Covalent Bruton tyrosine kinase (BTK) and B-cell lymphoma 2 (BCL2) inhibitors are standard of care for most patients with chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL). However, resistance to covalent BTK inhibitors may develop over time, and BCL2 inhibitors have a limited duration of disease control. After progressing on a covalent BTK inhibitor and a BCL2 inhibitor, therapeutic options are limited and outcomes are poor.
Noncovalent BTK inhibitors may address unmet needs in this population. A phase 1/2 trial demonstrated the efficacy of pirtobrutinib, a noncovalent BTK inhibitor, in heavily pretreated patients with CLL or SLL (NCT03740529). In this trial, 247 patients with relapsed/refractory CLL or SLL had received at least 1 prior BTK inhibitor; of these, 40.5% had also received a BCL2 inhibitor. Most (76.9%) patients discontinued prior BTK inhibitor therapy due to disease progression.
The overall response rate (ORR) was 73.3% (including 4 complete responses, 1 nodular partial response, and 176 partial responses) in the prior BTK inhibitor subgroup. In the prior BTK/BCL2 inhibitor subgroup, the ORR was 70.0%. Median progression-free survival rates were 22.1 and 16.8 months in the prior BTK inhibitor and prior BTK/BCL2 inhibitor subgroups, respectively. Only 2.8% of patients discontinued the study drug due to a treatment-related adverse event.
Nemtabrutinib, another noncovalent BTK inhibitor, also shows promising activity in pretreated CLL or SLL and is under clinical development ( NCT04728893).
Are you convinced by the evidence for noncovalent BTK inhibition in CLL/SLL? Do you need additional data before incorporating it into treatment plans?
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Sanjaykumar Hapani, MERCY HOSPITAL OKLAHOMA CITY, INCSeptember 19, 2024I agreeem with comments above -
Eric SchaeferSeptember 19, 2024I think based on phase I/II data there were clear response rates. Would like to see data from confirmatory trial. I would also likely use a BCL2 before a noncovalent BTK.
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Mark Huber, AVERA MARSHALLSeptember 19, 2024Yes, I just follow the data, pirtobrutinib clearly an effective agent. I suspect similar drugs in the same class will follow.
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NIHAL ABDULLASeptember 19, 2024I have been attending meetings where non-covalent BTKI are considered next line of treatment even with prior covalent BTKI use, in terms of both progression or from side effects profile also better.
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Yinong LiuAugust 10, 2024there is clear evidence of pirtobrutinib for pretreated patients, including those resistant to prior BTK and BCL2 inhibitors. it showed very good ORR and PFS.
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ALEXANDER BARSOUKAugust 10, 2024I would recommend pirtobrutinib after patients have progressed on covalent BTK and venetoclax, so in third line or later. In these patients offers promising efficacy and safety
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Mayer GorbatyAugust 09, 2024My impression is that the available evidence is adequate to integrate non-covalent BTK inhibitors into our treatment algorithm. It has a high response rate and is relatively well tolerated. It is not a cure. It allows us time to plan our next steps if and when the patient progresses through this line of treatment.
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Venu Madhav Konala, GCS/NorthsideJuly 17, 2024Clinical data is very convincing and I am currently using: non-covalent BTK inhibitors in patients who progressed on covalent BTK inhibitors and BCL-2 inhibitors. High overall response rate and heavily pretreated patients, well tolerated.
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Fernando De ZarragaJuly 15, 2024I am convinced thus far. Will need longer term data but certainly would be an option I would consider for the right patient in the relapsed setting.
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Abdel Hai AlqwasmiJuly 14, 2024absolutely, data is very impressive and convincing. While it would be nice to see long term data, it is not needed to start adopting the drug and using ut
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PREMILA MALHOTRAJuly 13, 2024I see the main use of non covalent BTk inhibitor use Mainly in pts who have progressed on covalent BTk inhibitor or Bcl 2 inhibitor
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Branden HsuJuly 12, 2024Clinical evidence for pirtobrutinib, in CLL/SLL shows promising efficacy, with a high overall response rate in heavily pretreated patients, including those resistant to prior BTK and BCL2 inhibitors. Long term follow-ups would be beneficial to establish roles in treatment
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Stephen Zrada, VIRTUA WEST JERSEY HOSPITALS VOORHEESJuly 11, 2024The science is sound. The data convinces me that noncovalent BTKi’s can be used to treat patients who progress on covalent BTKi’s. Will be looking out for long term data but looks good.
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Samir Dalia, MERCY HOSPITAL JOPLINJuly 11, 2024i think these drugs can work in previous btk failure. not sure if its ready to be moved upfront.
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Peter GeorgesJuly 10, 2024Yes I am convinced and will use as third line option after progression on covalent btki and bcl2 inhibitors.
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MATTHEW MCCARTYJuly 10, 2024After bcl2 and btk, non covalent btk offers a successful option to tx pts
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Albert DekkerJuly 10, 2024I think that this is a good agent. I have limited experience but all my experience has been good so far. The real question where this agent should be positioned in clinical practice. As next line after traditional TKI or as label after BCL2 sandwiched in between.
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KARL D'SILVAJuly 10, 2024Since, we do not have any good option in patients who have progressed on covalent BTK, non-covalent BTK is the next best option if the resistance mutation does not prevent us from using non-covalent BTK
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Elie Fahed, ROCKY MOUNTAIN ONCOLOGY CENTER, LLCJuly 10, 2024No good non chemo option is available after progression on BTK and Bcl2 inhibitor. As such noncovalent BTK inhibitors are the best option in this setting.
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Jason Salganick, IRONWOOD PHYSICIANS, PCJuly 10, 2024I agree with the use of non-covalent BTK inhibitors, especially in patients already refractory to BTK. Key opinion leaders also are in agreement.
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Sumit SawhneyJuly 10, 2024for pts who have progressed on covalent btk non covalent btk offer a good option but is not an option for first line ,donot have data that upon progression with non covalent that covalent binders will have efficacy
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Phillip ChaeJuly 10, 2024At current, I do not feel I need any major things before choosing to incorporate these drugs into my treatment plans. I think the trial was fairly well designed and the ORR is impressive. I only have experience with Pirtobrutinib and have had a good experience so far. Of course, long term follow up would be nice.
