New efficacy analysis comparing Brukinsa vs acalabrutinib in relapsed or refractory chronic lymphocytic leukemia

The analysis suggests a progression-free survival and complete response advantage for Brukinsa versus acalabrutinib, as well as potentially improved overall survival. These data will be presented during the 28th Annual International Congress on Hematologic Malignancies in Miami from February 29 - March 3.

“The CLL landscape is evolving rapidly, and this MAIC provides timely comparative effectiveness data for physicians, and reinforces zanubrutinib role as a foundational CLL treatment via a robust evaluation of the efficacy in the ASCEND and ALPINE studies; the presented analysis not only accounts for differences in key patient characteristics, but also clarifies the impact COVID-19 may have had on study outcomes,” said Mazyar Shadman, M.D. M.P.H, Study Author and Innovators Network Endowed Chair, Associate Professor of Hematology and Oncology, Lymphoid Malignancies and Immunotherapy, Fred Hutch Cancer Center and University of Washington. “Head-to-head randomized clinical trials are the gold standard when it comes to evaluating the potential impact of individual treatments for patients. MAICs are intended to be hypothesis-generating, provided they are conducted with appropriate rigor to minimize potential biases.”

In this MAIC, individual patient-level data from ALPINE was matched against the aggregate data from ASCEND. An unanchored MAIC was used due to the lack of a common comparator arm between the ALPINE and ASCEND trials. Given the differences in the timing of the studies, with respect to the onset of the COVID-19 pandemic, the analysis adjusted for the impact of COVID-19 in the ALPINE study.

In a previously published MAIC of Brukinsa versus acalabrutinib, there were significant limitations that precluded a robust efficacy comparison, including the exclusion of data from the final analysis of ALPINE, lack of adjustment for the impact of COVID-19 on the outcomes, lack of adjustment for key differences in patient characteristics, the effective sample size, and the exclusion of complete response rate and overall survival from the analysis.

“BeiGene is committed to continuing to further our understanding of the efficacy and safety of our therapies and their potential to help patients among other options,” said Mehrdad Mobasher, M.D., M.P.H., Chief Medical Officer, Hematology at BeiGene. “This MAIC addresses key questions raised in a previously published analysis, presenting a more holistic representation of the efficacy associated with Brukinsa versus acalabrutinib in relapsed or refractory chronic lymphocytic leukemia setting.”. Brukinsa is the only Bruton’s tyrosine kinase (BTK) inhibitor to demonstrate progression-free survival superiority vs ibrutinib in R/R CLL, as observed in the ALPINE trial. Acalabrutinib has demonstrated improvement in progression-free survival vs rituximab plus idelalisib/bendamustine in R/R CLL in the ASCEND trial and has also demonstrated progression-free survival noninferiority vs ibrutinib R/R CLL patients with chromosome 17p or 11q deletions in the ELEVATE-RR trial.

The MAIC suggests that investigator-assessed progression-free survival was improved for Brukinsa versus acalabrutinib in both the unadjusted population (HR=0.77 [95%CI: 0.55-1.07]), as well as the base case adjusted population (HR=0.68 [95%CI: 0.46-0.99]). Additionally, the odds ratio (OR) for complete response favored Brukinsa over acalabrutinib in the unadjusted (OR=2.88 [95%CI: 1.18-7.02]) and base case adjusted populations (OR=2.90; [95%CI: 1.13-7.43]). Results for the sensitivity analysis were consistent with the base case. The overall survival trend remained consistently in favor of Brukinsa.

While MAIC analyses can be hypotheses-generating, in the absence of head-to-head data, the safety of a drug may be best evaluated using all available evidence across indications. A recent independent Mayo Clinic meta-analysis of 61 trials involving 6,959 patients who received ibrutinib plus an anti-CD20 antibody, acalabrutinib, and Brukinsa extensively analyzed the adverse event profiles of the two therapies across several indications and reported key differences in the safety profiles of the two treatments.

Brukinsa is approved in 70 markets, including the U.S., China, EU, Great Britain, Canada, Australia, South Korea and Switzerland in selected indications, and it is under development for additional indications globally. The global Brukinsa development program includes more than 5,000 subjects enrolled to date in 29 countries and regions.

About MAICs : Match adjusted indirect comparisons are intended to be hypothesis generating, and do not establish superior efficacy or safety of one drug over another. Results should be viewed in the context of study limitations and available clinical data.

About ALPINE : ALPINE is a randomized, global, Phase III trial (NCT03734016) comparing Brukinsa with ibrutinib in previously treated patients with R/R CLL or small lymphocytic lymphoma (SLL). In the trial, a total of 652 patients across Europe (60%), the United States (17%), China (14%), and New Zealand and Australia (9%) were randomized to receive BRUKINSA (160 mg orally twice daily) or ibrutinib (420 mg orally once daily) until disease progression, death, or unacceptable toxicity.

The primary endpoint of overall response rate (ORR) was assessed by both investigator and independent review committee (IRC) using the modified 2008 iwCLL guidelines, with modification for treatment-related lymphocytosis for patients with CLL, and as per Lugano Classification for non-Hodgkin’s lymphoma for patients with SLL. Key secondary endpoints included PFS and the rate of atrial fibrillation or flutter; other secondary endpoints included duration of response, overall survival, and incidence of adverse events. There was a pre-specified hierarchical testing of non-inferiority followed by superiority for ORR as assessed by investigator and IRC. As ORR superiority was demonstrated, progression-free survival was tested for noninferiority and superiority under hierarchical testing.

In an extended follow-up of the ALPINE study at a median follow-up of 39 months, Brukinsa showed sustained PFS improvement versus ibrutinib (HR: 0.68 [95% CI, 0.53-0.86] P=0.0011) among R/R CLL/SLL patients, with durable PFS benefit observed across key subgroups, including patients with 17p deletion or TP53 mutation (HR: 0.52 [95% CI, 0.33-0.83] P=0.0047). PFS benefit was consistent across multiple sensitivity analyses, demonstrating that PFS advantage with Brukinsa was primarily driven by efficacy, and not better tolerability. The overall safety and tolerability profile was consistent with previous ALPINE analyses, including persistently lower rates of cardiovascular events reported with Brukinsa. The most commonly reported treatment emergent adverse events (20%) with Brukinsa were COVID-19-related infection, neutropenia, hypertension, and upper respiratory tract infection.