In R/R CLL, Zanubrutinib Offers 35% Improved PFS Over Ibrutinib; Edge Greater for Higher-Risk Patients

Results from the ALPINE trial were presented Tuesday at a late-breaking session of the 64th American Society of Hematology Annual Meeting and Exposition, held in New Orleans, Louisiana.

Patients with 1 prior treatment for chronic lymphocytic leukemia (CLL) or small lymphocytic leukemia saw 35% improvement in progression-free survival (PFS) when taking zanubrutinib instead of ibrutinib, as final results of a head-to-head trial show the second-generation Bruton tyrosine kinase (BTK) inhibitor pulling away from its first-generation rival.

In April, the phase 3 ALPINE trial (NCT03734016) reported a primary end point showing zanubrutinib topping ibrutinib in overall response rate (ORR). Today’s results show zanubrutinib achieving superiority in PFS over ibrutinib, after a median follow-up of 29.6 months. Results were presented in a late-breaking session at the 64th American Society of Hematology (ASH) Annual Meeting and Exposition in New Orleans, Louisiana,1 and simultaneously reported in the New England Journal of Medicine (NEJM).2

Zanubrutinib is sold in other indications as Brukinsa by BeiGene, which supported the study.

As noted by the study’s lead author, Jennifer R. Brown, MD, PhD, director of the CLL Center of the Division of Hematologic Malignancies at Dana-Farber Cancer Institute, this is the first time one BTK inhibitor has shown superiority over another in both PFS and ORR. Brown called the results practice changing, as did ASH Secretary Cynthia Dunbar, MD, chief of the Translational Stem Cell Biology Branch within the Intramural Research Program of the National Heart, Lung, and Blood Institute at the National Institutes of Health (NIH) in Bethesda, MD.

“Progression-free survival is pretty much our gold standard for efficacy, so our data suggest that zanubrutinib should really become the standard of care in this setting," Brown said in a statement.

Besides the large overall PFS benefit seen at nearly 2.5 years, (HR 0.65; 95% CI, 0.49 to 0.86; P = .002), investigators reported a PFS benefit at 24 months for zanubrutinib of 48% improvement among patients with a 17p deletion, a TP53 mutation, or both (HR 0.53; 95% CI, 0.31 to 0.88). Investigators in NEJM wrote that PFS benefits across other major subgroups “consistently favored zanubrutinib.”

The large overall PFS benefit assessed by investigators at 29.6 months was similar to results assessed by an independent review committee; at 24 months, investigators found PFS rates were 78.4% and 65.9%, favoring zanubrutinib.

Already, the National Comprehensive Cancer Network (NCCN) listed zanubrutinib as a preferred agent over ibrutinib in CLL in its guidelines, based on zanubrutinib’s improved safety profile. Brown noted this when asked whether there is still a role for ibrutinib in CLL.

She responded, “I am not aware of a patient population in which I would select ibrutinib as compared to zanubrutinib.”

Improved mechanism. Ibrutinib (Imbruvica) revolutionized CLL care after FDA granted approval for relapsed or refractory patients in February 2014. It was more effective and had fewer side effects than chemotherapy, but off target effects, especially those involving the heart, were a concern.

Zanubrutinib’s edge over ibrutinib is 2-fold. As Brown explained, the second-generation therapy is designed to have “greater BTK specificity than ibrutinib,” and its higher concentration offers more “sustained and complete” BTK inhibition and better efficacy. This improved mechanism reduces the cardiac effects associated with ibrutinib.

When asked about a separate trial involving the BTK inhibitor acalabrutinib (Calquence) vs ibrutinib in CLL, Brown said that trial involved high-risk patients only and was designed to show non-inferiority, not superiority.

During the late-breaking session, Brown was asked how the results for the ibrutinib arm compared with historical expectations. She offered several examples from clinical trials as well as real-world evidence to show that the ALPINE results are consistent with prior findings. “I think what we see with ibrutinib is what’s actually achievable for patients in clinical practice," she said.

Results. ALPINE involved 652 patients from 15 countries who were randomized to receive zanubrutinib (327 patients) or ibrutinib (325 patients). The 2 arms were balanced for demographic and disease characteristics; the median age was 67 for the zanubrutinib group vs 68 for the ibrutinib group; and the median prior lines of therapy was 1 for both groups. Notably, patients previously treated with a BTK inhibitor were excluded.

BeiGene reported the primary ORR end point at 24 months; final data reported at median follow-up of 29.6 months show ORR for zanubrutinib at 86.2% vs ibrutinib at 75.7%. The key secondary endpoint of PFS for zanubrutinib was assessed first for noninferiority and then for superiority; PFS was 35.0 months for the ibrutinib group and not reached for the zanubrutinib group.

Treatment discontinuation was lower for the zanubrutinib group (26.3%) compared with ibrutinib (41.2%), with most discontinuations due to adverse events (AEs), 16.2% vs 22.8%, respectively, or progressive disease, 7.3% vs 12.9%. Rates of AEs grade 3 or higher were 67.3% vs 70.4%, and serious AEs were 42.0% vs 50.0%. Dose interruption was 50.0% vs 56.8%, with dose reduction at 12.3% vs 17.0%, all favoring zanubrutinib. In sum, 48 patients (14.7%) treated with zanubrutinib died, compared with 60 (18.5%) treated with ibrutinib for overall survival favoring zanubrutinib (HR 0.76; 95 CI, 0.51 to 1.11).

Cardiac effects. In the other key secondary end point, rates of atrial fibrillation/flutter were 5.2% (17 patients) vs 13.3% (43 patients), favoring zanubrutinib. Discontinuation rates due to cardiac effects were 0.3% for zanubrutinib vs 4.3% for ibrutinib. There were no deaths due to cardiac disorders with zanubrutinib vs 6 (1.9%) with ibrutinib.

FDA approval pending. Today’s findings are expected to be the last piece that FDA will need before acting on BeiGene’s supplemental new drug application (sNDA) for zanubrutinib’s use in CLL, which was filed in February 2022. CLL, which is diagnosed in about 21,000 new patients a year and affects mostly older patients, accounts for about a quarter of all new leukemia cases.

Zanubrutinib is currently approved in the United States to treat 3 smaller populations: certain patients with mantle cell lymphoma and marginal zone lymphoma, and those with Waldenström’s macroglobulinemia. Figures from the American Cancer Society show that the combined number of new cases in these 3 cancers in the United States each year are about half the number of new US cases of CLL.

Because ALPINE excluded patients previously treated with a BTK inhibitor, The American Journal of Managed Care® asked during the press briefing if a future FDA label might include patients treated with a BTK inhibitor, including ibrutinib. Brown explained that the 2 drugs compared in the trial are both covalent inhibitors; in general, she said, if a patient developed disease progression on a covalent inhibitor, a second one would not be prescribed.

“However, if a person was on ibrutinib for a while and stopped for an adverse event, or is having an adverse event on ibrutinib, then that person could be switched to zanubrutinib, with potentially significant benefit,” she said

As for a label, Brown noted that the sNDA is based on results from both ALPINE and SEQUOIA, which examined zanubrutinib’s use in frontline treatment. “It’s likely to be a pretty broad label,” she said.


  1. Brown JR, Eichhorst B, Hillmen P, et al. Zanubrutinib demonstrates superior progression-free survival (PFS) compared with ibrutinib 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. Presented at: 64th American Society of Hematology Annual Meeting and Exposition; New Orleans, LA; December 10-13, 2022; Abstract LBA-6.
  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
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