Obinutuzumab (2) – Gazyvaro®

• Clinical trials
  • The GADOLIN trial is a randomised, controlled, open-label, multicentre trial comparing obinutuzumab in combination with bendamustine, followed by obinutuzumab maintenance therapy, with bendamustine monotherapy without maintenance therapy in the treatment of patients with indolent non-Hodgkin’s lymphoma.

a) Patients with follicular lymphoma (FL) who have not responded to treatment with rituximab or a rituximab-containing regimen, or whose disease has progressed during or up to 6 months after treatment

• mortality
  • In the GADOLIN study, treatment with obinutuzumab + bendamustine, followed by obinutuzumab maintenance therapy, showed a statistically significant prolongation in overall survival compared with bendamustine monotherapy without maintenance therapy (hazard ratio: 0.62 [0.39; 0.98], p = 0.0379).
  • The median overall survival has not yet been reached in either treatment group.
  • At the time of this interim analysis (data cut-off date: 1 May 2015), the number of events in both treatment groups is minor, even in relation to the data set on which the final analysis of overall survival is planned.
  • Given the long-term course of the disease, this gives rise to a degree of uncertainty which must be taken into account when interpreting the data, alongside the statistically significant result presented here.
• Morbidity – Progression-free survival (PFS)
  • Treatment with obinutuzumab + bendamustine, followed by obinutuzumab maintenance therapy, showed a statistically significant prolongation of PFS: 29.2 vs. 13.8 months, hazard ratio: 0.47 [0.34; 0.64], p < 0.0001.
  • The PFS endpoint was defined as the time from randomisation to disease progression (evidence of progression or relapse according to NHL response criteria) or death, regardless of cause, whichever occurred first.
  • The PFS endpoint is a composite endpoint comprising endpoints from the categories of mortality and morbidity.
  • Taking the above aspects into account, there are differing views within the G-BA regarding the clinical relevance of the PFS endpoint to patients. This does not affect the overall conclusion regarding the extent of the additional benefit.
• quality of life
  • Health-related quality of life was assessed in the GADOLIN study using the cancer-specific FACT-G questionnaire and the lymphoma-specific FACT-LymS questionnaire.
  • Based on the data subsequently submitted by the pharmaceutical manufacturer in its statement, the responder analyses for both measurement instruments show no statistically significant differences between the treatment groups, neither in terms of an improvement in quality of life nor in terms of a deterioration in quality of life.
  • In addition to the limited interpretative value of the results, which are based on data from only two assessment time points, the high potential for bias associated with this endpoint must also be taken into account when interpreting the results.
• Side effects
  • The GADOLIN study comprises two treatment phases: induction and maintenance therapy.
  • As the treatment regimens differ considerably between induction and maintenance therapy (intervention arm) and, furthermore, no maintenance therapy was administered in the comparator arm of the study, it is appropriate to consider the side effects separately for each treatment phase.
  • However, complete data are available only for a subset of patients in the comparator arm for the maintenance therapy phase (i.e. following induction therapy — no maintenance therapy was carried out in the comparator arm), as the observation periods for adverse events between the study arms were only harmonised following a subsequent amendment to the study protocol.
  • Consequently, only the results for the induction therapy period are suitable for a valid comparison.
  • Almost every patient in the study experienced at least one adverse event, both during treatment with obinutuzumab + bendamustine and during monotherapy with bendamustine.
  • Serious adverse events (SAEs) occurred in both treatment groups, with no statistically significant difference between them.
  • With regard to adverse events classified as ‘severe adverse events’ (CTCAE grade ≥ 3), the majority of patients in both treatment groups were affected, though there was no statistically significant difference between the treatment groups.
  • Similarly, no statistically significant difference was observed with regard to adverse events leading to discontinuation of the study medication or those leading to death.
  • With regard to adverse events classified as events of special interest, regardless of severity, serious neutropenia occurred statistically significantly more frequently in the obinutuzumab + bendamustine group; whilst thrombocytopenia occurred at a statistically significant higher rate with bendamustine monotherapy.
  • In summary, the endpoints relating to adverse events do not indicate either an advantage or a disadvantage for the medicinal product under evaluation in terms of side effects.
• Overall assessment
  • To assess the extent of the additional benefit of obinutuzumab in combination with bendamustine, followed by obinutuzumab maintenance therapy, the GADOLIN study provides results on mortality (overall survival), morbidity, health-related quality of life and side effects.
  • For the endpoint of overall survival, the results show a statistically significant prolongation of overall survival in the intervention group compared with the control group in the study.
  • However, the data from this interim analysis of the study are based on a minor number of events to date. Given the long-term course of the disease, this introduces uncertainty into the interpretation of the data, which is why an additional benefit is identified, the extent of which cannot currently be quantified.
  • The health status assessment (VAS of the EQ-5D) provides favourable results for a single operationalisation of the endpoint, albeit with limited statistical significance for the intervention group.
  • With regard to the effects of the treatments on health-related quality of life, the available results have only limited statistical significance. They show no statistically significant differences between the intervention group and the control group in the GADOLIN study.
  • The overall review of side effects reveals neither an advantage nor a disadvantage for the medicinal product under evaluation.
  • In this regard, valid conclusions for the comparative assessment can be drawn from the data only for the induction therapy phase, but not for the maintenance therapy phase.

Courtesy translation only, please refer to the German original.