Beyond covalent inhibition: how are non-covalent agents and BTK degraders reshaping CLL treatment?

Introduction

Bruton tyrosine kinase (BTK) inhibitors have transformed chronic lymphocytic leukemia (CLL) management, establishing B-cell receptor signaling as a key therapeutic target.¹However, despite improved clinical outcomes, treatment-related toxicities, acquired resistance, and uncertainties surrounding optimal therapeutic sequencing remain significant clinical challenges.² Alongside efforts to optimize covalent BTK inhibitor-based regimens, novel approaches, including non-covalent inhibitors and targeted protein degraders, are being investigated to address resistance and expand treatment options.² These advances offer opportunities to individualize therapy while raising questions about how emerging agents should be integrated into CLL treatment pathways.

Covalent BTK inhibitors: an evolving treatment paradigm

The introduction of ibrutinib established continuous covalent BTK inhibition as an effective alternative to chemoimmunotherapy.³ However, prolonged treatment can be associated with adverse events, including atrial fibrillation, hypertension, and bleeding, prompting the development of more selective second-generation agents.³ Head-to-head Phase III data from ELEVATE-RR (NCT02477696) demonstrated noninferior progression-free survival (PFS) with acalabrutinib versus ibrutinib (hazard ratio [HR] 1.00; 95% confidence interval [CI] 0.79–1.27), alongside improved tolerability for several adverse events.⁴ The Phase III ALPINE trial (NCT03734016) subsequently demonstrated superior PFS with zanubrutinib versus ibrutinib (HR 0.65; 95% CI 0.49–0.86; p=0.002).⁵

Continuous BTK inhibition remains an important treatment approach, particularly for patients with TP53-aberrant disease or those for whom venetoclax initiation presents additional challenges.³ The primary analysis of the Phase II CLL-FRAIL trial (NCT04883749) demonstrated the clinical activity of acalabrutinib in patients aged ≥80 years and/or classified as frail who had up to one prior line of therapy, with 72% of patients being treatment naïve). The primary endpoint of overall response rate (ORR) was 93.5% (95% CI 82.1–98.6%) among 46 patients who received at least three treatment cycles and the intention-to-treat ORR was 81.1% (95% CI 68.0–90.6%).⁶ However, treatment discontinuations due to adverse events highlighted the importance of individualized tolerability assessments.⁶

Discussing the longer-term findings from CLL-FRAIL, Florian Simon, MD, University Hospital Cologne, Cologne, Germany, highlighted the encouraging responses observed in patients with substantial disease burden:

“These are the patients who are actually improving a lot and who do well on the treatment and continue to do well. So, this was really encouraging to see that the trial produced long-term results which show a durable response to the treatment.”

Alongside efforts to improve continuous treatment, interest has increasingly focused on fixed-duration combinations to limit prolonged treatment exposure while maintaining disease control.³ Reflecting this shift, the Phase III AMPLIFY trial (NCT03836261) demonstrated improved PFS with fixed-duration acalabrutinib plus venetoclax compared with chemoimmunotherapy in previously untreated patients without del(17p) or TP53 mutations (HR 0.65; 95% CI 0.49–0.87).

Discussing the clinical implications in an interview with VJHemOnc, Alexey Danilov, MD, PhD, City of Hope, Duarte, CA, highlighted the appeal of treatment-free intervals:

“A fixed-duration therapy of 15 months or so is also very attractive to many patients, both from the standpoint of minimizing side effects as well as financial toxicity.”

Prof. Danilov also discusses the role of acalabrutinib lead-in treatment in reducing tumor burden before venetoclax initiation and the need for longer-term follow-up to establish remission durability.

Ultimately, treatment selection requires balancing disease biology, comorbidities, treatment burden, and patient preferences.³ However, despite improvements in tolerability and the expansion of fixed-duration approaches, acquired resistance remains an important limitation of covalent BTK inhibition. Mutations affecting the C481 binding residue of BTK can impair irreversible inhibitor binding, providing the rationale for alternative BTK-targeted strategies.⁸

Non-covalent BTK inhibitors: addressing resistance and redefining sequencing

Unlike covalent inhibitors, non-covalent BTK inhibitors bind reversibly without requiring C481, allowing activity against C481-mutant disease.⁸ Pirtobrutinib, a highly selective reversible inhibitor, demonstrated an ORR of 62% (95% CI 53–71%) in 121 evaluable patients previously treated with covalent BTK inhibitors in the Phase I/II BRUIN study (NCT03740529). Response rates were 71% (17/24) in patients with C481-mutant disease and 66% (43/65) in those with wild-type BTK.⁹ These findings provided early clinical evidence that BTK inhibition could remain effective following C481-mediated resistance.

Subsequently, the Phase III BRUIN CLL-321 trial (NCT04666038) demonstrated improved PFS with pirtobrutinib compared with investigator’s choice of idelalisib plus rituximab or bendamustine plus rituximab following covalent BTK inhibitor exposure (median PFS: 14.0 versus 8.7 months; HR 0.54; 95% CI 0.39–0.75).¹

Building on this evidence, the Phase III BRUIN CLL-322 trial (NCT04965493) investigated fixed-duration pirtobrutinib plus venetoclax and rituximab (PVR) versus venetoclax and rituximab (VR) in patients with previously treated CLL, approximately 80% of whom had received a prior covalent BTK inhibitor. PVR significantly improved PFS (HR 0.547; 95% CI 0.400–0.748), with estimated 24-month PFS rates of 87% versus 72%, respectively.¹

Discussing the findings at the 31st Congress of the European Hematology Association (EHA 2026), Matthew Davids, MD, Dana-Farber Cancer Institute, Boston, MA, highlighted the potential relevance of PVR for patients who had progressed on covalent BTK inhibitors:

“The magnitude of the benefit of PFS was actually even greater in the patients who had progressed on prior covalent BTK inhibitor with PVR compared to VR, suggesting that’s a population that may particularly benefit from this new regimen.”

Another investigational non-covalent inhibitor, nemtabrutinib, is being evaluated with venetoclax in the BELLWAVE-010 trial (NCT05947851). At EHA 2026, Paolo Ghia, MD, Vita-Salute San Raffaele University, Milan, Italy, reported preliminary ORRs of 100% (95% CI 78–100%) in the 45 mg cohort (n=15) and 88% (95% CI 62–98%) in the 65 mg cohort (n=16).¹² Despite these encouraging early efficacy findings reported, grade 3–5 treatment-related adverse events occurred in 73% and 75% of patients in the 45 mg and 65 mg cohorts, respectively, including one treatment-related fatal pneumonia in the higher-dose group, highlighting the need for continued safety evaluation.¹²

Providing further insights into BELLWAVE-010, Dr Ghia discussed the rationale for combining nemtabrutinib with venetoclax, highlighting the encouraging preliminary responses observed during dose escalation and the study’s progression into its randomized phase.

Despite these advances, resistance to non-covalent inhibitors can also emerge. Genomic analyses of patients progressing during pirtobrutinib treatment have identified acquired mutations, including T474I, L528W, and V416L, which can impair inhibitor activity and, in some cases, confer cross-resistance between BTK inhibitor classes.⁸ These findings highlight the limitations of sequential kinase inhibition and provide a rationale for alternative BTK-targeted strategies.

BTK degraders: the next frontier in targeted therapy

Targeted protein degradation represents a mechanistically distinct approach to addressing BTK inhibitor resistance. Rather than suppressing kinase activity alone, BTK degraders recruit the ubiquitin–proteasome system to eliminate BTK, potentially disrupting both catalytic and kinase-independent scaffolding functions. ^8,13

Investigational agents, including tacabrutideg (BGB-16673) and bexobrutideg (NX-5948), have demonstrated preliminary antitumor activity in heavily pretreated CLL, including patients previously exposed to covalent and non-covalent BTK inhibitors. ^14,15

Updated findings from the Phase I CaDAnCe-101 trial (NCT05006716) demonstrated an ORR of 85.1% and a 24-month PFS rate of 53.8% (95% CI 38.8–66.6%) with tacabrutideg in an analysis of 67 patients with relapsed/refractory CLL, after a median follow-up of 25.4 months.¹⁴ Grade ≥3 treatment-emergent adverse events occurred in 62.7% of patients, with 17.9% discontinuing treatment due to adverse events. Five treatment-emergent deaths were reported, none of which was considered treatment-related.¹⁴

Presenting the updated CaDAnCe-101 findings at the 2026 ERIC International Meeting (ERIC CLL 2026), Stephan Stilgenbauer, MD, University of Ulm, Ulm, Germany, discussed the promising efficacy and tolerability of tacabrutideg in heavily pretreated CLL and its potential future role in earlier treatment lines, including combination strategies with BCL2 inhibitors.

In another recent interview from ERIC CLL 2026, Prof. Danilov discussed the molecular rationale for degradation and the potential of BTK degraders to overcome resistance to existing inhibitors, highlighting their activity against a broader range of BTK mutations and the possibility of using these agents earlier in the treatment course:

“The degraders are effective against all of the above mutations. And therefore, it is possible that as these mutations, we believe, pre-exist in the form of small subclones, […] using a BTK degrader will eliminate those subclones early and then delay resistance.”

Early-phase findings with bexobrutideg have similarly demonstrated antitumor activity in heavily pretreated disease.¹⁵ Randomized Phase III studies, including CaDAnCe-304 (NCT06973187) and DAYBreak CLL-306 (NCT07516093), are investigating tacabrutideg and bexobrutideg, respectively, against pirtobrutinib following covalent BTK inhibitor exposure.^16,17 These studies will help determine whether protein degradation provides additional clinical benefit over non-covalent inhibition and whether degraders could be positioned earlier in CLL treatment pathways; longer-term comparative evidence is required to establish their efficacy, safety, and optimal sequencing.

However, degraders are not immune to resistance: the BTK A428D mutation, which has emerged in patients treated with BTK degraders, alters the structure of the drug-binding pocket and confers resistance to both BTK inhibitors and degraders.¹⁸ Preclinical data suggest that combining degraders with BCL2 inhibitors may help prevent the emergence of such resistant clones.¹⁸

Looking ahead: optimizing sequencing and personalized treatment

The expanding range of BTK-directed therapies is creating new opportunities for patients with CLL, but also greater complexity in determining how and when individual agents should be used. Treatment decisions will increasingly need to account for prior therapy exposure, molecular resistance mechanisms, comorbidities, and patient preferences, while advances in measurable residual disease (MRD)-guided strategies may help refine treatment duration and sequencing.^2,3

Beyond BTK-targeted strategies, immune-based approaches, including CAR T-cell therapies and bispecific antibodies, are also expanding treatment possibilities for heavily pretreated CLL.¹⁹ Discussing these emerging options in a recent interview, Prof. Danilov highlighted their potential following progression on targeted therapies:

“Cell therapy, T-cell engaging therapies, are a very good choice for patients who are failing targeted therapies. And I think those might also move into earlier lines of therapy as we learn how to use them better.”

As these therapeutic approaches advance, a key challenge will be determining how to translate promising clinical trial findings into effective, individualized treatment strategies. Establishing the optimal sequence of covalent and non-covalent BTK inhibitors, identifying patients who may benefit from protein degradation, and integrating emerging combination and immune-based approaches will require continued investigation. Ultimately, the goal is not simply to expand the number of available therapies, but to use them more effectively to achieve durable disease control while minimizing toxicity and treatment burden.