Zanubrutinib Produces Superior Efficacy Over Ibrutinib in Relapsed/Refractory CLL/SLL

The risk of progression or death was reduced by 35% when patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) were treated with zanubrutinib (Brukinsa) vs ibrutinib (Imbruvica), according to results from the phase 3 ALPINE study (NCT03734016) presented at the 2022 American Society of Hematology (ASH) Annual Meeting, and simultaneously published in the New England Journal of Medicine.^1,2

Findings from the open-label study met the criteria for noninferiority and superiority for zanubrutinib vs ibrutinib for objective response rate (ORR) and progression-free survival (PFS) by independent review committee (HR, 0.65; 95% CI, 0.49-0.86; P = .0024). The 24-month investigator assessed PFS rate was 79.5% with zanubrutinib compared with 67.3% with ibrutinib. The objective response rate (ORR), which was the primary end point of the study, was 86.2% with zanubrutinib compared with 75.7% for ibrutinib (P = .0007).

There were fewer adverse events (AEs) that led to treatment discontinuation observed with zanubrutinib (15.4%) vs ibrutinib (22.2%). Atrial fibrillation/flutter, which was assessed as a secondary end point in the ALPINE study, was significantly (P = .0004) less common with zanubrutinib (5.2%) vs ibrutinib (13.3%). There were no fatal cardiac events reported with zanubrutinib compared with 6 events in the ibrutinib arm.

“ALPINE is the first study to demonstrated PFS superiority in a head-to-head comparison of BTK inhibitors in patients with relapsed or refractory CLL or SLL. Zanubrutinib has now proven superiority to ibrutinib in both PFS and ORR,” lead study author Jennifer R. Brown, MD, PhD, from the Dana-Farber Cancer Institute, said during a presentation of the results. “Zanubrutinib has a better cardiac profile than ibrutinib, with lower rates of atrial fibrillation, serious cardiac events, cardiac events leading to treatment discontinuation, and fatal cardiac events.”

In the ALPINE study, 652 patients with relapsed or refractory CLL/SLL were randomized to receive zanubrutinib twice daily at 160 mg (n = 327) or ibrutinib once daily at 420 mg (n = 325). Of these patients, 3 in the zanubrutinib arm did not receive treatment. Fifty-three patients in this group discontinued due to AEs and 24 discontinued due to progressive disease. In the ibrutinib arm, 1 patient did not receive treatment, 74 discontinued due to AEs, and 42 discontinued due to progressive disease.

The investigators noted that patient characteristics were balanced between the arms, with 61.5% of patients in each group being age 65 years or older. The median age in the zanubrutinib group was 67 years vs 68 years in the ibrutinib group. Most patients in the study were male (65.1% with zanubrutinib and 71.4% for ibrutinib) and the median number of prior therapies received was 1 in both groups. Nearly three-fourths of patients in the zanubrutinib and ibrutinib arms, respectively, had IGHV-unmutated status (73.1% vs 73.5%) and 13.8% and 15.4% had del(17p) disease. Additionally, 9.2% of those in the zanubrutinib arm and 7.7% in the ibrutinib arm had TP53 mutations without del(17p).

After 29.6 months of follow-up, the median PFS was not yet reached in the zanubrutinib arm compared with 35.0 months with ibrutinib (95% CI, 33.2-44.3). In patients with del(17p) or TP53 mutations (n = 75 in each arm), by independent assessment the 24-month PFS rates were 77.6% vs 55.7% for zanubrutinib and ibrutinib, respectively (HR, 0.52; 95% CI, 0.30-0.88; P = .0134). PFS favored zanubrutinib across other major subgroups analyzed.

The investigator assessed PFS rates were similar to the independent review committee. The investigator-assessed 24-month PFS rates were 78.4% with zanubrutinib and 65.9% for ibrutinib-treated patients. The PFS also favored zanubrutinib over ibrutinib by investigator review for the del(17p)/TP53-mutant subgroup (HR, 0.53; 95% CI, 0.31-0.88).

An AE of any grade or cause was experienced by 98.1% of patients in the zanubrutinib arm and by 99.1% of those in the ibrutinib group. Grade 3 to 5 AEs were seen in 67.3% of those treated with zanubrutinib, with 10.2% of patients having a grade 5 AE. In the ibrutinib arm, 70.4% of patients experienced a grade 3 to 5 AE, with grade 5 events seen in 11.1% of patients. Serious AEs were experienced by 42.0% and 50.0% of patients in the zanubrutinib and ibrutinib arms, respectively.

The median treatment duration was 28.4 months with zanubrutinib vs 24.3 months for ibrutinib. AEs led to a dose reduction for 12.3% of those in the zanubrutinib arm and for 17.0% of those in the ibrutinib group. Dose interruptions were required due to AEs in 50.0% and for 56.8% of patients in the zanubrutinib and ibrutinib arms, respectively. Treatment discontinuations occurred in 15.4% and 22.2% of patients, respectively.

Cardiac AEs were experienced by 21.3% and 29.6% of those in the zanubrutinib and ibrutinib arms, respectively. Serious cardiovascular AEs were experienced by 6 patients in the zanubrutinib group (1.9%) compared with 25 in the ibrutinib arm (7.7%). Of these patients, 2 in the zanubrutinib group and 16 in the ibrutinib group had no previous cardiac-related medical history.

“Overall, safety was improved with zanubrutinib, with serious adverse events reduced with zanubrutinib, and adverse events leading to dose reduction, dose interruption, and discontinuation lower with zanubrutinib vs ibrutinib,” Brown said.

A new drug application is currently pending with the FDA for zanubrutinib as a treatment for patients with relapsed/refractory CLL/SLL. This application was based on earlier findings from an interim analysis of the ALPINE study along with phase 3 findings from the SEQUOIA study (NCT03336333), which showed improvements in PFS compared with bendamustine plus rituximab (Rituxan). The agency was originally scheduled to decide on the application in October but delayed their review, with a deadline under the Prescription Drug User Fee Act of January 20, 2023.

References

1. Brown JR, Eichhorst B, Hillmen P, et al. Zanubrutinib demonstrates superior progression-free survival (PFS) compared with ibrutinib for treatment of relapsed/refractory chronic lymphocytic leukemia and small lymphocytic lymphoma (R/R CLL/SLL): results from final analysis of ALPINE randomized phase 3 study. Blood. 2022;140(suppl 2):LBA-6. doi:10.1182/blood-2022-171538
2. Brown JR, Eichhorst B, Hillmen P, et al. Zanubrutinib or ibrutinib in relapsed or refractory chronic lymphocytic leukemia. N Engl J Med. Published online December 13, 2022. doi:10.1056/NEJMoa2211582