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.
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!
The Development of Bruton’s Tyrosine Kinase (BTK) Inhibitors from 2012 to 2017: A Mini-Review (very technical)
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"
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
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).
Richard R. Furman, MD, discusses differences among the different available BTK inhibitors for use in patients with B-cell malignancies. (June 2020)
Targeting Bruton’s Tyrosine Kinase in CLL , Inhye E. Ahn and Jennifer R. Brown (June 2021)
Dr. Jennifer Brown & expert faculty discuss the latest BTK Inhibitors in relapsed CLL (June 2020)
Encouragingly, it seems that BTK inhibitors can encourage T-cell replication and activity, improving T-cell immunity, though the circumstances aren't clear:
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.
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
CALQUENCE Met Primary Efficacy Endpoint in Head-to-Head Trial Against ibrutinib in CLL
"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"
Relapsed/Refractory trial results after 41 months (median experience)
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
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
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.
Ibrutinib continued to effectively control CLL in 61% of patients after a median of 6.5 years in one long term follow-up:
Towards personalised management of CLL? Ibrutinib study reveals new way to gauge patients’ response to treatment
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...
5. Luxeptinib/CG-806 (non-covalent) Phase 1a/b
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).
Updated Phase 2 study report from ASH2020
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
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!
BRUIN trial update 6th March 2021
Eli Lily are so confident about LOXO-305, next year they starting two late-stage clinical trials pitting its treatment against Imbruvica.
Members Osprey69, steve5441 and UKfulloflife are in a LOXO-305 trial: clinicaltrials.gov/ct2/resu...
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
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.
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
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.
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
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!
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.
Ongoing Trial Evaluates zanubrutinib in BTK-Intolerant B-Cell Malignancies - Dr Ian Flinn
Conversation with Dr Con Tam: healthunlocked.com/cllsuppo...
Overview by Joanna M Rhodes and Anthony R Mato (Dec 2020)
BGB3111 Response rate nears 100% in CLL/SLL onclive.com/view/bgb3111-re...
Zanubrutinib effective in CLL/SLL regardless of del 17 p status
Member experiences (including two early trial members, with 5 years experience on zanubrutinib, with one switching to Venetoclax)
Comparison side effects, second generation BTKs (Mainly reports on zanubrutinib vs ibrutinib, with a brief mention of acalabrutinib)
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.
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.
Study Explores Causes of Bleeding in Patients on Ibrutinib
Can long term ibrutinib patients stop treatment? This MSK sponsored trial aims to find out!
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
Other important BTKi posts:
COVID related FAQ from CLL Specialists (with specific reference to BTK and other treatments)
What to do when a BTKi stops working?
Screening and monitoring of the BTK C481S mutation in a real-world cohort of patients with relapsed/refractory chronic lymphocytic leukaemia
To complete the picture of common CLL drug alternatives, we have the following growing list:
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)
2) Reflects on the changing BTKi landscape
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...
Last updated 21st July 2021