Administrator in reply to Chi-town_Girl]

The iwCLL Guidelines Complete Remission (CR) requirements with respect to lymph node size are "None greater than or equal to 1.5 cm" (15mm). A 1.8cm node is so close to CR and sometimes nodes accumulate scar tissue, so that they can't fully shrink back.

[Chi-town_Girl in reply to AussieNeil]

Thank you so much Neil. Yes! I have also been told that sometimes lymph nodes never fully return to their original size (and this particular node measured 4.1 cm prior to treatment).

Thank you again, Neil!

[CLLerinOz Administrator]

There's some additional information about this combination in our post about the ASH 2023 conference, including a link to the relevant abstract presented at that conference.

healthunlocked.com/cllsuppo...

If you scroll through the replies from the link above, there's also a video interview with Dr Constantine Tam who presented at ASH.

CLLerinOz

[Smakwater in reply to CLLerinOz]

I missed that post. There is quite a lot there as well.

Thank you for providing that connection Oz.

JM

[Nana1961]

I was gonna do this trial but just found out it’s been delayed until end of July to mid August. Was suggested to start treat first of April but decided to try to wait for trial. It was supposed to open mid June.

I will probably do v&o or Zanubrutinib now.😢

[Smakwater in reply to Nana1961]

August will be here in a flash. You may want research qualification exclusions for previously treated.

[LumpyJeff816 in reply to Nana1961]

I'm in the study and the first two months is Zanubrutinib only, the Sonrotoclax comes later.

The Zanubrutinib has been an incredible miracle for me, it's like magic how fast it works with no side effects for my experience.

[LumpyJeff816]

I am in this study at the University of Kansas Medical Center, and am still in the Zanubrutinib only phase and will begin receiving Sonrotoclax at the end of the month. I started end of May 2024.

The Zanubrutinib alone has been like magic and I feel as if I'm normal again. Within 14 days on this stuff I went from being incredibly lumpy in my head, neck, chest area, being unable to swallow fully or breathe properly for a few months, to 100% feeling back to normal. No visible signs of cancer, and my energy levels through the roof where they were prior to diagnosis. There was a noticeable decrease in lymph tissues within 2 doses.

Considering I have unmutated type, I'm curious if I should hold off on Sonrotoclax (save it for later) and just continue with the Zanu's for as long as I can. Absolutely no side effects at all, multivitamins bothered my stomach more than these pills do. It's something I will discuss with the doctor early next week after we get blood/marrow results Mon/Tues.

Absolutely awesome research to come up with these drugs. And they're already researching a replacement for Zanubrutinib that will handle resistance when it occurs called Pirtobrutinib. Hopefully by the time I'm an older man (35 now) they will plug us into a computer and write out the bad code that causes the cancer.

If you're reading this and about to start treatment or considering options, Zanubrutinib has been a side effect free miracle for me. I will update on Sonroto once I start the ramp up.

[Smakwater in reply to LumpyJeff816]

Thank You for offering your experiences. There are a lot of people diagnosed with cll who need desperately to hear of successes like yours too substantiate their hope of regaining quality of life.

Great to hear that you are not only responding well, yet are also experiencing minimal side affects.

Hoping many more good days to come for you LumpyJeff816!

Seize the Day!!!

JM

[SofiaDeo in reply to LumpyJeff816]

Please don't leave the study. Not everyone has access & ability to do one, to gather this data we badly need. Since you've taken a slot someone else could have used, please don't leave for other than "this isn't working and they kicked me out", or "side effects became intolerable."

[DriedSeaweed in reply to LumpyJeff816]

There are risks taking zanubrutinib continuously. If you can do the Sonrotoclax too and get off all drugs you will do yourself a favor.

Pneumonia is elevated while on zanubrutinib.

Zanubrutinib can cause hypertension to get worse the longer you are on it.

Attacking the CLL by two mechanisims of action, an “orthogonal approach” as Dr. Koffman says, is better. Perhaps you can reuse sonrotoclax and zanubrutinib again after you get a long remission the first time.

Please don’t quit the trial. I think it would be something you would regret. Also, you are hurting the research…

I did Zanubrutinib plus venetoclax. Similar. I am only a couple years older than you. Blood pressure started to get really high later on from the zanubrutinib. Thank goodness it went down after I got off.

Hemorage is always a concern even though it is less than ibrutinib. I had to hold back when weight lifting and exercising. Now that I am off both drugs I get let loose and push hard.

If you can get your CLL cells to undetectible perhaps you can totally forget about your CLL for close to a decade. Take advantage of this opportunity.