Venetoclax in acute myeloid leukaemia: indication of considerable added benefit

The German Institute for Quality and Efficiency in Health Care (IQWiG) examined in an early benefit assessment whether venetoclax in combination with a hypomethylating agent (HMA) offers an added benefit over the appropriate comparator therapy for patients with newly diagnosed acute myeloid leukaemia (AML) who are ineligible for intensive chemotherapy. This assessment showed that patients survive longer on venetoclax in combination with the HMA azacitidine than on azacitidine alone. According to the findings, there is an indication of considerable added benefit in comparison with the appropriate comparator therapy for patients with newly diagnosed AML who are ineligible for intensive chemotherapy.

Third new therapeutic indication

Venetoclax was originally approved as monotherapy for the treatment of chronic lymphocytic leukaemia (CLL) and underwent a first full early benefit assessment in 2018 after its orphan drug status had been revoked due to exceeding the turnover threshold. An added benefit was not proven in either of the two research questions.

In a first extension of the therapeutic indication, the drug was also approved for CLL therapy in combination with rituximab. According to a resolution by the Federal Joint Committee (G-BA) following a dossier assessment and an addendum by IQWiG, there is an indication of a minor added benefit for this combination in patients for whom bendamustine in combination with rituximab is the suitable therapy for the individual patient. An added benefit for other groups of patients is not proven, however.

A second new therapeutic indication was assessed in 2020: first-line treatment of CLL with venetoclax in combination with obinutuzumab. Here, too, the G-BA decided after a dossier assessment and an addendum by IQWiG that an added benefit was not proven for either of the two research questions.

Since 2021, venetoclax has also been approved as part of a combination therapy for the first-line treatment of acute myeloid leukaemia if the patients are ineligible for intensive chemotherapy. This made another early benefit assessment necessary.

Prolongation of overall survival

In its dossier, the drug manufacturer cited analyses of the most recent (third) data cut-off of its ongoing randomized double-blind study Viale-A, which compares the combination of venetoclax + azacitidine with the combination of placebo + azacitidine. The data of just over 72 percent of the participants – those who are ineligible for intensive chemotherapy – were included.

At the time of this third data cut-off, about 66 percent of the patients in the intervention arm had died, and about 87 percent in the comparator arm. The median time to death was 12.6 months under venetoclax + azacitidine, compared with 9.1 months under placebo + azacitidine. This resulted in an indication of an added benefit.

Higher frequency of neutropenia

No usable data were available in the outcome categories of morbidity and health-related quality of life, so that no advantages or disadvantages of the new combination were shown here. There were both advantages and disadvantages for venetoclax in the category of side effects. In particular, there was a hint of greater harm of considerable extent in severe neutropenia. However, this did not call into question the positive effects, especially regarding overall survival.

Overall, there is an indication of considerable added benefit of venetoclax + azacitidine in comparison with the appropriate comparator therapy.

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.

More English-language information will be available soon (extract of the dossier assessment). If you would like to be informed when this document is available, please send an e-mail to info@iqwig.de.