Noncovalent BTK Inhibitors

To avoid the issue of drug resistance that can occur in patients treated with covalent BTK inhibitors, trials are underway to evaluate the efficacy of noncovalent BTK inhibitors. Early data from phase I or phase 2 trials demonstrated suboptimal tumor activity with both vecabrutinib and luxeptinib, while a phase 2 trial of nemtabrutinib reported an ORR of 57.9% at a median follow-up of 4.56 months in patients with B cell malignancies, including 68 individuals with CLL.1

Showing the strongest results thus far among the noncovalent BTK inhibitors currently under investigation, pirtobrutinib is “characterized by a very favorable pharmacokinetic profile, maintaining more than 90% of maximal BTK inhibition at trough, and also presents a greater than 300-fold selectivity for BTK over 98% of other kinases, potentially reducing the off-target toxicities,” wrote the authors of a review published in November 2022 in Current Opinion in Oncology.1

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According to preliminary findings from the phase I/II BRUIN trial, CLL patients (including many with high-risk features such as 17p deletion, TP53 mutation, 11q deletion, and unmutated IGHV status) treated with pirtobrutinib demonstrated an ORR of 63% at the 6-month follow-up, reaching up to 86% at 10 months.7 ORRs reached 69% in patients refractory to BTK inhibitors and BCL-2 inhibitors and 58% in patients refractory to BTK inhibitors, BCL-2 inhibitors, and phosphoinositide 3-kinase inhibitors.1

The most common AEs were grade 1 or 2 events (87%) such as fatigue and diarrhea, and neutropenia was the most common grade 3 adverse event, affecting 10% of the study population.1

Multiple clinical trials are continuing the evaluation of pirtobrutinib for use as monotherapy and in combination with BCL-2 inhibitors.1

With this growing number of effective treatment strategies, the “concept of choosing the best therapy according to patients’ comorbidities and needs is becoming a reality in CLL,” review authors concluded.1

For further discussion regarding the use of BTK inhibitors in CLL treatment, we checked in with Jennifer A. Woyach, MD, hematologist-oncologist at The Ohio State University (OSU) Comprehensive Cancer Center – The James and professor in the division of hematology at the OSU Wexner Medical Center.

What are currently the most promising BTK inhibitors for CLL treatment?

Dr Woyach:Currently, there are 3 covalent BTK inhibitors used in clinical practice – ibrutinib, acalabrutinib, and zanubrutinib. Acalabrutinib and zanubrutinib are second-generation inhibitors that were designed to improve selectivity for BTK. In head-to-head studies of each second generation inhibitor compared to ibrutinib in the relapsed/refractory setting, both showed improved tolerability for the second-generation inhibitor.5,6

Most studies of emerging BTK inhibitors are currently focused on noncovalent BTK inhibitors designed to work in the presence of mutations that lead to relapse with the covalent inhibitors. The one furthest along in development is pirtobrutinib, which has shown excellent efficacy in highly refractory CLL patients.7 There are currently a number of ongoing phase 3 trials of this drug in multiple settings. Numerous other noncovalent BTK inhibitors, including nemtabrutinib, are earlier in development but also appear promising.

How might these therapies be used to tailor treatment to individual patients?

Dr Woyach:When thinking about the covalent inhibitors, there are a few side effects that differentiate the medications. Both acalabrutinib and zanubrutinib are more tolerable than ibrutinib, but ibrutinib does have once-daily dosing which is appealing for some patients. Both acalabrutinib and zanubrutinib have lower rates of atrial fibrillation than ibrutinib, with zanubrutinib potentially having the lowest rates. However, hypertension appears to be less frequent with acalabrutinib than either ibrutinib or zanubrutinib. 

Acalabrutinib has a temporary side effect of headaches which is not seen frequently with the other medications. Sometimes these differences in side effects can help choose the best therapy for an individual patient. In addition, if a patient cannot tolerate 1 member of the class, there is opportunity to switch to a different inhibitor with improved tolerability.

Also, likely in the near future, the combination of ibrutinib and venetoclax may be approved for frontline treatment of CLL. This will give an option for a time-limited therapy involving a BTK inhibitor, which is of high interest. It is not yet clear which patients would be the optimal candidates for treatment with this regimen, but hopefully longer-term results and future studies will help elucidate this.

What are other key takeaways for clinicians regarding this topic?

Dr Woyach: BTK inhibitors, especially the second-generation covalent inhibitors acalabrutinib and zanubrutinib, are excellent options for treatment of CLL. It is not clear that there is any difference in efficacy among the 3 available BTK inhibitors, although the early results of the ALPINE study trend toward improved efficacy of zanubrutinib compared with ibrutinib. For most patients, any of the 3 is an appropriate choice. 

Once approved, noncovalent inhibitors of BTK will be an excellent option for patients who relapse after a covalent BTK inhibitor. Current and future studies will help us understand whether the sequence of therapies should always be a covalent inhibitor followed by a noncovalent inhibitor.

What are remaining needs in research investing BTK inhibitors for CLL?

Dr Woyach:Strategies to allow therapy discontinuation are of high interest, as this will decrease both the physical and financial toxicity of these agents. Current and future clinical trials are also needed to determine whether other agents besides venetoclax are ideal combination partners for the BTK inhibitors.

Additionally, with long-term follow up available from clinical trials as well as real-world data, we are understanding more and more about toxicity of these agents and the best way to mitigate toxicities. This will be increasingly important as more and more patients are treated with these highly effective medications.


  1. Beyond ibrutinib: novel BTK inhibitors for the treatment of chronic lymphocytic leukemia. Curr Opin Oncol. 2022;34(6):757-767. doi:10.1097/CCO.0000000000000897
  2. ASCEND: phase III, randomized trial of acalabrutinib versus idelalisib plus rituximab or bendamustine plus rituximab in relapsed or refractory chronic lymphocytic leukemia. J Clin Oncol. 2020;38(25):2849-2861. doi:10.1200/JCO.19.03355
  3. Efficacy and safety in a 4-year follow-up of the ELEVATE-TN study comparing acalabrutinib with or without obinutuzumab versus obinutuzumab plus chlorambucil in treatment-naïve chronic lymphocytic leukemia. Leukemia. 2022;36(4):1171-1175. doi:10.1038/s41375-021-01485-x
  4. Acalabrutinib versus ibrutinib in previously treated chronic lymphocytic leukemia: results of the first randomized phase III trial. J Clin Oncol. 2021;39(31):3441-3452. doi:10.1200/JCO.21.01210
  5. Zanubrutinib versus bendamustine and rituximab in untreated chronic lymphocytic leukaemia and small lymphocytic lymphoma (SEQUOIA): a randomised, controlled, phase 3 trial. Lancet Oncol. 2022;23(8):1031-1043. doi:10.1016/S1470-2045(22)00293-5
  6. First interim analysis of alpine study: results of a phase 3 randomized study of zanubrutinib vs ibrutinib in patients with relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma. Paper presented at: European Hematology Association 2021 Virtual Congress; June 2021; Abstract LB1900.
  7. Pirtobrutinib, a next generation, highly selective, non-covalent BTK inhibitor in previously treated CLL/SLL: updated results from the phase 1/2 BRUIN StudyBlood. 2021;138 (Suppl_1):391. doi:10.1182/blood-2021-147599