Study details
The phase 3 ALPINE study involved 415 adults with CLL/SLL refractory to one or more prior systemic therapies and measurable lymphadenopathy on imaging.
They were randomized 1:1 to zanubrutinib or ibrutinib until disease progression or withdrawal from the study.
Most patients had Binet stage A/B or Ann Arbor stage I/II disease, and 7.3% of patients treated with zanubrutinib and 10.1% of those assigned to ibrutinib had received more than three prior lines of therapy.
Over 60% of patients were aged 65 years or older and around 70% were men, with no significant differences between treatment groups.
Patients were randomized 1:1 to zanubrutinib or ibrutinib until disease progression or study withdrawal.
After a median follow-up of 15 months, the overall response rate was significantly higher with zanubrutinib than ibrutinib, at 78.3% versus 62.5% (P = .0006).
Subgroup analysis confirmed that the effect was seen regardless of age, sex, disease stage, number of prior lines of therapy, mutation status, or bulky disease.
Over a median follow-up of 14 months, the investigator-assessed 12-month PFS was 94.9% for zanubrutinib and 84.0% for ibrutinib (P = .0007). Overall survival at 12 months was 97% versus 92.7%, but the difference was not significant (P = .1081).
Patients treated with zanubrutinib experienced more grade 3 or higher adverse events than those given ibrutinib, at 55.9% versus 51.2%, although they had fewer adverse events leading to treatment discontinuation, at 7.8% versus 13.0%.
More importantly, there were fewer cardiac disorders of any grade with zanubrutinib versus ibrutinib, and any-grade atrial fibrillation was significantly less common, at 2.5% versus 10.1% (P = .0014).
Rates of hypertension and hemorrhage were similar between the two treatments, while rates of neutropenia were higher with zanubrutinib versus ibrutinib, at 28.4% versus 21.7%.
The phase 3 SEQUOIA study looked at an earlier stage of disease and included patients with previously untreated CLL/SLL (without 17p depletion) who were unsuitable for treatment with fludarabine, cyclophosphamide, and rituximab.
This trial involved 479 patients randomized to zanubrutinib or bendamustine (days 1 and 2) plus rituximab for six cycles of 28 days each (B+R).
The median age of patients was 70 years, and approximately 80% were at least 65 years old. Just over 60% were men and most (over 70%) were from Europe.
After a median of 26.2 months, independent review committee–assessed PFS was significantly longer with zanubrutinib versus B+R (hazard ratio, 0.42; P < .0001), with an estimated 24-month PFS of 85.5% versus 69.5%.
These results held whether patients were stratified by age, Binet stage, bulky disease, or 11q deletion status, and for patients with an unmutated, but not mutated, immunoglobulin heavy chain gene.
The overall response rate with zanubrutinib was 94.6% versus 85.3% with B+R, and estimated 24-month overall survival was 94.3% versus 94.6%.
Rates of adverse events of any grade were similar between the two treatment groups, although B+R was associated with a higher (grade ≥ 3) adverse event rate, at 79.7%, versus 52.5% for zanubrutinib, and a higher rate of treatment discontinuation because of adverse events, at 13.7% versus 8.3%.
Interestingly, any-grade hypertension was more common with zanubrutinib versus B+R, at 14.2% versus 10.6%, but much lower rates of neutropenia were more common with zanubrutinib, at 15.8% versus 56.8%.
The studies were sponsored by BeiGene. Dr. Hillmen has reported relationships with Janssen, AbbVie, Pharmacyclics, Roche, Gilead, AstraZeneca, SOBI, and BeiGene. Dr. Munir has reported relationships with AbbVie, AstraZeneca, Roche, Alexion, Janssen, MorphoSys, and SOBI. Other authors have also declared numerous relationships.
A version of this article first appeared on Medscape.com.