From the Journals

Phase 3 data: Zanubrutinib bests standard CLL treatment



The second-generation selective Bruton tyrosine kinase inhibitor (BTKi) zanubrutinib outperformed the standard treatment bendamustine-rituximab in untreated chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL), a new industry-funded phase-3 trial found.

At a median follow-up of 26.2 months, progression to worsening disease or death was much lower in patients with these conditions who took zanubrutinib (Brukinsa), compared with those who took bendamustine-rituximab (hazard ratio. 0.42; 95% confidence interval, 0.28-0.63; P < .00011). The study was published in The Lancet Oncology.

Researchers already knew that ibrutinib, another BTKi, improves progression-free survival, study coauthor Paolo Ghia, MD, PhD, professor of medical oncology at Vita-Salute San Raffaele University, Milan, said in an interview. “Now we confirmed that the same advantage can be seen” in zanubrutinib.

According to Dr. Ghia, bendamustine-rituximab has long been a standard treatment in blood cancers and is considered well tolerated and inexpensive. But BTKis such as first-in-line ibrutinib have shown better results, he said, “and progressively, we are going to abandon bendamustine-rituximab.”

However, ibrutinib causes significant adverse effects such as bleeding, worsening hypertension and arrhythmia, he noted. As a result, second-generation BTKi such as zanubrutinib have entered the picture. The Food and Drug Administration approved it in 2019 for mantle cell lymphoma, and it has since been approved for Waldenström’s macroglobulinemia and marginal zone lymphoma.

In 2021, an interim analysis in a trial of the drug in patients with previously treated CLL, compared with ibrutinib, found that “zanubrutinib was shown to have a superior response rate, an improved PFS, and a lower rate of atrial fibrillation/flutter.”

The drug’s manufacturer, BeiGene, launched the new open-label, multicenter study, in a bid for FDA approval of the drug as a frontline treatment for CLL and SLL. More than 150 hospitals in 14 countries participated in the trial from 2017 to 2019.

The subjects were all adults and at least 65 years old or with comorbidities; None had the genetic trait del(17)(p13.1); 241 were assigned to take zanubrutinib and 238 to bendamustine-rituximab. Another group consisted of 111 patients with CLL and del(17)(p13·1). According to the study authors, these patients are especially difficult to treat.

The vast majority of patients were White (92%-95% depending on group) and male (61%-71%); 90%-92% had CLL.

At follow-up, there was no difference in overall survival between the main zanubrutinib and bendamustine-rituximab groups; 29 (12%) of the 241 patients in the zanubrutinib group and 57 (24%) of 238 patients in the bendamustine-rituximab group had progressed or died (HR, 0.42; 95% CI, 0.27-0.66; P < .00011). Adverse events leading to discontinuation were more common in the bendamustine-rituximab group (14%) versus zanubrutinib (8%).

In the third group, which only received zanubrutinib, 14% of patients died at median follow-up of 30.5 months; 98% of patients had adverse effects, and 5% discontinued treatment.

The researchers wrote that “zanubrutinib showed superior progression­-free survival versus bendamustine-rituximab in older patients or those with comorbidities with untreated CLL, with a low incidence of cardiac arrhythmia. Similar efficacy was observed in patients with del(17p)­–positive disease.”

The study didn’t examine cost; zanubrutinib is quite expensive.

In an interview, hematologist-oncologist Anthony Mato, MD, of Memorial Sloan Kettering Cancer Center in New York said the new study is important although not surprising, since other medications in the same class have shown similar results. Zanubrutinib is an alternative to ibrutinib, although the latter remains “an excellent drug,” he said.

“The era of chemotherapy being a first choice is over,” he said. “We’ve had several randomized studies that show targeted therapies are better tolerated and have better outcomes. We now need to look through the choices to decide which one of these good options are the best for our patients.”

In an interview, hematologist-oncologist Joanna Rhodes, MD, of Northwell Health in Hempstead, N.Y., highlighted the side effect profile of zanubrutinib, noting that it is low and resembles that of other BTKis, making it “another excellent treatment option.”

“We are seeing that bruising, upper respiratory tract infections, diarrhea, and arthralgias are the most common side effects,” she said. “Bleeding also is a common side effect, which is consistent across the class of BTKis, with 5% of patients developing a major bleed. Also, 3% of patients treated with zanubrutinib developed atrial fibrillation, which is consistent with data from other trials. Treatment discontinuation rates were low (8%).”

The study was funded by BeiGene. The authors reported multiple disclosures. Dr. Mato reported research or consulting relationships with BeiGene, AstraZeneca, and AbbVie. Dr. Rhodes reported multiple research or consulting relationships with Abbvie, BeiGene, Genentech, and others.

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