The B-cell receptor signaling pathway plays a critical role in the pathogenesis of B-cell malignancies. Bruton’s tyrosine kinase (BTK) activation is a target for BTK inhibition (BTKi), with covalent BTKi changing the treatment landscape of B-cell malignancies. 

Nonetheless, adverse effects and treatment resistance are issues, and most patients eventually cease treatment with these agents secondary to treatment progression or toxicity. Non-covalent BTKis work by different mechanisms and serve as an alternative to covalent BTKis; they are effective in patients who are intolerant to or have demonstrated disease progression after treatment with covalent BTKi.

 

Brief history of covalent BTKi

 

In 1993, researchers first identified BTK as a key mediator in BCR signaling. BTK plays a role in innate immune system function involving dendritic cells/macrophages.

“The central role of BTK activation in BCR signalling provides strong biological rationale for BTK inhibition as an effective therapeutic intervention in B-cell malignancies, due to the resultant suppression of BCR signalling, and subsequent reduced B-cell proliferation and survival,” according to the authors of a review published in the Journal of Personalized Medicine.

Lewis KL, Cheah CY. Non-covalent BTK inhibitors-The new BTKids on the block for B-cell malignancies. J Pers Med. 2021;11(8):764.

 

 

Various covalent BTKi were developed following the discovery of BTK, including ibrutinib, zanubrutinib, and acalabrutinib, which are FDA-approved in relapsed/refractory and/or treatment naïve settings in various B-cell lymphoma subtypes.

 

The first covalent BTKi

 

Ibrutinib, the review authors explain, was discovered in 2006 and was initially developed for rheumatoid arthritis. Ibrutinib is an irreversible, small-molecule BTK inhibitor that binds covalently to the cysteine-481 binding site of BTK, thus blocking phosphorylation and subsequent activation, as well as inhibiting downstream signaling. Preclinical efficacy in B-cell malignancies was noted in 2010. In 2012, the results of a phase 1 clinical trial using ibrutinib to treat patients with B-cell malignancies were published. 

To date, robust trial and retrospective data support the effectiveness of ibrutinib in CLL, WM, MCL, and other B-cell malignancies. Ibrutinib yields frequent and durable responses in patients with high-risk biological features including TP53 aberrations, as demonstrated in the E1912 study, in which it was used as front-line therapy for CLL.

When combined with other agents such as venetoclax and rituximab, ibrutinib has demonstrated good efficacy. Preclinical studies indicate that when BTKi is combined with such drugs, they potentiate one another, with synergism yielding deeper and more durable responses, including in patients with TP53 aberrations.

Researchers writing in the Journal of Hematology & Oncology summarized the significance of ibrutinib:

Alu A, Lei H, Han X, et al. BTK inhibitors in the treatment of hematological malignancies and inflammatory diseases: mechanisms and clinical studies. J Hematol Oncol. 2022;15(1):138.

 

“The first-in-class agent, ibrutinib, has created a new era of chemotherapy-free treatment of B cell malignancies,” they stated. “Ibrutinib is so popular and became the fourth top-selling cancer drug worldwide in 2021. To reduce the off-target effects and overcome the acquired resistance of ibrutinib, significant efforts have been made in developing highly selective second- and third-generation BTK inhibitors and various combination approaches.” 

 

Other covalent BTKis

 

The authors of the Journal of Personalized Medicine review continue the story of covalent BTKi development. Ibrutinib was the first of several covalent BTKis, including FDA-approved acalabrutinib and zanubrutinib, which are both second-generation BTKis.

Other covalent BTKis in development include TG-1701, orelabrutinib, and tirabrutinib.

Mayo Clinic researchers discuss some of the clinical studies with these agents.

Chohan KL, Kapoor P. BTK Inhibitors and other targeted therapies in Waldenström macroglobulinemia. Hemato. 2023;4(2):135–157.

Tirabrutinib, for example, demonstrated an ORR of 94% in treatment-naïve patients and of 100% in relapsed and refractory (R/R) patients in a multicenter phase 2 trial. Grade 3 or higher adverse events of neutropenia (11%), leukopenia (7%), and lymphopenia (11%) were recorded. During a short 6-month follow-up, the PFS and OS rates were 100% in both groups. Based on these results, tirabrutinib was the first BTKi approved for the treatment of treatment-naive or R/R WM and lymphoplasmacytic lymphoma (LPL) in Japan. 

 

With orelabrutinib, grade 5 reactivation of hepatitis B occurred in one patient during a clinical trial and was considered treatment related. As for TG-1701, it is currently under investigation in B-cell malignancies.

The Mayo Clinic authors commented on the current clinical status of the covalent BTKis. “It is important to note that reactivation of hepatitis B may occur with BTKi therapy, and appropriate screening prior to therapy and treatment should be employed,” the authors wrote. “Overall, how these ‘me too’ covalent BTKi will be able to supplement ibrutinib in the absence of head-to-head trials demonstrating superior efficacy or toxicity remains to be seen.”

Owing to the off-target effects and the emergence of mutants in the BTK binding sites, unwanted side effects and acquired resistance may display in patients receiving BTKis.

Although covalent BTKis are remarkably effective, they can result in primary or acquired resistance or intolerance. Discontinuation rates are as high as 40% at 4 years of treatment.

 

Non-covalent BTKis

 

Unlike covalent BTKis, non-covalent iterations do not bind to the C481 site on BTK, thus offering a potential therapeutic alternative in patients with B-cell malignancies. Non-covalent BTKis are useful in individuals who have developed acquired resistance due to BTK C481 mutations following prior therapy with a covalent BTKi. One example is pirtobrutinib, which is indicated for relapsed or refractory MCL after at least two lines of systemic therapy, including a BTKi.

As discussed in the Journal of Personalized Medicine review, pirtobrutinib exhibits >300-fold selectivity on BTK vs 98% of other kinases, thus decreasing the risk of “off-target” toxicities.

Pirtobrutinib was granted accelerated approval in January 2023 based on the results of the BRUIN trial.

US Food and Drug Administration. FDA grants accelerated approval to pirtobrutinib for relapsed or refractory mantle cell lymphoma. January 27, 2023.

Patients in the trial had a median of three prior lines of therapy, with most having received ibrutinib (67%). Pirtobrutinib was administered at 200 mg PO qD. The ORR was 50%, the CRR was 13%, and the median DOR was 8.3 months.

 

Grade 3 or 4 laboratory abnormalities occurring in ≥10% were lower neutrophil counts, lymphocyte counts, and platelet counts. The PI warns of infections, hemorrhage, cytopenias, atrial fibrillation/flutter, and second primary malignancies.

The authors of the review published in the Journal of Personalized Medicine look forward to further investigations of the non-covalent agents.

“Non-covalent BTKi may offer a potential therapeutic approach. Several agents exhibit a favourable safety profile and encouraging efficacy across a variety of B-cell malignancies, but the durability of response remains unanswered at present due to relatively short follow up. There is compelling biological rationale for combining non-covalent BTKi with other novel agents to induce deeper and more durable responses, and data from covalent BTKi combination regimens to support this approach. We anticipate the results of randomized trials of these agents will lead to the availability of more effective and well tolerated agents for patients with B-cell malignancies who have experienced covalent BTKi treatment failure.”