The ASPEN study is the first phase III head-to-head study comparing the efficacy and safety of zanubrutinib and ibrutinib in symptomatic Waldenström Macroglobulinaemia (WM) patients. Results of this trial demonstrate that zanubrutinib is associated with a numerically higher rate of complete and very good partial responses and safety and tolerability over ibrutinib.
Currently, the first-generation Bruton’s Tyrosine Kinase (BTK) inhibitor ibrutinib is approved for all lines of therapy for patients with WM.1 Zanubrutinib is a novel BTK inhibitor that is specifically designed with the objective to maximise BTK occupancy and minimise inhibition of off-target kinases, such as TEC- and EGFR-family kinases.2 Based on the results obtained with zanubrutinib in a phase I/II study, the phase III ASPEN trial was designed to directly compare the safety and efficacy of ibrutinib and zanubrutinib in patients with WM.3
ASPEN was a randomised, open-label phase III trial in which WM patients harbouring a MYD88 mutation were randomly assigned (1:1) to receive either zanubrutinib (160 mg twice daily) or ibrutinib (420 mg once daily) in 28-day cycles until progression or intolerance (cohort 1). The study also included a third, non-randomised arm, in which WM patients without MYD88 mutation were treated with zanubrutinib (cohort 2). To be eligible for the trial, patients had to have relapsed/refractory (R/R) WM after ≥1 prior line of therapy or be treatment-naïve (TN) and unsuitable for standard chemoimmunotherapy. A prior treatment with a BTK inhibitor was not allowed. The primary endpoint of the ASPEN trial was the proportion of patients achieving a complete response (CR) or very good partial response (VGPR), as assessed by an independent review committee.4
From January 2017 until July 2018, a total of 164 relapsed/refractory (R/R) and 37 treatment-naive (TN) WM patients were enrolled in cohort 1 of the ASPEN trial. Of them, 199 patients received at least one dose of the study treatment. While the treatment groups were generally well balanced for important baseline factors, there were more older patients in the zanubrutinib arm (aged >75 years: 33% vs. 22%) and in this arm patients more frequently suffered from anaemia (haemoglobin ≤ 11g/dL) (66% vs. 54%) and were more likely to harbour a CXCR4 mutation (11% vs. 8%). At the time of the primary analysis, none of the patients in the trial had achieved a CR. However, the rate of VGPR, as assessed by an independent review committee was reported at 28% for zanubrutinib, which is higher than the 19% VGPR seen with ibrutinib. Although clinically relevant, this difference did not meet the criteria for statistical significance (2-sided p= 0.09). Zanubrutinib also demonstrated safety and tolerability.4
At the 11th International Workshop on Waldenström’s Macroglubulinemia (IWWM) in October 2022, Prof. Meletios Dimopoulos presented the long-term follow-up results of the ASPEN trial. After a median follow-up of 44.4 months, 66% of patients remained on treatment with zanubrutinib, as compared to 52% with ibrutinib. After almost 4 years of follow-up, the CR + VGPR rates by investigator was reported at 36.3% with zanubrutinib as compared to 25.3% with ibrutinib. Interestingly, the numerically higher rate of ≥VGPR in zanubrutinib-treated patients from cohort 1 also translated into a trend for a better improved PFS (HR[95%CI]: 0.63[0.36-1.12]). At the time of this analysis, the median PFS was not reached in either arm, 42-month PFS rates are 78.3% and 69.7% for zanubrutinib and ibrutinib, respectively. Also the median OS was not reached, hazard ratio estimates show a HR of 0.75 for zanubrutinib (HR[95%CI]: 0.75[0.36-1.59]). With zanubrutinib, patients with CXCR4 mutations show a VGPR rate of 21.2%, as compared to 10.0% with ibrutinib. In this subgroup, median time to VGPR was 11.1 months for zanubrutinib and 31.3 months for ibrutinib. In line with the primary analysis, 3.0% of adverse events in the zanubrutinib arm led to death (vs. 5.1% with ibrutinib), 8.9% to treatment discontinuation (vs. 20.4%) and 15.8% to dose reduction (vs. 26.5%) compared to ibrutinib. The rates of atrial fibrillation (23.5% vs. 7.9%), diarrhoea (34.7% vs. 22.8%), hypertension (25.5% vs. 14.9%) were lower with zanubrutinib than with ibrutinib. Infection occurred in 79.6% of patients treated with ibrutinib and in 79.2% of patients receiving zanubrutinib. Neutropenia was reported in respectively 20.4% and 34.7% of patients.5
Based on these results obtained with zanubrutinib, zanubrutinib received EMA-approval for the treatment of adult patients with WM in 2021 and is reimbursed in Belgium as of October 2022.6,7
In the phase III ASPEN trial, zanubrutinib was associated with a numerically higher rate of VGPR compared to ibrutinib and demonstrated less toxicity, particularly cardiovascular toxicity. Therefore, zanubrutinib is a new option in the standard of care for adult patients with WM.
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1122-BRU-PRC-095 – Approval date material Nov 2022
|Hospital Price (excl. VAT) BRUKINSA® 80 mg 120 Capsules : 5740,20€|
▼This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions.
NAME OF THE MEDICINAL PRODUCT: BRUKINSA 80 mg hard capsules. QUALITATIVE AND QUANTITATIVE COMPOSITION: Each hard capsule contains 80 mg of zanubrutinib. For the full list of excipients, see section 6.1. PHARMACEUTICAL FORM: Hard capsule. White to off-white opaque hard capsule of 22 mm in length, marked with “ZANU 80” in black ink. CLINICAL PARTICULARS: Therapeutic indications: BRUKINSA as monotherapy is indicated for the treatment of adult patients with Waldenström’s macroglobulinaemia (WM) who have received at least one prior therapy, or in first line treatment for patients unsuitable for chemo-immunotherapy. Posology and method of administration: Treatment with this medicinal product should be initiated and supervised by a physician experienced in the use of anticancer medicinal products. Posology: The recommended total daily dose of zanubrutinib is 320 mg. The daily dose may be taken either once daily (four 80 mg capsules) or divided into two doses of 160 mg twice daily (two 80 mg capsules). Dose modifications for adverse reactions: Recommended dose modifications of zanubrutinib for Grade 3 or greater adverse reactions are provided in Table 1.
Table 1: Recommended dose modifications for adverse reactions
Asymptomatic lymphocytosis should not be regarded as an adverse reaction, and these patients should continue taking BRUKINSA. Dose modifications for concomitant therapy: Dose modifications for use with CYP3A inhibitors or inducers (see sections 4.4, 4.5 and 5.2).
Table 2: Recommended dose modifications when co-administered with other medicinal products
Missed dose: A double dose should not be taken to make up for a forgotten dose. If a dose is not taken at the scheduled time, the next dose should be taken according to the normal schedule. Special populations: Elderly: No specific dose adjustment is required for elderly patients (aged ≥65 years). Renal impairment: No dose modification is recommended in patients with mild to moderate renal impairment (creatinine clearance (CrCl) ≥30 mL/min, estimated by Cockcroft-Gault). There is limited data on patients with severe renal impairment and end-stage renal disease (n=5). Patients with severe renal impairment (CrCl <30 mL/min) or on dialysis should be monitored for adverse reactions (see section 5.2). Hepatic impairment: Dose modifications are not needed in patients with mild (Child-Pugh class A) or moderate hepatic impairment (Child-Pugh class B). Patients with mild or moderate hepatic impairment were treated in BRUKINSA clinical studies. The recommended dose of BRUKINSA for patients with severe hepatic impairment (Child-Pugh class C) is 80 mg orally twice daily. The safety of BRUKINSA has not been evaluated in patients with severe hepatic impairment. Monitor these patients closely for adverse events of BRUKINSA (see section 5.2). Paediatric population: The safety and efficacy of BRUKINSA in children and adolescents below 18 years of age have not been established. No data are available. Method of administration: BRUKINSA is for oral use. The hard capsules can be taken with or without food. Patients should be instructed to swallow the capsules whole with water, and not to open, break or chew the capsules. Contraindications: Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Undesirable effects: Summary of the safety profile: The most commonly occurring adverse reactions (≥20%) were neutropenia† (56.2%), thrombocytopenia† (45.1%), upper respiratory tract infection§ (44.3%), haemorrhage/haematoma§ (32.2%), rash§ (29.8%), bruising§ (29.1%), anaemia† (28.9%), musculoskeletal pain§ (24.3%), diarrhoea (23.6%), pneumonia§ (22.1%) and cough (21.7%). The most common Grade 3 or higher adverse reactions (>5%) were neutropenia† 28.0%), pneumonia§ (11.6%), thrombocytopenia† (11.4%), and anaemia† (6.9%). Of the 779 patients treated with zanubrutinib, 3.6% of patients discontinued treatment due to adverse reactions. The most frequent adverse reaction leading to treatment discontinuation was pneumonia§ (1.8%). Adverse reaction leading to dose reduction occurred in 4.9% of patients. Tabulated list of adverse reactions: The safety profile is based on pooled data from 779 patients with B-cell malignancies treated with BRUKINSA in clinical studies with a median duration of exposure of 30.3 months. Adverse reactions in patients treated with BRUKINSA for B-cell malignancies are listed below by system organ class and frequency grouping. Frequencies are defined as follows: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000), not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness.
Table 3: Adverse reactions reported in clinical studies in patients with B-cell malignancies
* Grades were evaluated based on the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.03. † Based on laboratory measurements. § Includes multiple adverse reaction terms. # Includes events with fatal outcome. Other special population: Elderly: Of the 779 patients treated with BRUKINSA, 52% were 65 years of age or older. The incidence of Grade 3 or higher adverse events was slightly higher among elderly patients treated with zanubrutinib (71% of patients age ≥65 versus 64% of patients <65 years of age). No clinically relevant differences in safety were observed between patients ≥65 years and younger. Paediatric population: The safety and efficacy of BRUKINSA in children and adolescents below 18 years of age have not been established. Reporting of suspected adverse reactions: Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via Agence fédérale des médicaments et des produits de santé – Division Vigilance – Avenue Galilée 5/03 1210 BRUXELLES Boîte Postale 97 1000 BRUXELLES Madou – Site internet: www.notifieruneffetindesirable.be / E-mail: firstname.lastname@example.org. MARKETING AUTHORISATION HOLDER: BeiGene Ireland Limited. 10 Earlsfort Terrace – Dublin 2 – D02 T380 – Ireland. Tel. +353 1 566 7660 – E-mail: bg.ireland@ beigene.com MARKETING AUTHORISATION NUMBER(S): EU/1/21/1576/001. MODE OF DELIVERY: Medicinal product subject to medical prescription. DATE OF REVISION OF THE TEXT: 22 November 2021.
Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu.