Pomalidomid (1) – Imnovid®

• Clinical trials
  • This study is a multicentre, randomised, open-label Phase III trial.
  • Adult patients with relapsed or refractory multiple myeloma who had received at least two prior lines of treatment (including lenalidomide and bortezomib) were randomised to either an intervention group, in which pomalidomide was administered with low-dose-dose dexamethasone, or to a control group receiving high-dose dexamethasone.

Adult patients with relapsed and refractory multiple myeloma who had received at least two prior treatments, including lenalidomide and bortezomib, and who had shown progression during their most recent treatment

• mortality
  • In the study, ‘overall survival’ was assessed as a secondary endpoint.
  • At the time of the interim analysis of overall survival as planned in the study protocol (data cut-off: 7 September 2012), the median overall survival according to the Kaplan-Meier method in the control group was 34 weeks (95% CI [23.4–39.9]). Median overall survival had not yet been reached in the intervention group at the time of this data cut-off. The lower limit of the 95% confidence interval in the intervention group was 48.1 weeks. The result is statistically significant (HR = 0.53; 95% CI [0.37–0.74]).
  • At the time of the final analysis of overall survival as planned in the study protocol (data cut-off: 1 March 2013), the median overall survival in the intervention group was 12.7 months (95% CI [10.4 – 15.5]) versus 8.1 months (95% CI [6.9 – 10.8]) in the control group. The result is statistically significant (HR = 0.74; 95% CI [0.56 – 0.97]).
  • With regard to overall survival, supplementary results covering a longer follow-up period were submitted as part of the commenting procedure. These are based on an analysis of overall survival—not planned in the study protocol—following a median follow-up period of 15.4 months for the patients (data cut-off: 1 September 2013). The median overall survival was 13.1 months in the intervention group versus 8.1 months in the control group. The result is statistically significant (HR = 0.74; p-value = 0.009).
  • When considering the extent of the observed effects on prolonging overall survival, whilst taking into account the uncertainties regarding bias, the additional benefit with regard to the endpoint ‘overall survival’ is classified as considerable.
• Morbidity – Progression-Free Survival (PFS)
  • Progression-free survival (PFS), defined as the time from randomisation to death or disease progression according to the criteria of the International Myeloma Working Group (IMWG), was the primary endpoint of the study.
  • Notwithstanding these differing views, PFS is not to be taken into account in the present case because, even according to the pharmaceutical manufacturer’s submission, there are no clinical trials validating the laboratory values listed in the IMWG criteria for disease progression as surrogates.
  • It also became clear during the oral hearing that, in the opinion of experts, the laboratory parameters in question have no direct relevance to patients.
• quality of life
  • To assess the additional benefit in terms of quality of life, data are available for pomalidomide from the disease-specific patient questionnaire EORTC QLQ-MY20, the oncology-specific, cross-disease patient questionnaire EORTC QLQ-C30, and the generic patient questionnaire EQ-5D.
  • At no point during the data collection period were there any statistically significant differences in response rates between the study arms.
  • With regard to the quality of life results, there were no statistically significant differences between the study arms for the EORTC-MY20 and EQ-5D questionnaires.
  • For the EORTC QLQ-C30 questionnaire, statistically significant differences were found in only 2 out of 15 subscales: in the ‘Physical Function’ subscale in favour of the intervention group, and in the ‘Nausea and Vomiting’ subscale in favour of the control group.
  • However, no validated clinically relevant minimum important differences (MIDs) are available for the EORTC QLQ-C30 questionnaire.
  • When considering the endpoints in the ‘Quality of Life’ category, there is therefore no clear effect in favour of either study group. An additional benefit in terms of quality of life is therefore not proven.
• Side effects
  • The desired effects of pomalidomide are offset by adverse events (AEs).
  • No statistically significant differences were observed between the study arms in the proportions of patients experiencing at least one adverse event, at least one serious adverse event, at least one AE of CTC grade 3 or 4, or at least one adverse event leading to discontinuation of the study, there were no statistically significant differences between the study arms.
  • With regard to the AEs discussed in the EPAR as being of particular interest (neutropenia, thrombocytopenia, infection, haemorrhage, venous thromboembolic event, peripheral neuropathy, secondary primary malignancy), a statistically significant difference was found for neutropenia, to the detriment of the intervention arm.
  • Among the other individual AEs of CTC grade 3 or 4 presented by the pharmaceutical manufacturer, statistically significant differences to the detriment of the intervention arm were observed for febrile neutropenia and leucopenia, but not for infections.
  • As part of the commenting procedure, supplementary time-to-event analyses were submitted for the individual AEs to account for the differences in treatment duration between the study arms (intervention group: 12 weeks; control group: 8 weeks). These analyses revealed, for AEs of CTC Grade 3 or 4, significant differences to the detriment of the intervention arm in disorders of the blood and lymphatic system, neutropenia and febrile neutropenia, as well as significant differences in favour of the intervention arm for metabolic and nutritional disorders, hyperglycaemia, insomnia and myopathies.
  • Overall, the time-to-event analyses confirm the adverse reaction profile already reported in the dossier.
  • When viewed as a whole, the frequencies of AEs are generally comparable between the two treatment groups, although the AEs have different therapy-specific patterns.
  • Overall, the side effects observed in the intervention arm are classified as significant for patients, but predominantly as manageable and treatable. In particular, taking into account the severity of the condition and the lack of treatment options, these side effects do not, in the G-BA’s assessment, lead to a downgrading of the extent of the additional benefit.

Courtesy translation only, please refer to the German original.