Obinutuzumab (3) – Gazyvaro®

• Clinical trials
  • The GALLIUM trial is an open-label, randomised, controlled and multicentre Phase III trial in patients with indolent non-Hodgkin’s lymphoma (untreated advanced follicular lymphoma and marginal zone lymphoma) to assess the efficacy and safety of induction therapy with obinutuzumab in combination with chemotherapy compared with rituximab in combination with chemotherapy, followed by maintenance therapy with either obinutuzumab or rituximab in patients who responded to treatment.

a) Patients with previously untreated advanced follicular lymphoma

• The G-BA assesses the extent of the additional benefit of obinutuzumab – to be attributed solely from a legal perspective under Section 35a(1), sentence 11, first half-clause, 1 SGB V, based on the criteria in Section 5(7) of the AM-NutzenV, taking into account the severity of the disease and the therapeutic objective in the treatment of the disease, as a non-quantifiable additional benefit.
• An additional benefit exists in accordance with Section 35a(1), sentence 11, first half-clause, of SGB V, but is non-quantifiable because the scientific evidence currently does not permit this.
• mortality
  • overall survival
  • As at the DCO on 10 September 2016, there were 95 deaths (G-chemo arm: 43/601 patients (7.2 %); R-chemo arm: 52/601 (8.7%); HR: 0.82; 95% CI: [0.54; 1.22]; p = 0.32).
  • No statistically significant difference was observed between the treatment arms.
  • Median survival has not yet been reached in either treatment arm.
  • To date, fewer than 20% of patients have been followed for more than 4 years in terms of survival; therefore, the data are considered immature and should be interpreted with caution.
  • Furthermore, the results are derived from an unplanned interim analysis.
• Morbidity – Progression-free survival (PFS)
  • PFS was assessed by both the investigator (INV) and an independent review committee (IRC).
  • In the investigator-assessed PFS analysis, median progression-free survival had not been reached in either the intervention arm or the control arm. The effect had decreased slightly by the second data cut-off on 10 September 2016 and was HR: 0.68 (95% CI: [0.54; 0.87]; p = 0.0016).
  • As assessed by the IRC, a median PFS of 51.2 months was reached in the control arm at the time of the final PFS analysis; in the intervention arm, the median PFS was not reached at any point. At the data cut-off date of 10 September 2016, the effect in favour of the intervention was an HR of 0.72 (95% CI: [0.56; 0.93]; p = 0.0016).
  • The PFS endpoint is a composite endpoint comprising mortality and partial response (PR) or complete response (CR). For the operationalisation of progression (following PR) or recurrence (following CR), almost exclusively morphological imaging features relating to tumour extent or growth are taken into account. However, symptoms perceptible to the patient are not considered in this context.
  • Taking the above aspects into account, there are differing views within the G-BA regarding the 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 GALLIUM study using the cancer-specific FACT-G questionnaire and the lymphoma-specific FACT-LymS questionnaire.
  • The response rates were moderate and stood at approximately 70% in the G-Chemo arm until the end of maintenance therapy. In the R-Chemo arm, the rate fell below 70%, but remained roughly stable at 62% during the maintenance phase.
  • From the start of the study to month 12 of the maintenance phase, the mean FACT-G score increased by approximately 4 points in both study arms. No difference was observed between the comparison arms.
  • The analysis of the FACT-LymS also showed an increase in mean scores of 5 and 5.4, respectively, in both study arms. Only at cycle 3 did a statistically significant difference emerge between the treatment arms; however, this did not persist consistently across the other assessment time points.
  • With the exception of the improvement in the FACT-LymS of ≥ 5 points at month 12 of the maintenance phase, responder analyses for both assessment tools showed no statistically significant differences between the treatment arms.
• Side effects
  • The results from the data cut-off date of 10 September 2016 are used to assess safety.
  • An adverse event (AE) occurred in 99.7% of patients receiving the intervention and in 98% of patients receiving the control treatment.
  • Serious adverse events (SAEs) and severe AEs (NCI-CTCAE grade ≥ 3) occurred with statistically significant greater frequency in the G-Chemo arm than in the R-Chemo arm.
  • With regard to AEs of particular interest, a statistically significant difference was observed between G-Chemo and R-Chemo, with a disadvantage for the intervention in the incidence of infections, thrombocytopenia and cardiac events.
  • In summary, the endpoints relating to adverse events suggest a disadvantage for the medicinal product under evaluation in terms of side effects.
• Overall assessment
  • For the overall survival endpoint, the results show no statistically significant prolongation of overall survival in the intervention group compared with the control group in the GALLIUM trial.
  • However, the available survival data are derived from an unplanned interim analysis, should be regarded as immature and must therefore be interpreted with caution.
  • With regard to the effects of the treatments on health-related quality of life, no statistically significant differences were observed between the intervention group and the control group.
  • An overall assessment of side effects indicates a disadvantage for the medicinal product under evaluation. The disadvantages of the G-Chemo intervention predominate when considering severe AEs (NCI-CTCAE grade ≥ 3), severe SAEs (SAEs) and adverse events of particular interest.
  • Consequently, the G-BA assesses the extent of the additional benefit of obinutuzumab in combination with chemotherapy, followed by obinutuzumab maintenance therapy, as non-quantifiable on the basis of 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 the treatment of the disease.

Courtesy translation only, please refer to the German original.