Zanubrutinib Improves Outcomes Compared With Ibrutinib in R/R CLL/SLL, ALPINE Study Shows

Inhibition of Bruton tyrosine kinase (BTK) has transformed the treatment of chronic lymphocytic leukemia (CLL). While ibrutinib has led the way, zanubrutinib, a next-generation BTK inhibitor has the potential to change treatment again.

Zanubrutinib improves outcomes and reduces toxicity because it minimizes off-target inhibition of TEC- and EGFR-family kinases, which is seen with ibrutinib, explained Peter Hillmen, PhD, MB ChB, professor at the University of Leeds and honorary consultant hematologist at Leeds Teaching Hospitals NHS Trust.

Hillmen presented the interim results of the phase 3 ALPINE study during the Presidential Symposium at the European Hematology Association 2021 Virtual Congress.

ALPINE is a global, randomized, phase 3 study comparing zanubrutinib with ibrutinib in patients with relapsed/refractory CLL/small lymphocytic leukemia (SLL). In the preplanned interim analysis, the data cut off occurred at 12 months after randomization of the first 415 patients.

The patients were randomized 1:1 to receive either zanubrutinib 160 mg twice a day (n = 207) or ibrutinib 420 mg once a day (n = 208). The baseline patient and disease characteristics were well balanced between the 2 arms, according to Hillmen.

The primary end point was overall response rate (ORR) defined as partial response (PR) plus complete response. Secondary end points were atrial fibrillation, duration of response, progression-free survival (PFS), overall survival (OS), time to treatment failure, PR with lymphocytosis or higher, patient-reported outcomes, and safety.

ORR was “definitely superior” for zanubrutinib, Hillmen said. The ORR for zanubrutinib was 78.3% (95% CI, 72.0%-83.7%) vs 62.5% (95% CI, 55.5%-69.1%) for ibrutinib. The 12-month PFS was 94.9% for zanubrutinib vs 84.0% for ibrutinib. At 18 months, 20 patients on zanubrutinib had progressive disease compared with 42 patients on ibrutinib. OS wasn’t significantly different: 97.0% for zanubrutinib vs 92.07% for ibrutinib.

The majority of patients had an adverse event (AE), but zanubrutinib had less AEs leading to discontinuation (7.8% vs 13.0%) and less death due to AEs (3.9% vs 5.8%). Zanubrutinib had a slightly higher rate of neutropenia (28.4% vs 21.7%), but grade ≥3 infections were lower (12.7% vs 17.9%).

The interim analysis also evaluated atrial fibrillation/flutter, which was a prespecific safety end point. The rate was significantly lower with zanubrutinib (2.5%) compared with ibrutinib (10.1%).

“These data support that more selective BTK inhibition, with more complete and sustained BTK occupancy, results in improved efficacy and safety outcomes than a less specific BTK inhibitor,” Hillmen concluded.

In the Q&A, one attendee asked about comparing the results of ALPINE with ELEVATE-RR, which was presented a week earlier at the annual meeting of the American Society of Clinical Oncology. In that phase 3 trial comparing acalabrutinib with ibrutinib in patients with relapsed/refractory CLL, acalabrutinib had a noninferior PFS and significantly fewer events of atrial fibrillation.

Comparing the 2 is challenging for a number of reasons, though. Hillmen noted that the second-generation BTK inhibitors are not exactly the same as each other, so it wouldn’t be surprising to see a difference in terms of toxicity or efficacy. In addition, ALPINE only has interim data with a median duration of 15 months compared with ELEVATE-RR’s 3 years.

“We need to see more maturity in this trial to really compare,” Hillmen said. The ALPINE abstract was submitted to the meeting as a late-breaking abstract, so the data are still being analyzed.

However, there was one thing he noted that was apparent from both trials.

“I think both trials indicate that the tolerability of the second-generation BTK inhibitors…is improved,” Hillmen said.