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 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 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 Volunteer]

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