Zanubrutinib in chronic lymphocytic leukaemia: added benefit for certain patients

Zanubrutinib, a second-generation Bruton tyrosine kinase (BTK) inhibitor, is approved for several therapeutic indications. The German Institute for Quality and Efficiency in Health Care (IQWiG) investigated whether the drug has an added benefit compared with the appropriate comparator therapy for adult patients with chronic lymphocytic leukaemia (CLL) after a relapse or in the case of refractory disease, i. e. disease that has not responded to the previous treatment.

The (German-language) report was published in March 2023, an English translation in October 2023.

The Federal Joint Committee (G-BA) divided the patients into four groups based on their pretreatment, and defined different appropriate comparator therapies. Only for one of the groups did the drug manufacturer present suitable data from a study in its dossier. This study compared zanubrutinib with ibrutinib, a first-generation BTK inhibitor. The result of IQWiG’s assessment: There is a hint of a major added benefit in comparison with ibrutinib for patients under 65 years of age who have not yet received a BTK or B-cell lymphoma-2 (BCL-2) inhibitor. For older patients, there is also a hint of an added benefit, but the extent is minor. For patients who have already received a BTK or BCL-2 inhibitor or even both, an added benefit of zanubrutinib compared with the respective appropriate comparator therapy has not been proven due to a lack of suitable study data.

Treatment of one of the most common forms of leukaemia significantly improved

In CLL, one of the most common forms of leukaemia, the bone marrow produces large numbers of abnormal B-cells that gradually flood the blood, the bone marrow itself and various organs. It usually occurs at an older age. CLL is considered incurable; but therapies can slow down disease progression. The course of the disease depends on genetic risk factors. For example, the so-called 17p deletion in the abnormal B-cells is associated with shorter survival. Such mutations are particularly frequent in refractory CLL.

Until a few years ago, chemo-immunotherapy was considered the standard of care. However, this treatment could help B-cells with 17p deletions to prevail. Therefore, so-called BTK inhibitors such as ibrutinib have now established themselves as the new standard treatment. Ibrutinib increases average survival time, but is often associated with severe side effects. This is why further BTK inhibitors have been developed, which act more specifically and are thus supposed to be better tolerated. BCL-2 inhibitors such as venetoclax, which accelerate the death of the abnormal B-cells, are also used.

Pretreatment in study differs from clinical practice in Germany

In its dossier, the manufacturer presented suitable data only for pretreated patients with relapsed or refractory CLL who have not yet received either a BTK or a BCL-2 inhibitor; these data were from the still ongoing randomized controlled trial ALPINE. Just over three quarters of the patients had received pretreatment with chemo-immunotherapy, and a large proportion had genetic risk factors such as 17p deletion.

Current guidelines recommend chemo-immunotherapy for CLL either not at all or only for patients without genetic risk factors. It is therefore likely that, in the coming years, there will be only few patients in Germany with relapsed or refractory CLL who have not been pretreated with a BTK or BCL-2 inhibitor. This limits the practical relevance of the assessment results.

The study data show exclusively positive effects for zanubrutinib compared with ibrutinib: Patients under 65 years of age survived longer. In addition, certain severe side effects such as cardiac disorders were less frequent, and treatment was discontinued less often. Besides, men had fewer muscle spasms with the second-generation BTK inhibitor than with the older comparator drug.

Overall, for patients with relapsed/refractory CLL who have not yet received a BTK inhibitor and/or BCL-2 inhibitor, there is a hint of a major added benefit of zanubrutinib over ibrutinib if they are under 65 years of age, and hint of a minor added benefit if they are 65 or older. If a BTK and/or a BCL-2 inhibitor was already used in the pretreatment, an added benefit is not proven due to a lack of suitable study data.

G‑BA decides on the extent of added benefit

The dossier assessment is part of the early benefit assessment according to the Act on the Reform of the Market for Medicinal Products (AMNOG) supervised by the G‑BA. After publication of the dossier assessment, the G-BA conducts a commenting procedure and makes a final decision on the extent of the added benefit. You can find an overview of the results of IQWiG’s benefit assessment in an English extract. In addition, the website informedhealth.org published by IQWiG provides easily understandable information on this benefit assessment.