YABTKi or Yet Another BTK inhibitor - the A to... - CLL Support

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YABTKi or Yet Another BTK inhibitor - the A to Z list of Bruton's Tyrosine Kinase Inhibitors for CLL following Ibrutinib's success

AussieNeil profile image
AussieNeilAdministrator

I'll admit that YABTKi is not a recognised CLL related acronym, (see here for the lists healthunlocked.com/cllsuppo... ), but perhaps it should be! Following on from Ibrutinib's success, there's a growing list of BTK inhibitor drugs on trial, each endeavouring to be more selective (i.e. have less side effects) and/or avoiding the known (but thankfully small) resistance development risk with Ibrutinib. Thank you to the many contributors assisting me to keep this post current.

Background: Addressing the Medical Need in CLL: How BTK Inhibitors Are Improving Outcomes, by CLL specialists Drs Ian W. Flinn, Nichole Lamanna, Susan M. O'Brien, John Pagel and others.

clinicaloptions.com/oncolog...

Jm954's posts Next Generation BTK Inhibitors and why we need them healthunlocked.com/cllsuppo...

Twenty year development of Ibrutinib, comparison with Acalabrutinib and Zanubrutunib and much more!

nature.com/articles/s41375-...

The Development of Bruton’s Tyrosine Kinase (BTK) Inhibitors from 2012 to 2017: A Mini-Review (very technical)

researchgate.net/publicatio...

Second-Generation BTK Inhibitors Hit the Treatment Bullseye With Fewer Off-Target Effects healthunlocked.com/cllsuppo...

Pre ASH2020 presentation by three CLL specialists: Drs Ian W. Flinn, Susan M. O'Brien, and John Pagel. titled: "Addressing the Medical Need in CLL: How BTK Inhibitors Are Improving Outcomes"

healthunlocked.com/cllsuppo...

CLL: New Horizons With BTK Inhibitors - Clinical Care Options (registration)

Four downloadable slide sets:

1. Overview of the BCR Pathway and BTK in Tumor Development

2.BTK Inhibitors: Future Directions

3. BTK Inhibitors in Treatment-Naive CLL

4. BTK Inhibitors in Relapsed/Refractory CLL

clinicaloptions.com/oncolog...

Then from the 2019 American Society of Hematology (ASH) meeting, we have Dr Anthony Mato's review of the status of BTK inhibitor drugs (ibrutinib, acalabrutinib, and other, newer ones).

Building on BTK Inhibition in CLL (Free patient registration with OncLive).

onclive.com/web-exclusives/...

Richard R. Furman, MD, discusses differences among the different available BTK inhibitors for use in patients with B-cell malignancies. (June 2020)

onclive.com/view/dr-furman-...

Targeting Bruton’s Tyrosine Kinase in CLL , Inhye E. Ahn and Jennifer R. Brown (June 2021)

frontiersin.org/articles/10...

Dr. Jennifer Brown & expert faculty discuss the latest BTK Inhibitors in relapsed CLL (June 2020)

healthunlocked.com/cllsuppo...

Encouragingly, it seems that BTK inhibitors can encourage T-cell replication and activity, improving T-cell immunity, though the circumstances aren't clear:

healthunlocked.com/cllsuppo...

Acalabrutinib Showcases Long-Term Tolerability Across B-Cell Malignancies

Richard R. Furman, MD, discusses the findings from the analysis and highlights the differences between first and second-generation BTK inhibitors in CLL.

onclive.com/view/acalabruti...

Here's my current List and status of BTKi drugs. How many have I missed?

1. Acalabrutinib/Calquence (covalent) Approved in USA, Australia 17Nov2019 for first and subsequent line treatments. (In mid 2021, we had about 5 years of accumulated treatment data for CLL.)

Meta-analysis: Acalabrutinib showed better PFS and OS than other frontline CLL therapies, October 7, 2020

mdedge.com/hematology-oncol...

CALQUENCE Met Primary Efficacy Endpoint in Head-to-Head Trial Against ibrutinib in CLL

biospace.com/article/releas...

"In this first head-to-head trial of BTKis in CLL, Aca demonstrated non-inferior PFS with less cardiotoxicity and fewer discontinuations due to AEs vs Ib"

meetinglibrary.asco.org/rec...

Relapsed/Refractory trial results after 41 months (median experience)

ashpublications.org/blood/a...

NCCN recommend Acalabrutinib for all patients with relapsed/refractory CLL, including:

• Patients with or without del17p/TP53 mutations

• Frail patients with significant comorbidity OR patients aged ≥65 and younger patients with significant comorbidities

• Patients aged <65 years old without significant comorbidities

Community discussion: healthunlocked.com/cllsuppo...

Acalabrutinib Monotherapy in Hematologic Malignancies: Updated Safety and Efficacy Results

clinicaloptions.com/oncolog...

2. ARQ 531 (MK1026) (non-covalent) Phase 1

ASH 2019: Dr Deborah Stephens on ARQ 531, a reversible BTK inhibitor to treat CLL that is no longer responding to ibrutinib or acalabrutinib

cllsociety.org/2020/06/ash-...

hawkeagle is on an ARQ trial.

3. DTRMWXHS-12 (DTRM-12) Phase Ia/Ib

4. Ibrutinib/Imbruvica (covalent) Where this all started, following FDA approval for MCL in November 2013 and CLL in July 2014. (In mid 2021, we had about 10 years of accumulated treatment data for CLL.)

Long-term safety of single-agent ibrutinib in patients with chronic lymphocytic leukemia in 3 pivotal studies (from ASH 2019) See the visual abstract which illustrates how the adverse event profile considerably improves year by year with the exception of cardiovascular side effects.

ashpublications.org/bloodad...

Ibrutinib continued to effectively control CLL in 61% of patients after a median of 6.5 years in one long term follow-up:

healthunlocked.com/cllsuppo...

Towards personalised management of CLL? Ibrutinib study reveals new way to gauge patients’ response to treatment

healthunlocked.com/cllsuppo...

First-line treatment with ibrutinib has meaningfully improved the poor prognosis in the high-risk TP53 population (ASH2020): cancernetwork.com/view/john...

Member experiences: healthunlocked.com/cllsuppo...

healthunlocked.com/cllsuppo...

5. Luxeptinib/CG-806 (non-covalent) Phase 1a/b

cancernetwork.com/chronic-l...

aptose.com/product-pipeline...

cancer.gov/publications/dic...

Six patients at 65mg dose who harboured the C481S resistance mutation achieved a highly impressive 67% partial remission rate.

6. NRX0492 degrades normal BTK and BTK that has become resistant to other BTK inhibitors. Human testing hopefully will start late 2020. This may initiate a whole new class of drugs for degrading other target proteins. There is a phase 1 clinical trial for prostate cancer being done by another company. See: cllsociety.org/2020/06/ash-...

7. Orelabrutinib - ICP-022 (covalent)

InnoCare Pharma has announced that its BTK inhibitor orelabrutinib received approval from the China National Medical Products Administration (NMPA) in two indications: the treatment of patients with relapsed/refractory chronic lymphocytic leukemia (CLL) /small lymphocytic lymphoma (SLL), and the treatment of patients with relapsed/refractory mantle cell lymphoma (MCL).

businesswire.com/news/home/...

Updated Phase 2 study report from ASH2020

ash.confex.com/ash/2020/web...

R/R study for B-cell malignancies (CLL included) at MDA/Mayo and a few other USA locations. clinicaltrials.gov/ct2/show...

8. Pirtobrutinib/LOXO-305 (non-covalent) Phase 1/2. Works on patients with acquired resistance to available BTKis and Venetoclax Starting at the 50 mg QD dose, LOXO-305 delivered >IC90 target coverage for wild-type and C481S-mutated BTK, based on estimates from cell-based potencies

mdedge.com/hematology-oncol...

prnewswire.com/news-release...

Chan Yoon Cheah, MBBS, Linear Clinical Research and Sir Charles Gairdner Hospital, Perth, Australia, discusses early results of the Phase I/II BRUIN trial (NCT03740529): youtube.com/watch?v=u4_QT_L...

Pirtobrutinib also shows efficiency against Richter's Transformation!

healthunlocked.com/cllsuppo...

BRUIN trial update 6th March 2021

healthunlocked.com/cllsuppo...

Eli Lily are so confident about LOXO-305, next year they starting two late-stage clinical trials pitting its treatment against Imbruvica.

healthunlocked.com/cllsuppo...

Members Osprey69, steve5441 and UKfulloflife are in a LOXO-305 trial: clinicaltrials.gov/ct2/resu...

healthunlocked.com/cllsuppo...

9. Spebrutinib (AVL-292, CC-292) (covalent) Phase 1 and no longer in development for CLL

10. Tirabrutinib/ONO-4059 (covalent) for non-Hodgkin lymphoma and/or CLL. Renamed GS-4059 and now in trial NCT02457598 Phase 1

oncnet.com/news/tirabrutini...

11. TG1701 (covalent) Phase 1

TG-1701 alone and in combination with U2 (Umbralisib and Ublituximab), has an encouraging safety profile with clinical and pharmacodynamic activity at all dose levels evaluated.

healthunlocked.com/cllsuppo...

CLLerinOz is on a TG-1701 clinical trial

12. UBX-303 - New entry 21st July 2021 (Thanks Cllerinoz)

UBX-303 is a Bruton’s tyrosine kinase (BTK) targeting molecule that 'has been designed to demonstrate efficacy by degrading over-expressed BTK proteins and has a different modality than current BTK inhibitors. Its distinct mechanism of action, the decomposing and removal of BTK proteins in cells, is expected to bring about overall advantages, in particular demonstrating superior efficacy, overcoming resistance, and increasing selectivity for target proteins

healthunlocked.com/cllsuppo...

13. Vecabrutinib/SNS-062 (non-covalent) Phase 1b (Phase 2 is not proceeding) :(

Although vecabrutinib continues to exhibit an excellent safety profile, there is insufficient evidence of activity in BTK-inhibitor resistant B-cell malignancies to advance the drug into the planned Phase 2 portion of the trial.

healthunlocked.com/cllsuppo...

14. Zanubrutinib/Brukinsa (covalent) Phase 2 (approved for MCL)

The (USA) National Comprehensive Cancer Network (NCCN) updated their physician guidelines to recommend Zanubrutinib for first and second line treatment for CLL/SLL on 3rd December 2020

healthunlocked.com/cllsuppo...

Brukinsa provides patients with CLL with improvements in response and reduced rates of atrial fibrillation or flutter compared to ibrutinib, in head to head comparison, funded by BeiGene, naturally!

cancernetwork.com/view/inte...

ALPINE Relapsed/Refractory trial

At a median follow-up of 15 mo, ORR was significantly higher with zanubrutinib vs ibrutinib. 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%, 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.

healthunlocked.com/cllsuppo...

Ongoing Trial Evaluates zanubrutinib in BTK-Intolerant B-Cell Malignancies - Dr Ian Flinn

onclive.com/view/ongoing-tr...

Conversation with Dr Con Tam: healthunlocked.com/cllsuppo...

Overview by Joanna M Rhodes and Anthony R Mato (Dec 2020)

dovepress.com/zanubrutinib-...

BGB3111 Response rate nears 100% in CLL/SLL onclive.com/view/bgb3111-re...

Zanubrutinib effective in CLL/SLL regardless of del 17 p status

haematologica.org/article/v...

onclive.com/conference-cove...

Member experiences (including two early trial members, with 5 years experience on zanubrutinib, with one switching to Venetoclax)

healthunlocked.com/cllsuppo...

healthunlocked.com/cllsuppo...

healthunlocked.com/cllsuppo...

healthunlocked.com/cllsuppo...

Comparison side effects, second generation BTKs (Mainly reports on zanubrutinib vs ibrutinib, with a brief mention of acalabrutinib)

healthunlocked.com/cllsuppo...

Resistance-Associated Mutations in CLL Patients Treated With Novel Agents

In 80% of patients with ibrutinib failure, acquired mutations in BTK and PLCG2 genes were detected. No common resistance-associated mutations or deregulated signaling pathways have been reported in idelalisib failure. Acquired mutations in the BCL2 gene were detected in patients who had failed on venetoclax.

Resistance-associated mutations tend to occur between the second and fourth years of treatment and may be detected several months before clinical relapse.

Also discussed is the development of next-generation agents for CLL patients who have acquired resistant mutations to current inhibitors.

healthunlocked.com/cllsuppo...

Adverse Events From Ibrutinib in Real-World CLL: More Research Needed

Dr Stefano Molica, MD, of Ospedaliera Pugliese-Ciaccio, Italy, and colleagues recently published data from an analysis looking at changes in glycemia, cholesterol, triglycerides, and HDL in 43 patients with CLL who received single-agent ibrutinib. This real-world analysis had several interesting outcomes.

cancertherapyadvisor.com/ho...

Study Explores Causes of Bleeding in Patients on Ibrutinib

healthunlocked.com/cllsuppo...

Can long term ibrutinib patients stop treatment? This MSK sponsored trial aims to find out!

clinicaltrials.gov/ct2/show...

Estimated enrollment 75 patients, commencing 22nd December 2020. MSK, New York is recruiting. The trial is also available in North Carolina and Pennsylvania.

Adding the BAFF receptor antibody Ianalumab may be another way

healthunlocked.com/cllsuppo...

Other important BTKi posts:

healthunlocked.com/cllsuppo...

healthunlocked.com/cllsuppo...

healthunlocked.com/cllsuppo...

Generic Imbruvica?

healthunlocked.com/cllsuppo...

COVID related FAQ from CLL Specialists (with specific reference to BTK and other treatments)

healthunlocked.com/cllsuppo...

What to do when a BTKi stops working?

healthunlocked.com/cllsuppo...

Screening and monitoring of the BTK C481S mutation in a real-world cohort of patients with relapsed/refractory chronic lymphocytic leukaemia

healthunlocked.com/cllsuppo...

To complete the picture of common CLL drug alternatives, we have the following growing list:

healthunlocked.com/cllsuppo...

Jennifer Woyach, MD, Associate Professor in the Division of Hematology at The Ohio State University

1) Highlights Role of BTK Inhibition in Treatment Landscape for CLL (along with Ventoclax, Obinutuzumab, Rituximab)

targetedonc.com/view/expert...

2) Reflects on the changing BTKi landscape

targetedonc.com/view/jennif...

Dr Woyach's take home message: "I would just say that CLL is advancing very rapidly. We have a lot of drugs that are very effective, and I think the most important thing is that we shouldn't become complacent with the success that we've had so far. We should continue to work to develop new trials to put patients on track and to continue to optimize therapy for patients with CLL."

My Perspective on 3 Questions I Am Asked on BTK Inhibitors for CLL - Dr Ian Flinn, Director, Lymphoma Research Program, Sarah Cannon Research Institute Nashville, Tennessee. Source: Addressing the Medical Need in CLL: How BTK Inhibitors Are Improving Outcomes

clinicaloptions.com/oncolog... Answers on Ibrutininb vs Acalabrutinib or Zanubrutinib, adding an anti- CD20 to BTKi treatment. Note comment on extreme lymphocytosis (very high lymphocyte count) on BTKi's:- "Lymphocytosis can occur in patients with CLL during BTK inhibitor therapy and can be extreme; some clinicians use this as a rationale for adding an anti-CD20 antibody to a patient’s CLL regimen. That said, I have only rarely seen this to be a real issue in my patients with CLL—frankly, I worry more about infusion‑related reactions that occur by administering an anti-CD20 antibody to a patient with such a high white blood cell count than I worry about the potential of lymphocytosis harming the patient. In general, I do not see lymphocytosis as a good reason to add an anti-CD20 antibody to a BTK inhibitor."

This is an unlocked post, which will turn up in Internet searches: healthunlocked.com/cllsuppo...

Neil

Last updated 21st July 2021

78 Replies

This is incredible, thank you Neil. I was fascinated to read this, including the news about the other diseases too, like MS and Lupus, etc.

I also have to say that this photo is just wonderful. 🙂

Debbie

Mystic75 profile image
Mystic75 in reply to DebKat999

💕

DebKat999 profile image
DebKat999 in reply to Mystic75

💕

Mystic75 profile image
Mystic75 in reply to DebKat999

:)

AussieNeil profile image
AussieNeilAdministrator in reply to DebKat999

Quite a few drugs used to treat CLL are also used for treating auto-immune illnesses. That's because reducing the B-lymphocyte count reduces the production of auto-immune antibodies that cause the challenging symptoms of these diseases. Naturally taking these drugs has the same effect on those taking them for auto-immune disease management as it does for us - lowered immunity.

Neil

Shaheenji profile image
Shaheenji in reply to AussieNeil

I know a person using ibrutinib and other two using venteloclax for autoimmune diseases like Rheumatoid arthritis etc.?

Thank you, Neil! This is such great news!

This May be a stupid question but, why do they all end in "nib". And that pic is so beautiful. I love kangaroos. Thanks Neil.

AussieNeil profile image
AussieNeilAdministrator in reply to Sushibruno

It's an astute question with a useful answer. The endings of targeted drugs medical names (not the marketing names) tell you about how the drug works. 'inib' is short for inhibitor and the 'brut' tells you that BTK is being inhibited. Likewise drug names for monoclonal antibodies end in 'mab' for monoclonal antibody.

You're a great teacher Neil thanks🙂.

Neil you think you can ship me one of those kangaroos😂?

AussieNeil profile image
AussieNeilAdministrator in reply to Sushibruno

Provided you are prepared to pay the huge fine! ;)

😳🙂

in reply to Sushibruno

actually the entire spectrum of prescription drugs have rules about their 'nomencleture'. for their chemical names. Brand names-Like Imbruvica pare entirely made up for marketing-'they are trademarks.

Sushibruno profile image
Sushibruno in reply to

Thank you👌

Did you take the photo? Very cute!

AussieNeil profile image
AussieNeilAdministrator in reply to PlanetaryKim

Yes, we have around 30 kangaroos and wallabies that we can walk amongst in a conservation area about 3km/2 miles from our home. I have seen wild ones closer to our home. Recently we saw two koalas - one in the wild and one in the park on the same afternoon.

Beautiful!

Wow! they are very cute in the photo. There are reportedly a few wild wallabies in UK, I don't remember where, but they escaped and became a breeding colony.

There are a some long established colonies where I live on the Isle of Man

Hi Neil,

Cute Roo and Joey.

Many thanks for the list, I've no others and you've added a couple to my list which I have to admit I had got overwhelmed trying to maintain.

To be clear to anyone reading, the scope of this list is BTK inhibitors.

Staying in the field of inhibitors (so I'm not discussing all the wonderful immunotherapy agents we also have) there are also other kinds of inhibitors e.g. ABT-199 Venetoclax which is a BCL-2 inhibitor.

There I do get a bit confused, because I have a memory of being educated that there are three kinds of inhibitors, but I've got the following on my list:

- BTK (your list above)

- BCL-2 Inhibitors e.g. ABT-199

- PI2K delta

- Syk

- Syk + JAK

So as usual I'm a little confused here . . .

P.S. To anyone wondering where the "Brutinib" name name from, I remember (from HU I think) reading about a chap called Ogden Bruton, (Somebody will have to remind me exactly how his work inspired Pharmacrylics to do their stuff and use Ogden's surname many many years later.) Neil has explained the "inib" above.

en.wikipedia.org/wiki/Ogden...

Note the sentence in that wiki:

"The gene associated with this defect is also named after him: Btk, abbreviation for Bruton's tyrosine kinase"

Again if I'm at all confused here (quite likely), please just correct my reply here.

Wishing you all well,

Ernest

Thank you Neil!

Thanks for the new information but most of all for the photo. I’m still smiling. ☺️ Sally

Don't forget LOXO-305. Tomorrow there is an oral presentation at ASH 2019:

ash.confex.com/ash/2019/web...

I've heard a rumor that this drug is looking very good in heavily pre-treated patients.

AussieNeil profile image
AussieNeilAdministrator in reply to avzuclav

Wow! Another non-covalent BTKi that inhibits wild-type and C481-mutated BTK preclinically and in that phase 1 trial it was confirmed to work on "patients with acquired resistance to available BTKis and venetoclax".

Added to the list, thanks.

Neil

While we're doing all the 'splainin - what is "wild type"

Virginia

avzuclav profile image
avzuclav in reply to virdieblue

Wild type means "as it occurs in nature" aka normal. en.wikipedia.org/wiki/Wild_...

virdieblue profile image
virdieblue in reply to avzuclav

How can there be a "normal" classification for cancer?

avzuclav profile image
avzuclav in reply to virdieblue

In this case, we're just talking about the BTK gene which is "normal" for most of us.

Some patients acquire a BTK gene mutation while on a BTK inhibitor (at the cysteine 481 location within the BTK gene, aka C481).

virdieblue profile image
virdieblue in reply to avzuclav

Thank you for clearing that up!

YABTKi... DTRMWXHS-12 (DTRM-12).

A Phase Ia/Ib Study Exploring the Synthetic Lethality of the Orally Administered Novel BTK Inhibitor, Dtrmwxhs-12 (DTRM-12), in Combination with Everolimus and Pomalidomide in Patients with Relapsed/Refractory CLL, DLBCL or Other B-Cell Lymphomas

ash.confex.com/ash/2019/web...

AussieNeil profile image
AussieNeilAdministrator in reply to avzuclav

That gives a total of TEN BTKi drugs being used to treat CLL, either in trials or approved.

I couldn't find any information on the selectivity or resistance profile of DTRMWXHS-12 (DTRM-12), but the plots in your reference of how the blood serum concentration varied with different doses sure was interesting. At the 50mg dose, you don't maintain as high an extended blood serum level as you do at higher doses, despite the 50 to 100mg dose curves reaching the same peak - the 100mg provided a longer coverage time. I've noticed reports on half life variation with dose on other BTKi drugs and the take home message is that the half life may not be as good at lower doses.

avzuclav profile image
avzuclav in reply to AussieNeil

Here's a couple slides from tonight's oral presentation at ASH.

twitter.com/calliecoombsmd/...

PaulaS profile image
PaulaSVolunteer

Wonderful photo, Neil. Such beautiful animals.

Good news about new BTK inhibitors too. :-)

Paula

Great Post Neil, many thanks, hope you are not living in the terrible fires ravaging parts of Australia.

Marc

Great post, great pic!

Has anyone been on any of these drugs? I talked to one person who was on vecabrutinib (sns-062) at a 300mg dose. Curious to know if anyone has had personal experience. Seems like that drug provides some stable disease so far but not much else.

AussieNeil profile image
AussieNeilAdministrator in reply to Asclepiusone

While most of our community members on BTK inhibitors are taking Ibrutinib, we have members who are collectively taking at least 3 of the other listed BTKi drugs.

Canuck901 profile image
Canuck901 in reply to AussieNeil

Cool, would like to know the results of them. Are people taking these others because Of resistance to ibrutinib?

AussieNeil profile image
AussieNeilAdministrator in reply to Canuck901

Here's a recent summary, but there has been updated information provided at this month's ASH conference.

healthunlocked.com/cllsuppo...

People might switch to an alternative due to either resistance developing or unacceptable side effects. I'm not sure of the split between resistance and side effect issues, but approximately 20% of those prescribed Ibrutinib discontinue taking it for either of those reasons.

Neil

With a total respect for people’s privacy, and well wishes for their well being and long term health successes, if anyone would be willing to share, I would be very interested in hearing their experiences on these new BTKi drugs. Best to all.

CLLerinOz profile image
CLLerinOzVolunteer in reply to Asclepiusone

I know this isn’t the sort of personal feedback you’re after but it may be helpful. It’s an update on the BTKi called Zanubrutinib that was just presented at ASH2019 by Dr Con Tam.

onclive.com/conference-cove...

How are the results ?

AussieNeil profile image
AussieNeilAdministrator in reply to Canuck901

See this earlier post

healthunlocked.com/cllsuppo...

AussieNeil profile image
AussieNeilAdministrator

I've updated my post to include reports from ASH 2019 about Vecabrutinib and Zanubrutinib.

Of the 7 patients with stable disease on Vecabrutinib, 4 had BTK C481S mutations and 3 had BTK C481 wild type disease. This was from a trial of patients with challenging mutations. "At screening, among the 23 patients with CLL, 78% had mutated or deleted TP53, 61% had BTK C481 mutations, 13% had phospholipase C gamma 2 (PLCg2) mutations, and 57% had del(17p). Some 83% had unmutated IVHV."

The Zanubrutinib reports were from the SEQUOIA and AU-003 trials and showed encouraging results with a much larger number of trial patients.

Neil

GS-4059 is in your list -- it has a name: tirabrutinib. Here's an ASH 2019 abstract reporting on it in combination with entospletinib and obinutuzumab for CLL:

ash.confex.com/ash/2019/web...

and a few slides from an oral presentation for WM:

twitter.com/lymphomahub/sta...

AussieNeil profile image
AussieNeilAdministrator

"Jennifer Woyach, MD, associate professor, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center–James, discusses ongoing research with BTK inhibitors in chronic lymphocytic leukemia (CLL).

:

...in the phase II CAPTIVATE trial, which was presented at the 2019 ASH Annual Meeting, investigators confirmed the potential for fixed-duration therapy with the combination of venetoclax (Venclexta) and the BTK inhibitor ibrutinib (Imbruvica) in patients with newly diagnosed CLL who are less than 70 years of age.

:

Similar results have been seen with the combination of venetoclax and ibrutinib plus obinutuzumab (Gazyva) in an institutional study conducted at The Ohio State University. With long-term follow-up, it appears that few patients who discontinue treatment are relapsing, says Woyach."

onclive.com/onclive-tv/dr-w...

Neil

Good info! Thank you! I’ve had a slight rash with 420 mg imbruvica and acid reflux issues. Also bleeding gums, nose, under the skin you name it! Dropped down to 280 mg. Much better but I had been wondering about that new drug you brought to my attention. I’m going to suggest it to my oncologist again as an alternative Incase I get the same issues back

AussieNeil profile image
AussieNeilAdministrator

In the paper All in the family: back-to-back kinase inhibitors for the treatment of chronic lymphocytic Leukemia, by Meghan C Thompson , Lindsey E Roeker and Anthony R Mato, haematologica.org/article/v... the authors argue that the growing range of BTK inhibitors are making it possible to switch BTKi drugs when intolerance is an issue, rather than the classic approach of switching to another drug class:- "...these studies challenge the traditional sequencing paradigm of switching drug classes in the setting of CLL therapy discontinuation for intolerance.

:

While venetoclax is an acceptable option in the setting of BTKi intolerance, CLL remains an incurable, chronic disease and there is a strong scientific rationale to maximize clinical benefit from each drug class prior to exposing patients to the selective pressures of another therapeutic class. In the case of the common problem of intolerance to ibrutinib it is best to keep the solution “all in the (BTKi) family.”

This paper gives a good explanation of how Ibrutinib and Venetoclax work differently and hence symbiotically to provide a high proportion of complete responses in time limited therapy. See the image at the end of this reply. Thanks gardening-girl.

nature.com/articles/s41408-...

This paper from April 29th 2021, summarises the current very promising situation with combination treatments:- Ibrutinib combinations in CLL therapy: scientific rationale and clinical results healthunlocked.com/cllsuppo...

Relevant is this Mechanisms of resistance to targeted therapies in CLL - an EHA slide presentation

healthunlocked.com/cllsuppo...

For those for whom a BTKi is not or is no longer suitable, to complete the picture of common CLL drug alternatives, we have the following:-

CD20 monoclonal antibodies, following the success of Rituximab/Mabthera

- Obinutuzumab/Gazyva (FDA approved for first treatment use with Chlorambucil and Venetoclax fda.gov/drugs/resources-inf... )

Venetoclax plus Obinutuzmab approved in the UK for first treatment. (Likewise in Australia, but only when older chemo treatments won't work). For member experiences, see: healthunlocked.com/cllsuppo...

Phase 2 study of MRD driven time limited therapy with Zanubrutinib, Obintuzumab and Venetoclax (BOV) in untreated patients - incredible results achieved with very high rates of uMRD in this time limited treatment combination

healthunlocked.com/cllsuppo....

- Ofatumumab/Arzerra

- Ublituximab/(TG-1101)

See Anti-CD20 treatment for B-cell malignancies: current status and future directions: tandfonline.com/doi/full/10... for an overview of preclinical and clinical data, and how the pharmacodynamic properties of these newer CD20 MABs translate into clinical benefit for patients.

There is also a subcutaneous version of Rituximab

Then we have the PI3K inhibitors

- Idelalisib (approved for second line treatment)

- Duvelisib (also known as IPI-145)

Duvelisib May Improve Health-Related QoL in Relapsed or Refractory CLL and SLL compared with ofatumumab (Arzerra)

targetedonc.com/view/duveli...

- Umbralisib (development codes RP5264 and TGR 1202) See: healthunlocked.com/cllsuppo...

- ACP-319 (also known as AMG-319)

Then after the success of the BCL-2 inhibitor venetoclax/Venclexta, we have

- BeiGene's BGB-11417

- Bio-Path's BP1002

- Lupeng's LP-108

- Lisaftoclax's APG-2575

BeiGene's BGB-11417 is being trialled in Australia: healthunlocked.com/cllsuppo...

Lisaftoclax (APG-2575), a novel BCL-2 inhibitor (BCL-2i), with an oral presentation of the first clinical trial being given at ASCO21. "...in a first-in-human phase 1 trial (NCT03537482).1

Twelve of 15 evaluable patients with relapsed/refractory CLL/SLL experienced a partial response (PR) to treatment with lisaftoclax, which translated to an objective response rate (ORR) of 80%. In this population, the median number of treatment cycles was 9 (range, 5-24) and the median time to response was 2 cycles (range, 2-8)."

cancernetwork.com/view/earl...

LP-108: clinicaltrials.gov/ct2/show...

Combination trial of ublituximab and umbralisib (U2) plus U2 and Venetoclax

healthunlocked.com/cllsuppo...

We have some members on the promising U2 Plus Venetoclax (Ultra V) trial

healthunlocked.com/cllsuppo...

Ublituximab plus ibrutinib (GENUINE) for relapsed/refractory high risk CLL

healthunlocked.com/cllsuppo...

Patients with relapsed or refractory chronic lymphocytic leukemia (CLL) with high-risk features benefited from the addition of the anti-CD20 monoclonal antibody ublituximab to ibrutinib, according to results of the phase-3 GENUINE study (ClinicalTrials.gov Identifier: NCT02301156), published in The Lancet.

The overall response rate in the intention-to-treat population of the study was significantly higher in patients treated with the combination compared with those receiving ibrutinib monotherapy (83% vs 65%; P =.020).

cancertherapyadvisor.com/ho...

We also have Bio-Path's BP1002, another BCL-2 inhibitor being tested in a relapsed/refractory CLL clinical trial: globenewswire.com/news-rele...

Excitingly, we now have anti-ROR1 monoclonal antibody treatments on the way. With ROR1 over-expressed in CLL we may be able to eliminate our CLL tumour with less impact on our healthy B - lymophocytes and hence better maintain or even improve our adaptive immunity: pubmed.ncbi.nlm.nih.gov/222...

- Cirmtuzumab (UC-961) is the first and very promising anti-ROR1 humanised monoclonal antibody in early-stage clinical trials for various cancers including chronic lymphocytic leukemia.

en.m.wikipedia.org/wiki/Cir...).

Then there's CAP-100 an anti- CCR7 monoclonal antibody starting phase 2 and phase 1a clinical trials (clinicaltrials.gov #NCT04704323)

The chemokine receptor CCR7 is essential for migration of immune cells to lymphoid organs. This pivotal receptor is over-expressed in hematological malignancies with lymph node involvement, such as CLL. CAP-100 interrupts tumor cell migration to lymph nodes, strong cell killing (ADCC) and inhibition of survival of tumor cells in the lymph nodes.

See: prnewswire.com/news-release...

For those with TP53 mutated or 17p del CLL, provided there is an intact non-benign mutant p53 protein. The APR-246 binds to the p53 protein and restores its function.

Eprenetapopt (APR-246) - a new small molecule to restore TP53 function

healthunlocked.com/cllsuppo...

Or you could just drive CLL cells to their death by enabling over stimulation!

healthunlocked.com/cllsuppo...

Then we have the exciting developments in CAR-T and CAR-NK.

I would hope that this growing number of new drugs (and I'm sure I have missed more), should encourage anyone approaching the need for treatment.

This lengthy paper (thanks JM954), covers many of the above drugs and how they work individually and in combination: link.springer.com/article/1...

More updates will be presented in the June 2021 ASCO and EHA meetings: healthunlocked.com/cllsuppo...

CLL drugs and the immune system

healthunlocked.com/cllsuppo...

Finally, Good news about targeted therapies and autoimmune cytopenias

'Ibrutinib, idelalisib and venetoclax have a beneficial impact on preexisting AICs associated with CLL andTreatment-emergent AICs are more frequent, though easily manageable, during treatment with venetoclax than with ibrutinib or idelalisib.'

healthunlocked.com/cllsuppo...

Last updated 1st August 2021

Neil

Tumor cell dynamics under ibrutinib or venetoclax treatment.
AussieNeil profile image
AussieNeilAdministrator in reply to AussieNeil

TG Therapeutics’ umbralisib monotherapy in relapsed/refractory (R/R) lymphomas is unlikely to have extensive market traction, experts said. The same sentiment holds for its combination with ublituximab (U2) in relapsed/refractory (R/R) and treatment-naïve chronic lymphocytic leukaemia (CLL) despite both showing an improved safety profile to competitors, they added. However, FDA approval is still highly expected based on positive registrational trial data, they said.

pharmaceutical-technology.c...

Really great info! Would it be worth moving the info for other treatments to a separate thread? So it’s easier to follow.

AussieNeil profile image
AussieNeilAdministrator in reply to UniversallyPersonal

I wanted to keep all the information together, in part because BTKis are often a component of a combination treatment :)

AussieNeil profile image
AussieNeilAdministrator

Acalabrutinib monotherapy in patients with relapsed/refractory chronic lymphocytic leukemia: updated phase 2 results

"At a median follow-up of 41 months, median PFS has not been reached in previously treated CLL patients on the BTK inhibitor acalabrutinib.

:

Atrial fibrillation and major bleeding AEs (all grades) occurred in 7% and 5% of patients, respectively. Most patients (56%) remain on treatment; the primary reasons for discontinuation were progressive disease (21%) and AEs (11%). The overall response rate, including partial response with lymphocytosis, with acalabrutinib was 94%; responses were similar regardless of genomic features (presence of del(11)(q22.3), del(17)(p13.1), complex karyotype, or immunoglobulin variable region heavy chain mutation status)."

ashpublications.org/blood/a...

Neil I remember this post, first because of the beautiful pic, and because I gave you a like.

AussieNeil profile image
AussieNeilAdministrator

Acalabrutinib May Be A Safer Alternative to Ibrutinib in CLL

In a real-world analysis presented at the 2019 American Society of Hematology Annual Meeting, outcomes of real-world patients with CLL treated with acalabrutinib were reviewed to determine the benefit in a more realistic patient population. Overall, investigators noted that the discontinuation rate of acalabrutinib in patients who could not tolerate ibrutinib was low, which suggests the agent is a well-tolerated alternative to ibrutinib for patients who are likely to benefit from BTK inhibition but cannot tolerate the toxicities associated with ibrutinib.

targetedonc.com/view/acalab...

do you have a similar list of PBS MCL drugs please?

AussieNeil profile image
AussieNeilAdministrator in reply to 1susiE

Sorry, we have a challenging enough time keeping up with new CLL drugs! Quite a few are used to also treat MCL, but dosage and treatment protocol may differ. Side effects would largely overlap however.

AussieNeil profile image
AussieNeilAdministrator

Richard R. Furman, MD, discusses the findings from the analysis and highlights the differences between first- and second-generation BTK inhibitors in CLL.

onclive.com/web-exclusives/...

The second-generation BTK inhibitor acalabrutinib (Calquence) demonstrated favorable long-term tolerability in patients with B-cell malignancies, according to a pooled analysis spanning several hematologic malignancies, explained Richard R. Furman, MD, who underscored the importance of having a continuous, well-tolerated treatment.

:

Only 9% of patients discontinued acalabrutinib due to treatment-related adverse effects (AEs).

The most common AEs, which were headache (35%) and diarrhea (26%), were mostly grade 1/2 and occurred within the first 6 months of treatment. Secondary primary malignancies, atrial fibrillation, and hypertension were infrequent and of low grade.

:

Because of differences in specificity, you see fewer off-target effects with acalabrutinib and zanubrutinib than we do with ibrutinib. As such, we see different AE profiles. Also, because of the differences in how drugs are metabolized, we see differences in their interactions with other drugs.

Vecabrutinib update, bad news.

“Although vecabrutinib continues to exhibit an excellent safety profile, there is insufficient evidence of activity in BTK-inhibitor resistant B-cell malignancies to advance the drug into the planned Phase 2 portion of the trial. One partial remission was observed after 11 treatment cycles in a CLL patient treated in Cohort 5 (300 mg BID) and a number of patients treated across the dose range explored (25 mg to 500 mg BID) saw stable disease; however, no other remissions have been observed,” said Dayton Misfeldt, Interim Chief Executive Officer of Sunesis. “We will complete the Phase 1b and evaluate the best path forward for vecabrutinib. We are grateful for the patients and their families who participated in this trial, as well as the investigators and research staff at our trial sites.”

ir.sunesis.com/news-release...

Justasheet1 profile image
Justasheet1 in reply to avzuclav

Avz,

I hope the other non- covalent, reversible BTK’s don’t share this outcome. Loxo looks very promising.

Jeff

AussieNeil profile image
AussieNeilAdministrator in reply to avzuclav

Very disappointing (particularly for the brave trial participants), to hear that vecabrutinib didn't demonstrate sufficient effectiveness to proceed to phase 2.

I've updated my post entry on vecabrutinib to reference your reply.

Thanks!

YABTKi - orelabrutinib - ICP-022

R/R study for B-cell malignancies (CLL included) at MDA/Mayo and a few other USA locations. clinicaltrials.gov/ct2/show...

avzuclav profile image
avzuclav in reply to avzuclav

ASH 2020 abstract for orelabrutinib, looks promising.

1320 Updated Results from the Phase II Study of Orelabrutinib Monotherapy in Chinese Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia/Small Cell Leukemia

ash.confex.com/ash/2020/web...

"So, orelabrutinib showed a significant higher CR rate comparing to other BTK inhibitors at a similar treatment period and we anticipate a further increase of CR rate with longer duration of treatment."

AussieNeil profile image
AussieNeilAdministrator

Some possibly encouraging news for those intolerant of Ibrutinib or Acalabrutinib treatment and for those in the USA with this challenge, the possibility to join a clinical trial at one of 30 sites, to see if Zanubrutinib/Brukinsa resolves intolerance. Zanubrutinib appears to have a lower adverse effect profile than the approved BTKi drugs Acalabrutinib and Ibrutinib. The trial results will be eagerly awaited by those that do well on the former, but struggle with adverse effects.

At the 2020 ASCO Virtual Scientific Program, Flinn presented a poster showcasing the ongoing phase 2 BGB-3111-215 trial (NCT04116437) evaluating zanubrutinib in patients with previously treated B-cell malignancies intolerant to prior ibrutinib or acalabrutinib.

Investigators plan to enroll approximately 60 patients with CLL, small lymphocytic lymphoma, Waldenström macroglobulinemia, mantle cell lymphoma, or marginal zone lymphoma intolerant of prior BTK inhibition whose treatment-emergent adverse effects (TRAEs) resolve to grade 1 or lower prior to initiating treatment with zanubrutinib.

The primary end point of the study is the recurrence and change in severity of TRAEs with zanubrutinib compared with ibrutinib and/or acalabrutinib, according to Flinn.

Enrollment, which is currently underway, will span across 30 primary community medical centers from across the United States.

onclive.com/view/ongoing-tr...

Neil

AussieNeil profile image
AussieNeilAdministrator

Dr Jeff Sharman's clinical thoughts on the use of non-covalent bonding BTK inhibitors to overcome resistance developing in patients treated with the covalent bonding inhibitors Acalabrutibib, Ibrutinib and Zanubrutinib.

clinicaloptions.com/oncolog...

This is potentially very good news. While it is rare for covalent BTKi resistance to occur, being able to switch to a non-covalent BTKi could enable patients doing well on this form of targeted therapy to remain on BTKi treatment for well over a decade before needing to switch to another targeted therapy, despite developing resistance!

Neil

DRM18 profile image
DRM18 in reply to AussieNeil

I can’t like this post—this entire thread of yours—enough, sir. Thank you!

Justasheet1 profile image
Justasheet1 in reply to DRM18

DRM,

The way I took it initially was that you couldn’t like the post and had enough.

After rereading it, I see that’s not how you meant it. You actually love it.

Jeff

DRM18 profile image
DRM18 in reply to Justasheet1

Love might be too weak a word, Jeff.

—Dave

AussieNeil profile image
AussieNeilAdministrator

"AstraZeneca’s Calquence (acalabrutinib), a next-generation selective Bruton’s tyrosine kinase (BTK) inhibitor, has been approved in the European Union (EU) for the treatment of adult patients with chronic lymphocytic leukaemia (CLL), the most common type of leukaemia in adults.

The approval by the European Commission was based on positive results from two Phase III clinical trials, ELEVATE-TN in patients with previously untreated CLL and ASCEND in patients with relapsed or refractory CLL.1,2 This follows a recommendation for approval by the Committee for Medicinal Products for Human Use of the European Medicines Agency in July 2020."

pipelinereview.com/index.ph...

CLLerinOz profile image
CLLerinOzVolunteer

Hi Neil

Clinical Care Options (CCO) has just uploaded an excellent webcast that was recorded pre ASH2020 and is titled: "Addressing the Medical Need in CLL: How BTK Inhibitors Are Improving Outcomes"

It is presented by three CLL specialists: Drs Ian W. Flinn, Susan M. O'Brien, and John Pagel.

It's a 2 hour webcast so not for the time poor but it's divided into sections for Treatment Naive and Relapsed/Refractory patients and is a really excellent discussion of the role BTK inhibitors currently play in the provision of CLL treatment.

clinicaloptions.com/oncolog...

CCO provides clinical education for health professionals and requires registration for viewing its resources. Registration is free.

Great list!

When I started on Ibrutinib it was the new non chemo treatment. My doctor pointed to a lot of research happening with new treatments for CLL. Because patients live for a long time research on treatments are quite well funded. It is nice to see that many of the treatments developed also prove to be useful for other diseases.

Howdy AussieNeil and thank you for the wealth of information you have posted. God bless

Awesome post. Big thanks Neil for keeping this up to date.

Best wishes,

Ernest

CLLerinOz profile image
CLLerinOzVolunteer

A new interview in Targeted Oncology with Jennifer A. Woyach, MD, associate professor of hematology at The Ohio State University in Columbus, Ohio, ‘shares insights about the role of the first-generation agent ibrutinib and the BTK class more generally’.

BTK inhibitors have changed the treatment paradigm in CLL.’

‘ ... ibrutinib, and potentially this class of BTK inhibitors, can overcome the negative prognostic value of a TP53 abnormality—at least in the short to intermediate term.’

‘The biggest question right now is whether BTK inhibitors are best administered alone or in combination with other agents, such as venetoclax. There are studies that are designed to answer that question, but it’s going to take a long time to get those results because these drugs work so well. However, this is something that is going to be very important to tease out because it has many implications on toxicity—especially chronic toxicity—as well as financial implications since a combination comes with an upfront increase in cost; it may be more economical in the long-term if a long treatment-free interval can be experienced.’

targetedonc.com/view/jennif...

Dear Neal, I missed this post the first go around. In view of the above, what should we think of a haematologist who says to a treatment naive, fit CLLer, unmutated, T-12, that if treatment becomes necessary, they will recommend ibrutinib? Aren't some of the second generation BTK inhibitors performing better than ibrutinib with better tolerability? Or is there still the idea to leave "room" to choose another BTK-I if one fails on ibrutinib?

AussieNeil profile image
AussieNeilAdministrator in reply to JustAGuy

We now have about 10 years of patient data for Ibrutinib. Acalabrutinib is, like Ibrutinib a covalently bonding drug, so resistance development is probably the same. Acalabrutinib's lower side effect profile is the main advantage over Ibrutinib. Ibrutinib has the advantages of being easier to reduce the dosage and being able to shift when in the day you take it (it is taken once per day vs twice per day), plus it doesn't have the requirement to go off PPI drugs used to control acid reflux/ gastroesophageal reflux disease (GERD).

So, given the above, it's arguably more about matching what would best suit the patient, given both appear to be equally effective against CLL. I would say that the main reason to question being prescribed Ibrutinib, is when you have high blood pressure and/or atrial fibrillation, or are considered at risk of developing these, or are concerned about Ibrutinib's higher side effect profile. That is after all, a significant reason for discontinuing Ibrutinib treatment. At least now we can switch to Acalabrutinib, Zanubritinib, etc.

Neil

CLLerinOz profile image
CLLerinOzVolunteer

Hi Neil,

This recently published article provides an overview of non-covalent BTK inhibitors for CLL.

mdpi.com/2075-4426/11/8/764...

Worth noting is that it includes information about a couple of non-covalent BTK inhibitors which have not progressed for use in CLL: Fenebrutinib (GDC-0853) and Vecabrutinib (SNS-062).

However, it does contain information about non-covalent BTK inhibitors in general and about Pirtobrutinib (LOXO-305) and MK-1026 (formerly ARQ-531) specifically.

A monumental review, thanks Neil. Post saved.

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