The virtual European Haematology Association meeting (EHA 2021) held on 9-17 June saw the first interim results presented from the Phase III ALPINE study, which is investigating the efficacy of BeiGene ’s Bruton Tyrosine Kinase (BTK) inhibitor, Brukinsa, (zanubrutinib) compared to AbbVie and Johnson And Johnson ’s Imbruvica (ibrutinib) in patients with relapsed or refractory chronic lymphocytic leukaemia (CLL) and small lymphocytic lymphoma.

At a median follow-up of 15 months, the overall response rate (ORR ), which is the primary endpoint of the trial, was significantly longer in the Brukinsa-treated patients, and stands at 78.3% for Brukinsa versus 62.5% for Imbruvica. The results are based on 415 patients enrolled in the study, who had received at least one prior line of therapy.

The treatment of CLL was transformed by the approval of the first BTK inhibitor, Imbruvica, in 2014. There are, however, relatively high rates of cardiovascular toxicities associated with Imbruvica. It is hoped that second-generation BTK inhibitors could reduce the incidence of adverse events, while at least maintaining efficacy, by reducing binding to off-target kinases such as TEC and EGFR.

Brukinsa also came out on top compared to Imbruvica in terms of safety, with patients in this arm presenting with significantly fewer incidents of atrial fibrillation or flutter, which is a secondary endpoint of the trial (2.5% vs 10.1%). The rates of major bleeding events, adverse events leading to discontinuation, and adverse events leading to death were also lower in the Brukinsa-treated patients compared to Imbruvica, although Brukinsa-treated patients did present with higher rates of neutropenia (28.4% vs 21.7%).

This was not the only second-generation BTK inhibitor being discussed at EHA this year. The first results from the Phase III ELEVATE-RR trial, which is designed to compare Imbruvica to AstraZeneca ’s Calquence (acalabrutinib) in previously treated CLL patients with del11q and del17p mutations, were also showcased. In this study, Calquence demonstrated non-inferiority compared to Imbruvica (the primary endpoint of the trial) and resulted in significantly fewer events of atrial fibrillation of any grade (9.4% vs 16.0%). No patients in the Calquence arm had to discontinue treatment as a result of atrial fibrillation, which seven patients in the Imbruvica arm did.

The superior tolerability, and particularly the reduction in atrial fibrillation, of both Brukinsa and Calquence compared to Imbruvica supports the use of second-generation BTK inhibitors in second-line CLL. It remains to be seen how these second-generation inhibitors will compare to each other.