Panobinostat (1) – Farydak®

• Clinical trials
  • The PANORAMA-1 trial is a multicentre, multinational, randomised, placebo-controlled, double-blind Phase III trial with parallel groups and a sequential-group design.

adult patients with relapsed and/or refractory multiple myeloma who have received at least two prior lines of treatment, including bortezomib and an immunomodulatory agent

• For adult patients with relapsed and/or refractory multiple myeloma who have received at least two prior lines of treatment, including bortezomib and an immunomodulatory agent, panobinostat in combination with bortezomib and dexamethasone offers a non-quantifiable additional benefit.
• The G-BA classifies the extent of the additional benefit of panobinostat in combination with bortezomib and dexamethasone as non-quantifiable, based on the criteria set out in Section 5(7) of the AM-NutzenV, taking into account the severity of the disease and the therapeutic objective in treating the disease is non-quantifiable.
• An additional benefit exists but is non-quantifiable because the scientific evidence does not permit this.
• In the present case and indication, the decisive factor is that no advantage of panobinostat in combination with bortezomib and dexamethasone over bortezomib and dexamethasone could be demonstrated in terms of patient-relevant endpoints, meaning that it is not possible to quantify the additional benefit.
• mortality
  • overall survival
  • In the PANORAMA-1 study, overall survival was assessed as a secondary endpoint. It was defined as the time from randomisation to death, regardless of the underlying cause of death.
  • The median overall survival was 26.12 months in the panobinostat arm and 19.52 months in the placebo arm. This difference, with a hazard ratio of 0.84 [95% CI: 0.55–1.28], is not statistically significant.
  • The median survival time was 25.5 months in the panobinostat arm and 19.5 months in the placebo arm, with a hazard ratio of 1.01 [95% CI: 0.69 – 1.5]. No statistical difference was observed.
  • With regard to overall survival, no conclusion can be drawn from the available results as to the extent of the additional benefit.
• morbidity
  • PFS
  • The primary endpoint, PFS, was defined as the time from randomisation to disease progression, recurrence of the disease or death.
  • In the PANORAMA-1 study, the median progression-free survival was 12.5 months [95% CI: 7.3 – 14.0] and 4.7 months [95% CI: 3.7 – 6.1] in the control arm. The hazard ratio is 0.47 [95% CI: 0.69 – 1.5].
  • PFS is a composite endpoint comprising endpoints from different endpoint categories (mortality and morbidity).
  • The ‘death’ component of the composite PFS endpoint is considered patient-relevant and is assessed as a standalone endpoint via the secondary endpoint ‘overall survival’.
  • Furthermore, the morbidity component ‘disease progression’ was assessed, in accordance with the operationalisation, not on the basis of symptoms but using imaging and laboratory procedures.
  • The differences in PFS observed in the study are not reflected in a difference in median overall survival.
  • Taking the above aspects into account, there are differing views within the G-BA regarding the patient relevance of the PFS endpoint.
  • The overall conclusion regarding the extent of the additional benefit remains unaffected by this.
  • Response
  • The ‘response rate’ was defined as the proportion of patients in whom remission was achieved; in the study, this was assessed as the proportion of patients with complete remission, near-complete remission and partial remission.
  • The ‘response rate’ endpoint is also a composite endpoint. The individual components are predominantly derived from imaging procedures or laboratory tests; consequently, the data were not collected on the basis of symptoms.
  • For this reason, this endpoint alone is not considered directly relevant to patients and cannot be used to assess the extent of the additional benefit.
  • Treatment-free time without disease progression
  • The post-hoc endpoint ‘treatment-free time without disease progression’, as defined in the present operationalisation, is derived directly from the difference between the PFS and the duration of treatment with the study medication per patient.
  • No conclusion can be drawn regarding the extent of the additional benefit.
• quality of life
  • Quality of life during the PANORAMA-1 trial was to be assessed using the EORTC-QLQ-C30, EORTC-QLQ-MY20 and FACT/GOG-NTX questionnaires.
  • Valid data on the results of the EORTC-QLQ-C30, EORTC-QLQ-MY2 and FACT/GOG-NTX questionnaires would have been desirable, but are not available due to incomplete data collection.
  • Consequently, no conclusions can be drawn regarding the extent of the additional benefit in terms of quality of life.
• Side effects
  • Adverse events occurred at least once in almost all patients.
  • In the subpopulation compliant with the approval criteria, the assessment of the ‘side effects’ endpoint indicates a greater potential for harm with panobinostat in combination with bortezomib and dexamethasone compared with bortezomib and dexamethasone alone.
  • Of the adverse events directly relevant to patients that occurred most frequently overall, gastrointestinal events (e.g. diarrhoea, nausea, vomiting) were observed significantly more frequently in the panobinostat arm.
  • Patients in the panobinostat arm were statistically significantly more frequently affected by adverse events of grade 3 or higher (e.g. thrombocytopenia, neutropenia, diarrhoea, nausea).
• Conclusion
  • Taking the available results as a whole, the G-BA arrives at the following assessment of the extent of the additional benefit: there is an additional benefit, but it is non-quantifiable because the available scientific data do not currently permit a quantifiable statement on the extent of the additional benefit for patient-relevant endpoints.

Courtesy translation only, please refer to the German original.