BeiGene Announces New Efficacy Analysis Comparing BRUKINSA® vs Acalabrutinib in Relapsed or Refractory Chronic Lymphocytic Leukemia

Matching adjusted indirect comparison addresses key questions and limitations associated with previously presented analysis and suggests efficacy advantage of BRUKINSA vs acalabrutinib

BeiGene, Ltd. (Nasdaq: BGNE; HKEX: 06160; SSE: 688235), a global oncology company, today announced a new matching adjusted indirect comparison (MAIC) of the efficacy of BRUKINSA^® (zanubrutinib) versus acalabrutinib in relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL) based on data from the Phase 3 ALPINE and Phase 3 ASCEND trials. 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,¹ 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.² 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.^3,4

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. For additional details of the analysis, please refer to the full poster presentation.

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.⁵

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 3 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.⁶

About BRUKINSA^® (zanubrutinib)

BRUKINSA is a small molecule inhibitor of BTK designed to deliver complete and sustained inhibition of the BTK protein by optimizing bioavailability, half-life, and selectivity. With differentiated pharmacokinetics compared with other approved BTK inhibitors, BRUKINSA has been demonstrated to inhibit the proliferation of malignant B cells within a number of disease-relevant tissues.

U.S. Indications and Important Safety Information for BRUKINSA (zanubrutinib)

INDICATIONS

BRUKINSA is a kinase inhibitor indicated for the treatment of adult patients with:

• Chronic lymphocytic leukemia or small lymphocytic lymphoma
• Waldenström’s macroglobulinemia
• Mantle cell lymphoma (MCL) who have received at least one prior therapy
• Relapsed or refractory marginal zone lymphoma (MZL) who have received at least one anti-CD20-based regimen

The MCL and MZL indications are approved under accelerated approval based on overall response rate. Continued approval for these indications may be contingent upon verification and description of clinical benefit in confirmatory trials.

IMPORTANT SAFETY INFORMATION

Warnings and Precautions

Hemorrhage

Fatal and serious hemorrhage has occurred in patients with hematological malignancies treated with BRUKINSA monotherapy. Grade 3 or higher hemorrhage, including intracranial and gastrointestinal hemorrhage, hematuria and hemothorax have been reported in 3.6% of patients treated with BRUKINSA monotherapy in clinical trials, with fatalities occurring in 0.3% of patients. Bleeding of any grade, excluding purpura and petechiae, occurred in 30% of patients.

Bleeding has occurred in patients with and without concomitant antiplatelet or anticoagulation therapy. Coadministration of BRUKINSA with antiplatelet or anticoagulant medications may further increase the risk of hemorrhage.

Monitor for signs and symptoms of bleeding. Discontinue BRUKINSA if intracranial hemorrhage of any grade occurs. Consider the benefit-risk of withholding BRUKINSA for 3-7 days pre- and post-surgery depending upon the type of surgery and the risk of bleeding.

Infections

Fatal and serious infections (including bacterial, viral, or fungal infections) and opportunistic infections have occurred in patients with hematological malignancies treated with BRUKINSA monotherapy. Grade 3 or higher infections occurred in 24% of patients, most commonly pneumonia (11%), with fatal infections occurring in 2.9% of patients. Infections due to hepatitis B virus (HBV) reactivation have occurred.

Consider prophylaxis for herpes simplex virus, pneumocystis jiroveci pneumonia, and other infections according to standard of care in patients who are at increased risk for infections. Monitor and evaluate patients for fever or other signs and symptoms of infection and treat appropriately.

Cytopenias

Grade 3 or 4 cytopenias, including neutropenia (22%), thrombocytopenia (8%) and anemia (7%) based on laboratory measurements, developed in patients treated with BRUKINSA monotherapy. Grade 4 neutropenia occurred in 11% of patients, and Grade 4 thrombocytopenia occurred in 2.8% of patients.

Monitor complete blood counts regularly during treatment and interrupt treatment, reduce the dose, or discontinue treatment as warranted. Treat using growth factor or transfusions, as needed.

Second Primary Malignancies

Second primary malignancies, including non-skin carcinoma, have occurred in 13% of patients treated with BRUKINSA monotherapy. The most frequent second primary malignancy was non-melanoma skin cancer reported in 7% of patients. Other second primary malignancies included malignant solid tumors (5%), melanoma (1.2%), and hematologic malignancies (0.5%). Advise patients to use sun protection and monitor patients for the development of second primary malignancies.

Cardiac Arrhythmias

Serious cardiac arrhythmias have occurred in patients treated with BRUKINSA. Atrial fibrillation and atrial flutter were reported in 3.7% of 1550 patients treated with BRUKINSA monotherapy, including Grade 3 or higher cases in 1.7% of patients. Patients with cardiac risk factors, hypertension and acute infections may be at increased risk. Grade 3 or higher ventricular arrhythmias were reported in 0.2% of patients.

Monitor for signs and symptoms of cardiac arrhythmias (e.g. palpitations, dizziness, syncope, dyspnea, chest discomfort), manage appropriately, and consider the risks and benefits of continued BRUKINSA treatment.

Embryo-Fetal Toxicity

Based on findings in animals, BRUKINSA can cause fetal harm when administered to a pregnant woman. Administration of zanubrutinib to pregnant rats during the period of organogenesis caused embryo-fetal toxicity, including malformations at exposures that were 5 times higher than those reported in patients at the recommended dose of 160 mg twice daily. Advise women to avoid becoming pregnant while taking BRUKINSA and for 1 week after the last dose. Advise men to avoid fathering a child during treatment and for 1 week after the last dose. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.

Adverse Reactions

In this pooled safety population, the most common adverse reactions, including laboratory abnormalities, in ≥30% of patients who received BRUKINSA (N=1550) included decreased neutrophil count (42%), upper respiratory tract infection (39%), decreased platelet count (34%), hemorrhage (30%), and musculoskeletal pain (30%).

Drug Interactions

CYP3A Inhibitors: When BRUKINSA is co-administered with a strong CYP3A inhibitor, reduce BRUKINSA dose to 80 mg once daily. For coadministration with a moderate CYP3A inhibitor, reduce BRUKINSA dose to 80 mg twice daily.

CYP3A Inducers: Avoid coadministration with strong or moderate CYP3A inducers. Dose adjustment may be recommended with moderate CYP3A inducers.

Specific Populations

Hepatic Impairment: The recommended dose of BRUKINSA for patients with severe hepatic impairment is 80 mg orally twice daily.

Please see full U.S. Prescribing Information and U.S. Patient Information.

About BeiGene

BeiGene is a global oncology company that is discovering and developing innovative treatments that are more affordable and accessible to cancer patients worldwide. With a broad portfolio, we are expediting development of our diverse pipeline of novel therapeutics through our internal capabilities and collaborations. We are committed to radically improving access to medicines for far more patients who need them. Our growing global team of more than 10,000 colleagues spans five continents, with administrative offices in Basel, Beijing, and Cambridge, U.S. To learn more about BeiGene, please visit www.beigene.com and follow us on LinkedIn and X (formerly known as Twitter).

Forward-Looking Statements

This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 and other federal securities laws, including statements regarding the potential of BeiGene’s therapies to help patients; the efficacy and safety of BRUKINSA versus acalabrutinib in patients with R/R CLL; BeiGene’s advancement, anticipated clinical development, regulatory submissions and commercialization of zanubrutinib, particularly as a treatment for R/R FL; and BeiGene’s plans, commitments, aspirations, and goals under the heading “About BeiGene.” Actual results may differ materially from those indicated in the forward-looking statements as a result of various important factors, including BeiGene's ability to demonstrate the efficacy and safety of its drug candidates; the clinical results for its drug candidates, which may not support further development or marketing approval; actions of regulatory agencies, which may affect the initiation, timing and progress of clinical trials and marketing approval; BeiGene's ability to achieve commercial success for its marketed medicines and drug candidates, if approved; BeiGene's ability to obtain and maintain protection of intellectual property for its medicines and technology; BeiGene's reliance on third parties to conduct drug development, manufacturing, commercialization, and other services; BeiGene’s limited experience in obtaining regulatory approvals and commercializing pharmaceutical products; BeiGene’s ability to obtain additional funding for operations and to complete the development of its drug candidates and achieve and maintain profitability; and those risks more fully discussed in the section entitled “Risk Factors” in BeiGene’s most recent annual report on Form 10-K, as well as discussions of potential risks, uncertainties, and other important factors in BeiGene's subsequent filings with the U.S. Securities and Exchange Commission. All information in this press release is as of the date of this press release, and BeiGene undertakes no duty to update such information unless required by law.

To access BeiGene media resources, please visit our News & Media site.

¹ Kittai AS, et al. A matching-adjusted indirect comparison of acalabrutinib versus zanubrutinib in relapsed or refractory chronic lymphocytic leukemia. Am J Hematol. 2023 Dec;98(12):E387-E390. doi: 10.1002/ajh.27110. Epub 2023 Oct 9. PMID: 37811799.

² Brown JR, et al. Zanubrutinib or Ibrutinib in Relapsed or Refractory Chronic Lymphocytic Leukemia. N Engl J Med. 2023 Jan 26;388(4):319-332. doi: 10.1056/NEJMoa2211582. Epub 2022 Dec 13. PMID: 36511784.

³ Ghia P, et al. ASCEND: Phase III, Randomized Trial of Acalabrutinib Versus Idelalisib Plus Rituximab or Bendamustine Plus Rituximab in Relapsed or Refractory Chronic Lymphocytic Leukemia. J Clin Oncol. 2020 Sep 1;38(25):2849-2861. doi: 10.1200/JCO.19.03355. Epub 2020 May 27. PMID: 32459600.

⁴ Sharman JP, et al. Acalabrutinib with or without obinutuzumab versus chlorambucil and obinutuzmab for treatment-naive chronic lymphocytic leukaemia (ELEVATE TN): a randomised, controlled, phase 3 trial. Lancet. 2020 Apr 18;395(10232):1278-1291. doi: 10.1016/S0140-6736(20)30262-2. Erratum in: Lancet. 2020 May 30;395(10238):1694. PMID: 32305093; PMCID: PMC8151619.

⁵ Hwang S, et al. P632: COMPARISON OF TREATMENT-EMERGENT ADVERSE EVENTS OF ACALABRUTINIB AND ZANUBRUTINIB IN CLINICAL TRIALS IN B-CELL MALIGNANCIES: A SYSTEMATIC REVIEW AND META-ANALYSIS. Hemasphere. 2023 Aug 8;7(Suppl ):e47546cf. doi: 10.1097/01.HS9.0000969432.47546.cf. PMCID: PMC10428881.

⁶ J. R. Brown, et. Al. Extended Follow-up of ALPINE Randomized Phase 3 Study Confirms Sustained Superior Progression-Free Survival of Zanubrutinib Versus Ibrutinib for Treatment of Relapsed/Refractory Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma (R/R CLL/SLL). Blood 2023; 142 (Supplement 1): 202. doi: https://doi.org/10.1182/blood-2023-174289.

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