Despite having revolutionized the management of R/R MCL and CLL, covalent inhibitors of BTK demonstrate increased protein binding, have short half-lives, and exhibit decreased oral bioavailability, with only brief exposure to inactivate BTK. One-third of patients will develop primary BTK inhibitor resistance, and nearly all develop secondary resistance—despite response rates of single-agent BTK inhibitors being relatively high. Mechanisms of resistance to covalent BTK inhibitors are not fully elucidated and differ by malignancy type. Resistance, intolerance, toxicity, and disease progression are all factors that contribute to treatment discontinuation in patients taking covalent BTK inhibitors.
When covalent BTK inhibitors are no longer an option, noncovalent BTK inhibitors that are highly selective for BTK can reestablish response and propel the care of patients with R/R MCL and CLL forward. Efficacy of BTK inhibition delivered via noncovalent BTK inhibition could permit patients with B-cell malignancies to further extend the clinical benefit delivered via BTK inhibition by permitting the sequential use of inhibitors that bind by means of both covalent and noncovalent mechanisms.
Which of your patients are best suited for treatment with noncovalent BTK inhibitors?
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MATTHEW MCCARTY2yrI use a non covalent btk in the third line setting after covalent btk and bcl2
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Sanjaykumar Hapani, MERCY HOSPITAL OKLAHOMA CITY, INC2yrOVerall car-t ability to be deilivered in outpatient non-academic centers will allow us to help more patients
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Sanjaykumar Hapani, MERCY HOSPITAL OKLAHOMA CITY, INC2yrwe like all options a lot as pt benefit a lot, btk is way to go
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Salim Contractor2yrPatients who have progressed on covalent BTK inhibitors,not candidates for CART or as bridging therapy to CART also
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Phillip Chae2yri would offer to relapsed ,cll,or mantle cell patients who progress on covalent btk or intolerant. i would also offer it to those patients on later lines like 3rd or later who have progressed and are not willing to take more aggressive IV therapy or CAR-T
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Donald Fleming, DAVIS MEMORIAL HOSPITAL2yrI agree noncovalent BTI good option but why not CART
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JOSHUA STRAUSS2yrI think non-covalent BTKI's are a great option for MCL/CLL patients who become intolerant to second gen covalent BTKi's or who progress on them. It seems to be an excellent way to continue a tolerable and convenient oral regimen without having to change up the patients lifestyle or tox profile too much. Patients will appreciate the ability to continue on the BTKi mechanism as long as they can
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Holavanahall Keshavaprasad2yrWould consider non covalent BTki for pts previously treated with CoValent BTK inhibitors and found to be resistant or intolerant. Non-Covalent BTK inhibitors could be used before [for bridging ]or for relapse after CAR-T therapy
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NIHAL ABDULLA2yrSo am getting more convinced those on Imbruvica should be switched due to sudden cardiac deaths from cardiac arrhythmia. Better to switch to next gen BTK.
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Donald Fleming, DAVIS MEMORIAL HOSPITAL2yrIf noncovalent more effective and no more toxic, then why not use first?
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Donald Fleming, DAVIS MEMORIAL HOSPITAL2yrit makes one wonder why not use most effective first.
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Venu Madhav Konala, GCS/Northside2yrPatients who progressed on covalent BTK inhibitors, as well as prior covalent BTK inhibitors and BCL2 inhibitors, post CAR-T cell therapy or bridging to CAR-T cell therapy can be considered for non-covalent and reversible BTK inhibitors.
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Stephen Zrada, VIRTUA WEST JERSEY HOSPITALS VOORHEES2yrIf a pt had a durable response to a covalent, I would be more inclined to use a non-covalent BTKi. However, I may not want to use the non-covalent BTKi immediately after the covalent BTKi if there are other treatment options available (i.e venetoclax obinutuzumab in CLL).
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KARL D'SILVA2yrpatients who have progressed on covalent BTK inhibitors in second line are candidates for non-covalent BTk, if they cannot get CAR-T therapy. patients also who have progressed on BTK, CAR-T therapy are excellent candidates for non-covalent BTK inhibtors
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Elie Fahed, ROCKY MOUNTAIN ONCOLOGY CENTER, LLC2yrAny patient who progressed on a covalent BTK and a Bcl2 inhibitor
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Samir Dalia, MERCY HOSPITAL JOPLIN2yrPatients who progressed after ibrutinib or acalabrutinib can be placed on a non covalent btk at progression or rechallanged after a bcl2 inhibitor as well.
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MICHAEL NISSENBLATT2yrupon rogression on covalent BTK inhibitors noncovalent BTK inhibitors ar estill efficacious in r/r/ cll and mcl and likely other b cell malignancies.
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Jason Salganick, IRONWOOD PHYSICIANS, PC2yrA patient already exposed (especially recently) to a BTK should and can get a non-covalent BTK (like pirobrutinib) as the next line of therapy
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Sumit Sawhney2yrpts with relapsed ,cll,or mantle cell who progress on covalent btk are candidates for non covalent btk
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Branden Hsu2yrPatients in pretreated BTK inhibitors in the 3rd line setting, or possibly in 4th line post BTK and CAR-T therapy, are all eligible for the noncovalent inhibitor
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Peter Georges2yrPatients with relapsed mantle cell lymphoma previously treated with a covalent BTk-i who are felt not to be a candidate for Car-t cell therapy, or even as Bridge therapy for patient who progressed on covalent btk-I and are awaiting CAR-t cell therapy. Additionally, I see a role for noncovalent BtKI in patient who have progressed post Car.