乌鸦传媒

Zanubrutinib (Brukinsa) was superior to chemoimmunotherapy as frontline treatment for older or comorbid patients with chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL), the phase III SEQUOIA study showed.

Among 479 randomized patients, 92% of whom had CLL, progression-free survival (PFS) was significantly improved with the Bruton tyrosine kinase (BTK) inhibitor compared with bendamustine combined with rituximab (HR 0.42, 95% CI 0.28-0.63, P<0.0001) at a median follow-up of 26 months, reported Constantine Tam, MD, of Alfred Hospital in Melbourne, and colleagues.

Estimated PFS rates at 2 years were 85.5% in the zanubrutinib group and 69.5% in the bendamustine-rituximab group, they noted in .

These results suggest that "might be regarded as a potential standard of care for this population," they wrote, adding that the efficacy with zanubrutinib was comparable to that of the BTK inhibitors ibrutinib (Imbruvica) and acalabrutinib (Calquence), which are FDA approved in the first-line setting.

Specifically, ibrutinib demonstrated an estimated PFS rate of 87% at 24 months in the Alliance A041202 trial, while acalabrutinib monotherapy showed an estimated 24-month PFS rate of 87% in .

As for adverse events of particular interest with BTK inhibitors, any-grade atrial fibrillation was observed in 3% of patients in both the zanubrutinib and bendamustine-rituximab groups -- well below the rate of 12.6% reported with ibrutinib in the Alliance trial. Major bleeding events were observed in 5% of patients in the zanubrutinib group, which is comparable to that reported for other BTK inhibitors, but more than the 2% of patients in the bendamustine-rituximab group.

In a nonrandomized group of 111 patients with del(17)(p13.1) -- a group with historically poor outcomes with chemoimmunotherapy -- the 24-month estimated PFS rate was 88.9% with zanubrutinib, "confirm[ing] published data showing that zanubrutinib is effective in patients with CLL with del(17)(p13.1)," Tam and colleagues wrote.

Furthermore, in prespecified subgroup analyses, PFS was consistently longer with zanubrutinib versus bendamustine-rituximab independent of age, sex, or high-risk disease status, including Binet stage C, bulky disease, or presence of unmutated IGHV. However, there was no statistically significant benefit observed in the small subgroups of patients with SLL, and those with a TP53 mutation or mutated IGHV status.

Tam and colleagues noted that a limitation to the study was the choice of chemoimmunotherapy as the comparator group, which was due to the fact that trial enrollment began in 2017, and it was not until 2018 that ibrutinib, alone or in combination with rituximab, was shown to outperform fludarabine, cyclophosphamide, and rituximab, as well as bendamustine-rituximab, in treatment-naive CLL.

"Despite these limitations, the SEQUOIA trial supports the use of zanubrutinib as a first-line option in most settings," wrote Pablo Mozas, MD, and Julio Delgado, MD, PhD, of Hospital Clinic in Barcelona, in an

They noted that they are "eagerly" awaiting further data from SEQUOIA on age-unselected and comorbidity-unselected populations, outcomes according to sequencing with other therapies, long-term prognosis based on del(17)(p13.1) and TP53 or IGHV mutational status, and biological studies from blood and bone marrow samples.

"Most importantly, direct head-to-head comparisons with available and upcoming BTK inhibitors, such as pirtobrutinib, would be valuable," they added.

In the randomized portion of SEQUOIA, patients without del(17)(p13.1) were randomly assigned to receive oral zanubrutinib 160 mg twice daily in 28-day cycles until disease progression or unacceptable toxicity or 6 cycles of intravenous bendamustine-rituximab. Patients with del(17)(p13.1) were directly assigned to receive oral zanubrutinib.

Patients had a median age of 70 years, and were mostly men. Patients with clinically significant cardiovascular disease, such as recent myocardial infarction, unstable angina, severe congestive heart failure, uncontrolled hypertension, or uncontrolled arrhythmias, were excluded, while patients with controlled atrial fibrillation could enroll.

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