Lisocabtagene maraleucel in second-line for B-cell lymphoma: added benefit for certain patients

The approval of lisocabtagene maraleucel includes the treatment of adults with various forms of B-cell lymphoma, i.e. diffuse large B-cell lymphoma (DLBCL), high-grade B-cell lymphoma (HGBL), primary mediastinal large B-cell lymphoma (PMBCL) and follicular lymphoma grade 3B (FL3B), who relapse within 12 months from completion of, or are refractory to, first-line chemoimmunotherapy.

The German Institute for Quality and Efficiency in Health Care (IQWiG) examined in an early benefit assessment whether the drug offers an added benefit for these patients in comparison with the appropriate comparator therapy (ACT). The (German-language) report was published in September 2023, an English translation in January 2024. A distinction can be made between two groups of patients: those who are eligible for high-dose therapy and those who are not.

Since no usable data are available for patients who are not eligible for high-dose therapy, an added benefit is not proven for this patient group. For the other patient group, however, conclusions can be drawn from data of a randomized controlled trial. According to the findings, there is a hint of a non-quantifiable added benefit of lisocabtagene maraleucel in comparison with the ACT for patients under 65 years of age.

A usable study is available only for one of three patient groups

The Federal Joint Committee ( G‑BA) differentiated between three groups of patients and defined separate treatment alternatives for each of them: If high-dose therapy is an option, the new drug had to be compared with induction therapy with mesna, ifosfamide, mitoxantrone and etoposide (MINE), which, in case of response, was followed by high-dose therapy with autologous or allogeneic stem cell transplantation.

If high-dose therapy is not an option, the ACT was treatment of physician’s choice, taking into account different drugs depending on the type of lymphoma. For these patients, the manufacturer dossier does not contain any data suitable for a benefit assessment.

The situation is different for patients who are eligible for high-dose therapy: The ongoing TRANSFORM study allows to draw conclusions relating to the research question – even if the induction therapy in the study does not correspond to the induction therapy of the ACT, which necessarily had to be adjusted following the ruling on so-called therapeutic soloists (“Solisten-Urteil”) of the Federal Social Court of 22 February 2023.

Instead of an induction therapy with MINE, rituximab and platinum-based induction regimens were used before high-dose therapy and autologous stem cell transplantation in the comparator arm of the TRANSFORM study. The rituximab and platinum-based regimens largely correspond to the specifications of the current S3 guideline and have long been established in clinical care practice. There is nothing to suggest that an induction therapy with the regimens used in the TRANSFORM study is less effective than an induction therapy with MINE. Since, in addition, the two other components of treatment in the comparator arm, i.e. high-dose therapy and stem cell transplantation, correspond to the ACT, the TRANSFORM study can be interpreted for the benefit assessment in this specific data constellation.

Only younger patients benefit from the new drug

However, the reliability of the study results is reduced due to this discrepancy: It is not possible to derive more than hints, e.g. of an added benefit, the extent of which cannot be determined.

Some effects in the TRANSFORM study depend on the patients’ age. Advantages of lisocabtagene maraleucel compared with induction, high-dose therapy and autologous stem cell transplantation in the outcomes of “overall survival” and “failure of curative treatment” were only shown in patients under 65 years of age. There were also advantages in some side effect outcomes. This was offset by some disadvantages of lisocabtagene maraleucel versus the comparator treatment, which were also shown in the outcome category of side effects.

Overall, advantages predominate for patients under the age of 65; for older patients, neither positive nor negative effects predominate. In conclusion, for patients under 65 years of age with DLBCL, HGBL, PMBCL or FL3B who relapse within 12 months from completion of, or are refractory to, first-line chemoimmunotherapy and who are eligible for high-dose therapy, there is a hint of a non-quantifiable added benefit of lisocabtagene maraleucel compared with the ACT. An added benefit is not proven for older patients, however.

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.