Zanubrutinib Tops Ibrutinib in Relapsed or Refractory CLL

Treatment with the second-generation Bruton tyrosine kinase (BTK) inhibitor led to better oncologic outcomes compared with ibrutinib (Imbruvica) for patients with relapsed/refractory chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL), according to an interim analysis of the phase III ALPINE study.

Over a median follow-up of 15 months, the overall response rate — the primary endpoint of the study — was 78.3% with zanubrutinib (Brukinsa) versus 62.5% with ibrutinib, reported Peter Hillmen, MBChB, PhD, of the University of Leeds in England.

In addition, the 12-month progression-free survival (PFS) rate was 94.9% with zanubrutinib compared with 84.0% with ibrutinib. Thus, “there was a significant advantage in favor of zanubrutinib in terms of progression-free survival, with a hazard ratio of 0.40,” Hillmen noted during a presentation at the European Hematology Association virtual congress. “And if we look at patients with aggressive disease, at the 18-month time point, 20 patients had progressed on zanubrutinib compared to 42 patients with ibrutinib.”

Patients on zanubrutinib also had a significantly lower incidence of atrial fibrillation/flutter, a prespecified safety endpoint, compared with patients on ibrutinib (2.5% vs 10.1%, 2-sided P=0.0014).

“These data support that more selective BTK inhibition, with more complete and sustained occupancy, results in improved efficacy and safety outcomes,” said Hillmen.

These results come on the heels of those from the ELEVATE-R/R trial, comparing ibrutinib with acalabrutinib (Calquence), another second-generation BTK inhibitor, which were recently presented at the American Society of Clinical Oncology annual meeting. There, John Byrd, MD, of the Ohio State University Comprehensive Cancer Center in Columbus, reported that acalabrutinib demonstrated similar efficacy to ibrutinib, but with less cardiotoxicity, in patients with previously treated CLL.

The ALPINE trial enrolled 652 patients with relapsed/refractory CLL/SLL who had received at least one prior therapy. The interim analysis included data from the first 12 months after the randomization of the first 415 patients, who received either zanubrutinib 160 mg twice daily or ibrutinib 420 mg once daily.

Overall survival was not significantly different between the two arms, with 97% of patients alive in the zanubrutinib arm at 12 months compared with 92.7% of patients in the ibrutinib arm.

About half of patients in each arm experienced grade 3 or higher adverse events (55.9% with zanubrutinib and 51.2% with ibrutinib). Patients in the zanubrutinib arm versus the ibrutinib arm had lower rates of major bleeding (2.9% vs 3.9%), as well as lower rates of adverse events leading to discontinuation (7.8% vs 13.0%) or death (3.9% vs 5.8%).

There were no significant differences in incidence of hemorrhage or hypertension between the two arms, while a slightly higher percentage of patients in the zanubrutinib arm developed neutropenia (28.4% vs 21.7%).

When asked about a comparison between the three BTK inhibitors, Hillmen, who was also an investigator in the ELEVATE-R/R trial, pointed out that the two second-generation drugs, acalabrutinib and zanubrutinib “are not exactly the same as each other.”

“They have different specificities and different off-target inhibitions,” he said. “So, I wouldn’t be surprised to see a difference in toxicity, or even efficacy, between the two — or more — second-generation inhibitors.”

He also noted that there was a difference in the duration of the two studies. ALPINE had a median duration of just over 15 months, while ELEVATE-R/R had a median duration of at least 3 years. “The other difference is that ELEVATE-R/R was selective for del(17p) or del(11q) patients, whereas this trial took all-comers with relapsed CLL,” he added.

“I think we need to see more maturity in this [ALPINE] trial,” he concluded. Both ALPINE and ELEVATE-RR indicated that the tolerability of second-generation BTK inhibitors is improved, “certainly in terms of cardiac toxicity.”

“The authors from the ALPINE trial are to be congratulated for their study results that support [that] zanubrutinib is safer than ibrutinib and offers at least similar efficacy for this disease,” Byrd told MedPage Today. “The collective data support the use of second-generation BTK inhibitors in CLL based upon improved safety and similar efficacy.”

“The choice of which second-generation BTK inhibitor should be used probably is best determined by phase III data,” he noted. “At this time point, use of acalabrutinib is probably more supported by phase III data.”