Second-Generation BTK Inhibitors Seek to Build Off Ibrutinib Success in CLL

Published on: 

These second-generation inhibitors include acalabrutinib, zanubrutinib, and tirabrutinib, and researchers hope they can overcome the off-target toxicity and treatment resistance that can be experienced with ibrutinib.

Building on the progress made in chronic lymphocytic leukemia (CLL) treatment with ibrutinib, second-generation Bruton tyrosine kinase (BTK) inhibitors continue to be studied in ongoing trials in an attempt to improve the safety and efficacy of treatment. In a recent paper in Hematology/Oncology Clinics of North America, a pair of researchers outline the available data and paint a picture of what’s likely to come.

These second-generation inhibitors include acalabrutinib, zanubrutinib, and tirabrutinib, which researchers hope can overcome the off-target toxicity and treatment resistance that can be experienced with ibrutinib.

“Attributed to greater selectivity for the BTK versus off-target kinases, data so far suggest that next-generation BTK inhibitors are generally well tolerated and have a more favorable toxicity profile compared with ibrutinib,” commented the researchers. “This advantage includes a decreased incidence of atrial fibrillation and grade 3 or higher hypertension.”


The phase 3 ASCEND study of acalabrutinib in 300 patients with relapsed or refractory disease demonstrated that the BTK inhibitor resulted in significantly longer median progression-free survival (PFS) compared with rituximab plus idelalisib or bendamustine, for an estimated 88% 12-month PFS vs 68%, respectively. Results are also anticipated for the phase 3 ELEVATE-RR trial, which is comparing acalabrutinib and ibrutinib head-to-head in patients with CLL with high-risk features.

The treatment is also being studied as a combination regimen, with obinutuzumab and venetoclax in treatment-naive patients. Safety data also show common adverse events of diarrhea (18%-52%), headache (22%-51%), neutropenia (14%-25%), and anemia (7%-14%).


“Similarly, the ACE-CL-001 study reported a 48-month event-free survival of 90%, which is higher than recently reported for ibrutinib55 and, thus, suggestive of better tolerability,” the authors wrote. “This finding is supported by safety outcomes in a group of 33 ibrutinib-intolerant patients treated with acalabrutinib, with only 9% requiring drug discontinuation owing to toxicity.”


Zanubrutinib is currently being compared against ibrutinib in the ALPINE study of patients with relapsed or refractory CLL. The treatment has previously showed efficacy among treatment-naive and relapsed/refractory patients in a phase 1/2 study, which showed an overall response rate (ORR) of 97% at 25 months. At 2 years, the ORR and PFS among patients with del(17p) were 94% and 75%, respectively.

Positive data have been published on the BTK inhibitor in combination with obinutuzumab, and several studies are currently ongoing to explore the efficacy of zanubrutinib in combination with other agents.

According to the researchers, zanubritnib’s high selectivity for BTK without epidermal growth factor receptor has allowed for lower rates of diarrhea and rash compared with ibrutinib (21% vs 42% and 13% vs 51%, respectively).


Early data show that tirabrutinib alone yielded response rates of 96% among a 20 patients, and 2 phase 2 studies recently hinted at promising efficacy with the treatment and idelalisib with or without obinutuzumab.

Data from a phase 2 study show that the majority (75%) of adverse events associated with tirabrutinib were grade 1 or 2. Grade 3 treatment-related bleeding was reported in 1 patient, and there were no cases of diarrhea, cardiac dysrhythmias, or arthralgias.

“BTK inhibitors are in development, with the aim to improve on efficacy and off-target side effects of ibrutinib,” the authors concluded. “Randomized, prospective data are required to confirm these observations and better characterize rates and severity of individual side effects.”

Additional factors to consider when choosing agents for BTK inhibitor therapy include durability of response, possibility of long-term toxicity, potential combination treatment options, resistance mechanisms, and transformation risk.


Lasica M, Tam C. Bruton tyrosine kinase inhibitors in chronic lymphocytic leukemia. Hematol Oncol Clin N Am. 2021;35(4):761-773. doi:10.1016/j.hoc.2021.03.006