Superior objective response rate with zanubrutinib compared to ibrutinib in patients with relapsed/refractory chronic lymphocytic leukaemia

While ibrutinib has led the way, next-generation Bruton’s tyrosine kinase inhibitor zanubrutinib has the potential to further improve outcomes in patients with relapsed/refractory chronic lymphocytic leukaemia. In this respect, an interim analysis of the phase III ALPINE study demonstrated that zanubrutinib is associated with a superior objective response rates and longer progression-free survival than ibrutinib.

Treatment of chronic lymphocytic leukaemia (CLL)/small lymphocytic lymphoma (SLL) has been transformed with the advent of effective inhibitors of B cell signalling, such as the Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib. Zanubrutinib is an irreversible, potent, next-generation BTK inhibitor designed to maximise BTK occupancy and minimise off-target inhibition of TEC- and EGFR-family kinases. The increased specificity of zanubrutinib may minimise toxicities related to ibrutinib off-target inhibition and may further improve efficacy outcomes. ALPINE is a global, randomised, phase III study comparing zanubrutinib vs. ibrutinib in patients with relapsed/refractory (R/R) CLL/SLL. At EHA 2021, the results of a pre-planned interim analysis, scheduled approximately 12 months after the first 415 out of 652 patients were enrolled, were presented.

ALPINE study design

In ALPINE, 652 patients with R/R CLL/SLL who had received at least one prior systemic treatment were randomised (1:1) to zanubrutinib (160 mg, twice a day) or ibrutinib (420 mg, once daily). All patients must have measurable lymphadenopathy by CT or MRI and could not have received prior BTK inhibitor therapy or treatment with warfarin or other vitamin K antagonists. Primary endpoint of the study was objective response rate (ORR) non-inferiority and superiority as assessed by the investigator. Baseline patient and disease characteristics were well balanced between both arms in terms of age, gender, disease stage, ECOG performance status, prior lines of therapy, prior chemo-immunotherapy, and del(17p) and/or mutant TP53. Almost 20% of patients had del(17p) and/or mutant TP53.

Objective response rates by investigator assessment

After a median follow-up of more than 15 months, the ORR was significantly higher with zanubrutinib than with ibrutinib (78.3% vs. 62.5%, 2-sided p= 0.0006). Complete responses (CR) were observed in 1.9% of patients in the zanubrutinib arm as compared to 1.4% with ibrutinib. When studying the subgroup of patients with del(17p) (N=50), the ORR was 83.3% for patients receiving zanubrutinib and 53.8% for patients receiving ibrutinib. The ORR favoured zanubrutinib across all key patient subgroups. Furthermore, the progression-free survival (PFS) analysis demonstrated that zanubrutinib was superior to ibrutinib. The 12-months landmark event free rate was 94.9% with zanubrutinib vs. 84.0% with ibrutinib (HR [95%CI]: 0.40 [0.23-0.69], p= 0.0007). Overall survival (OS) results were comparable, with a 97.0% 12-month OS rate with zanubrutinib and 92.7% for patients treated with ibrutinib (HR [95%CI]: 0.54 [0.25-1.16], p= 0.1081).

Key safety analysis demonstrated that the majority of patients in the trial experienced an adverse event (AE) with just over 50% of patients having a grade ≥3 adverse event. Fatal AEs were reported for 3.9% of patients receiving zanubrutinib and in 5.8% of patients treated with ibrutinib. AEs leading to dose reductions and dose interruptions were comparable between both arms, whereas treatment discontinuation was more frequent with ibrutinib (13.0% vs. 7.8%). Rates of arthralgia (14.0% vs. 9.3%) and muscle spasms (11.1% vs. 2.9%) were higher with ibrutinib as compared to zanubrutinib. With respect to AEs of special interest, rates of neutropenia (28.4% vs. 21.7%) were higher with zanubrutinib while grade ≥3 infections were lower with zanubrutinib (12.7% vs. 17.9%). The rate of atrial fibrillation and flutter, a pre-specified safety endpoint, was significantly lower with zanubrutinib vs. ibrutinib (2.5% vs. 10.1%, 2-sided p= 0.0014).

Conclusion

In the phase III ALPINE study, zanubrutinib demonstrated a superior response rate, an improved PFS and a lower rate of atrial fibrillation and flutter compared to ibrutinib. As such, these data suggest that selective BTK inhibition, facilitating a more complete and sustained BTK occupancy, results in improved efficacy and safety outcomes in patients with R/R CLL.

Reference

Hillmen P, 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 leukaemia/small lymphocytic lymphoma. Presented at EHA 2021; abstract LB1900.