Zanubrutinib outperforms ibrutinib in advanced CLL, small lymphocytic lymphoma
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Zanubrutinib induced a superior overall response rate compared with ibrutinib among patients with relapsed or refractory chronic lymphocytic leukemia or small lymphocytic lymphoma, according to study results.
Data from an interim analysis of the randomized, global, phase 3 ALPINE trial, presented during the European Hematology Association 2021 Virtual Congress, also showed higher 12-month PFS and OS rates with zanubrutinib (Brukinsa, BeiGene), as well as a lower rate of atrial fibrillation/flutter, compared with ibrutinib (Imbruvica; Pharmacyclics, Janssen).
“[Although] ibrutinib has transformed the outlook for patients with CLL, not all patients respond to treatment and toxicities associated with prolonged exposure remain an issue,” Peter Hillmen, MBChB, PhD, professor of experimental hematology at University of Leeds in the U.K., said in a BeiGene-issued press release. “The ALPINE trial is the only head-to-head study in CLL to demonstrate an efficacy advantage for a more selective Bruton tyrosine kinase [BTK] inhibitor over ibrutinib.”
Zanubrutinib, a small-molecule inhibitor of BTK, is in development for use as monotherapy or in combination with other agents for treatment of various B-cell malignancies. It is approved in the U.S. for treatment of adults with mantle cell lymphoma who received at least one previous therapy.
During EHA, Hillman and colleagues reported results of a planned interim analysis of the ALPINE trial that included 415 patients with previously treated relapsed or refractory CLL or small lymphocytic lymphoma. Patients received either zanubrutinib dosed at 160 mg twice daily (n = 207) or ibrutinib dosed at 420 mg once daily (n = 208).
Similar proportions of patients in the zanubrutinib and ibrutinib groups were aged older than 65 years (62.3% vs. 61.5%), male (68.6% vs. 75%), had more than three previous lines of therapy (7.2% vs. 10.1%), had tumors that exhibited 17p deletion (11.6% vs. 12.5%) and had TP53 mutations with 17p deletion (8.2% vs. 5.8%).
Investigator-assessed ORR, defined by prespecified noninferiority of zanubrutinib vs. ibrutinib, served as the primary endpoint. Secondary endpoints included PFS, OS, event rate of atrial fibrillation/flutter and incidence of adverse events.
Median follow-up was 15.3 months.
The study met its primary endpoint, with an investigator-assessed ORR of 78.3% (95% CI, 72-83.7) with zanubrutinib compared with 62.5% (95% CI, 55.5-69.1) with ibrutinib (P = .0006). Results of the ORR analysis by independent review committee also showed a higher rate with zanubrutinib vs. ibrutinib (76.3% vs. 64.4%), but the difference was not statistically significant.
Among patients with tumors that exhibited 17p deletion, researchers observed an investigator-assessed ORR of 83.3% with zanubrutinib vs. 53.8% with ibrutinib.
Zanubrutinib also demonstrated higher 12-month rates of investigator-assessed PFS (94.9% vs. 84%; descriptive HR = 0.4; 95% CI, 0.23-0.69) and OS (97% vs. 92.7%; descriptive HR = 0.54; 95% CI, 0.25-1.16) and a lower rate of atrial fibrillation/flutter (2.5% vs. 10.1%; P = .0014).
More patients assigned ibrutinib vs. zanubrutinib experienced at least one adverse event of any grade (99% vs. 95.6%), the most common of which included anemia (15% vs. 13.2%), arthralgia (14% vs. 9.3%), diarrhea (19.3% vs. 16.7%) and muscle spasm (11.1% vs. 2.9%). A higher percentage of patients in the zanubrutinib group experienced neutropenia (19.6% vs. 15.5%), upper respiratory tract infection (21.6% vs. 14%) and urinary tract infection (10.8% vs. 8.2%), according to data in the BeiGene press release.
Grade 3 or higher events appeared more common in the zanubrutinib group (55.9% vs. 51.2%), although serious adverse events were less common (27.5% vs. 32.4%) compared with ibrutinib.
Dose reductions associated with adverse events occurred among 11.3% of patients assigned zanubrutinib vs. 12.1% assigned ibrutinib, and dose interruptions occurred among 39.7% vs. 40.6%. Eight treatment-related deaths occurred in the zanubrutinib group vs. 12 in the ibrutinib group.
Results of the final ORR analysis and a formal PFS analysis are expected in 2022.
“The positive data from the interim analysis of the ALPINE trial, including a superior ORR by investigator assessment, supportive initial data in PFS and OS, and a significantly lower rate of atrial fibrillation of any grade, reinforce our belief that the differentiated profile of Brukinsa can provide clinical benefits for patients with CLL,” Jane Huang, MD, BeiGene’s chief medical officer for hematology, said in the company-issued press release. “As evidenced in ALPINE and ASPEN, our head-to-head trials of zanubrutinib against the first-generation BTK inhibitor ibrutinib, this potentially best-in class molecule can provide meaningful responses and consistent safety advantages for these patients. In addition to ALPINE, we are evaluating zanubrutinib in the phase 3 SEQUOIA trial in treatment-naive CLL and expect to share topline results as early as later this year.”
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Hillmen P, et al. Abstract LB1900. Presented at: European Hematology Association 2021 Virtual Congress; June 9-17, 2021.
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