Researchers Offer Guidance on Choosing Appropriate BTK Inhibitor in CLL

With 3 Bruton’s tyrosine kinase (BTK) inhibitors on the market, researchers of a new study have outlined considerations for choosing an agent in patients with chronic lymphocytic leukemia (CLL).

Offering an effective, tolerable, and chemotherapy-free option for patients with CLL, BTK inhibitors have drastically changed the landscape of the disease. They first hit the market in 2013 with the approval of ibrutinib, which is now considered a standard first-line option. There is also acalabrutinib, approved for CLL in 2019, and zanubrutinib, which although not approved for CLL is recommended by the National Comprehensive Cancer Network. Further, this past February, the FDA accepted a supplemental new drug application of zanubrutinib for adult patients with CLL or small lymphocytic lymphoma.

“Now that ibrutinib is no longer the sole BTK inhibitor on the market for the treatment of CLL, clinicians are faced with the challenge of selecting the most appropriate BTK inhibitor, weighing the advantages and disadvantages of each,” wrote the researchers. “Selection of the appropriate BTK inhibitor is multifactorial and depends on side effect profile, comorbidities of the patient, concomitant medications and potential drug–drug interactions, cost, ease of administration, and desired outcomes of therapy.”

Their study findings appeared recently in Therapeutic Advances in Hematology.

Among the agents, acalabrutinib and zanubrutinib have been associated with more favorable safety profiles compared with ibrutinib due to their increased selectivity for the BTK kinase. For relapsed/refractory disease, data from the phase 3 ELEVATE-RR and phase 2ALPINE trials show that with the exception of headache and neutropenia, acalabrutinib and zanubrutinib were associated with less adverse events than ibrutinib.

Ibrutinib has been linked to an increased risk of cardiovascular adverse events compared with the other 2 agents, suggesting that acalabrutinib or zanubrutinib be preferred in cases of preexisting cardiovascular disease. Notably, patients on anticoagulation treatment were excluded from the ELEVATE-RR trial, leading the researchers to suggest that zanubrutinib be considered for patients at risk of major bleeds. Data from the multiarm SEQUOIA trial showed that was safe in patients on anticoagulation or antiplatelet therapy.

The researchers explained the agents’ efficacy is similar, with no significant differences seen in overall survival (OS) between the 3. They noted, howeverm that longer-term follow-up for OS is needed. Early data suggests that zanubrutinib may have more favorable progression-free survival over ibrutinib among patients with relapsed/refractory disease.

“All 3 BTK inhibitors on the market are available as brand-only medications and come at a significant cost, as BTK monotherapy is typically continued indefinitely, until disease progression or intolerable toxicity,” explained the researchers. “This is because of the limited ability of BTK inhibitor monotherapy to eradicate MRD [minimal residual disease]. This and other considerations have led to interest in time-limited or finite duration regimens, such as those of venetoclax with an anti-CD20 monoclonal antibody or venetoclax with ibrutinib. Another promising strategy has been the addition of venetoclax in patients on ibrutinib to induce MRD eradication.”

Ibrutinib will be the first of the 3 treatments to see a generic version come to market, with that expected to occur in 2032.

Improved options for safety and efficacy in these patients may also come from additional BTK inhibitors currently in the pipeline, including ARQ-531, a reversible, noncovalent BTK inhibitor that recently demonstrated activity in patients resistant to covalent BTK inhibitors in a phase 1 dose escalation study. Vecabrutinib, also being studied in ongoing phase 1 trials, is anticipated to have less off-target activity due to its reversibility and noncovalent binding, which would increase tolerability.

Reference

Lovell A, Jammal N, Bose P. Selecting the optimal BTK inhibitor therapy in CLL: rationale and practical considerations. Ther Adv Hematol. Published online August 9, 2022. doi:10.1177/20406207221116577