ALPINE Trial Points to Favorability of Zanubrutinib in Relapsed/Refractory CLL/SLL Versus Ibrutinib


Data from EHA 2021 showed that zanubrutinib was associated with better outcomes over ibrutinib for patients with relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma

Superior responses and progression-free survival (PFS) rates coupled with lower rates of atrial fibrillation/flutter were reported with the use of zanubrutinib (Brukinsa) compared with ibrutinib (Imbruvica) in patients with relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), according to data presented at the 2021 European Hematology Association (EHA) Congress from the phase 3 ALPINE trial (NCT03734016).

“The treatment of CLL has been transformed by the advent of effective inhibitors of the B-cell receptor pathway such as the BTK inhibitor ibrutinib,” lead study author Peter Hillmen, MB ChB, PhD, a consultant in clinical hematology at Leeds Teaching Hospitals NHS Trust and honorary professor of hematology at University of Leeds, said during a presentation of the findings. “We hypothesized that zanubrutinib may minimize toxicities related to ibrutinib off-target inhibition, and zanubrutinib may improve efficacy outcomes.”

Hillmen and colleagues set out to conduct the phase 3 ALPINE study to assess the efficacy and safety profile of zanubrutinib compared to ibrutinib in patients with relapsed/refractory CLL/SLL who received at least 1 prior systemic therapy. The authors recruited 652 patients, of which 415 were randomized to receive either zanubrutinib at 160 mg BID (n = 207) or ibrutinib at 420 mg once daily (n = 208).

Overall response rate (ORR), comprising a partial or complete response, as assessed by investigator served as the study’s primary endpoint. Additional endpoints included duration of response (DOR), progression-free survival (PFS) and overall (OS), as well as atrial fibrillation of any grade, patient outcomes and safety.

Baseline characteristics were well balanced between the two arms. The median age for the zanubrutinib and ibrutinib arms was 67 years, and patients in both arms (68.6% vs 75.0%, respectively) were mostly male.

At a data cutoff of approximately 12 months, the ORR among patients in the zanubrutinib arm (78.3%; 95% CI, 72-83.7) was far superior than in the ibrutinib arm (62.5%; 95% CI, 55.5-69.1). When taking partial and complete responses, as well as partial response-lymphocytosis into account, Hillmen noted, ORR was 88.4% for the zanubrutinib arm and 81.3% for the ibrutinib arm.

The findings also demonstrated that patients who received zanubrutinib achieved a superior 12-month PFS rate (94.9%) than those who received ibrutinib (84%; HR = 0.4; 95% CI, 0.23-0.69; P = .0007). The 12-month OS rate, however, was relatively similar between the two arms (97% vs 92.7%, respectively; HR = 0.54; 95% CI, 0.25-1.16; P = .1081).

Regarding safety, almost all patients in both the zanubrutinib (95.6%) and ibrutinib (99%) experienced any grade adverse event (AE). Moreover, more than half of each arm (55.9% vs 51.2%, respectively) reported any grade ≥ 3 AE. Sixteen patients in the zanubrutinib arm, along with 27 patients in the ibrutinib arm had to discontinue treatment because of AEs. There were deaths associated with AEs — 8 in the zanubrutinib arm and 12 in the ibrutinib arm. Diarrhea (16.7 % vs 19.3%, respectively), neutropenia (19.6% vs (15.5%), anemia (13.2% vs 15%), upper respiratory tract infection (21.6% vs 14%) and arthralgia (9.3% vs 14%) were among some of the most frequently experienced AEs.

AEs of special interest included, but were not limited to, cardiac disorders, atrial fibrillation and flutter, hemorrhage and hypertension. Of note, atrial fibrillation and flutter of any grade was drastically reduced in the zanubrutinib (2.5%) arm compared to the ibrutinib (10.1%) arm.

Currently, 87.4% of patients in the zanubrutinib arm remain on treatment compared to 75.5% of the ibrutinib arm.

“In this interim analysis of the randomized phase 3 ALPINE study in patients with relapsed refractory CLL, zanubrutinib was shown to have a superior response rate, improved progression-free survival rates and a lower rate of atrial fibrillation (and) flutter than ibrutinib,” Hillmen concluded. “These data support that more selective BTK inhibition, with more complete and sustained BTK occupancy, results in improved efficacy and safety outcomes.”


Hillmen P, Eichhorst B, Brown JR, et al. First interim analysis of ALPINE study: Results of a phase 3 randomized study of zanubrutinib vs ibrutinib in patients with relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma. Presented at: 2021 European Hematology Association Congress; June 9-17, 2021; Virtual. Abstract LB1900.

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