Original Title: Arzneimittel-Richtlinie/Anlage XII: Axicabtagen-ciloleucel. AWG A: rezidiviertes oder refraktäres diffus großzelliges B-Zell-Lymphom (DLBCL) AWG B: rezidiviertes oder refraktäres primär mediastinales B-Zell-Lymphom (PMBCL)

Authors' objectives: The Federal Joint Committee [Gemeinsamer Bundesausschuss (G-BA)] has the legal task of carrying out additional benefit assessments for all newly approved drugs with new active ingredients immediately after market entry. The result of this assessment is the basis for deciding how much the statutory health insurance pays for a new drug with a new active ingredient. According to federal law, the additional medical benefit for orphan drugs is considered to be proven through the grant of the marketing authorisation. The G-BA determines the extent of the additional benefit for the number of patients and patient groups for which there is a therapeutically significant additional benefit. The G-BA determines the extent of the additional benefit for orphan drugs that do not exceed a turnover of 50 million Euros in the last twelve calendar months, on the basis of the approval and the studies justifying the approval. These assessments are carried out by the Medical Consultancy Department of the Office of the G-BA. Categories of additional benefit for orphan drugs are ‘non quantifiable’, ‘minor additional benefit’, ‘considerable additional benefit’ or ‘major additional benefit’. The assessment must be completed within three months of the relevant date for submission of the evidence and must be published on the internet. The G-BA passes a resolution on the benefit assessment within three months of its publication.

Authors' results and conclusions: Axicabtagen-Ciloleucel is approved for the treatment of adult patients with relapsed or refractory diffuse large cell B-cell lymphoma (DLBCL) and primary mediastinal large cell B-cell lymphoma (PMBCL) after two or more systemic therapies. The benefit assessment of Axicabtagen-Ciloleucel is based on the pivotal study ZUMA-1, which is a prospective, open-label, multicenter, single-arm Phase I/II study evaluating the efficacy and safety of Axicabtagen-Ciloleucel in patients with chemotherapy-refractory DLBCL (including subtype TFL) and PMBCL. The bias potential of the ZUMA-1 study is considered high due to the uncontrolled study design. Furthermore, the lack of information on the characteristics of the included study population (FAS) as well as on individual endpoints (mortality and safety) of the lymphoma entities evaluated here increases the uncertainty of the results. In the presented studies for historical comparison, essential and relevant information on patient characteristics and study progress is missing. Furthermore, the operationalization of the endpoints in the historical populations differs compared to the ZUMA-1 study or cannot be assessed due to missing information on the operationalization of the endpoints. Therefore, the studies on historical comparison were not considered in the present benefit assessment. Mortality Of the included study participants (DLBCL, TFL and PMBCL), 47% (n = 52) died by the time of the data cut of the update analysis in Phase II. No Phase I or individual lymphoma entities (TFL and PMBCL) data could be obtained from the pharmaceutical company's records for the FAS population. For these reasons and due to the lack of a valid comparison, it is not possible to assess the efficacy of axicabtagen ciloleucel. Quality of Life Quality of life was not assessed in the ZUMA-1 study in the present cohort 1 and cohort 2. Benefit statements on quality of life can therefore not be derived. Safety Adverse events occurred in all study participants and adverse events with a severity level ≥ 3 occurred in almost all study participants. In particular, a cytokine release syndrome occurred in almost all study participants, but mostly with a severity of 1 or 2. Neurological events also occurred very frequently, mostly with a severity of CTCAE ≥ 3. About half of all study participants suffered from a serious adverse event. Due to the lack of a valid comparison and the limitations of the validity of the safety data, a final assessment of the safety of axicabtagen ciloleucel in patients with DLBCL (including TFL) and PMBCL is not possible.

Project Status: Completed

URL for project: https://www.g-ba.de/bewertungsverfahren/nutzenbewertung/408/#english

Year Published: 2019

URL for published report: https://www.g-ba.de/downloads/39-1464-3771/2019-05-02_AM-RL-XII_Axicabtagen-Ciloleucel_D-406_D-416_EN.pdf

Requestor: The Federal Joint Committee (G-BA)

URL for additional information: https://www.g-ba.de/downloads/92-975-2741/2018-11-01_Nutzenbewertung-G-BA_Axicabtagen-Ciloleucel-D-406.pdf, https://www.g-ba.de/downloads/92-975-2925/2019-05-02_Amendment-G-BA_Axicabtagen-Ciloleucel_D-406.pdf

English language abstract: An English language summary is available

Publication Type: Full HTA

Country: Germany

Organisation Name: The Federal Joint Committee

Contact Address: Gutenbergstr. 13, 10587 Berlin, Germany

Contact Name: Fachberatung Medizin [Department of Medical Consultancy]

Contact Email: Fachberatung-Medizin@g-ba.de

Copyright: https://www.g-ba.de/sys/impressum/