Obinutuzumab (1) – Gazyvaro®

• Clinical trials
  • The CLL11 trial is a randomised, three-arm, open-label, phase III trial with a parallel-group design, which investigates the efficacy and safety of obinutuzumab in patients with chronic lymphocytic leukaemia.

adult patients with untreated chronic lymphocytic leukaemia (CLL) who, due to comorbidities, are not suitable for treatment with a full dose of fludarabine

• mortality
  • The secondary endpoint of overall survival was defined as the time (in months) between the day of randomisation and death (regardless of cause of death).
  • Overall survival in the intervention and control groups did not differ significantly at the time of the stage 2 analysis (GClb versus RClb) (HR = 0.66; 95% CI [0.41; 1.06]; p = 0.085).
  • A median survival time could not be determined in either the GClb arm or the RClb arm due to the minor number of deaths.
  • The scientific data therefore do not allow for a quantification of the extent of the additional benefit of obinutuzumab in terms of mortality.
  • The data on overall survival must be regarded as immature due to the short duration of the study compared with life expectancy.
  • Given the advanced age of the patient population in question and the associated non-disease-related, competing causes of death, as well as existing treatment options should further treatment be required, the probability that this endpoint will prove significant even in future data analyses is low.
• morbidity
  • In the CLL11 registration trial, progression-free survival (PFS) was assessed by two different bodies: the investigator and an independent, blinded expert committee (IRC).
  • To demonstrate additional benefit, the pharmaceutical manufacturer used IRC-assessed progression-free survival as the more objective measure, as it is assumed to have a minor potential for bias.
  • The secondary endpoint, IRC-assessed PFS, is defined as the time (in months) from randomisation to the occurrence of a PFS event.
  • PFS events are disease progression (evidence of progression or recurrence) according to IWCLL criteria or death (regardless of cause), whichever occurred first.
  • At the time of the stage 2 analysis, the median IRC-assessed PFS was 26.7 months in the GClb group versus 14.9 months in the RClb group (HR = 0.42; 95% CI [0.33; 0.54]; p < 0.001), corresponding to a difference of 11.8 months.
  • The endpoint ‘IRC-defined PFS’ is a composite endpoint comprising endpoints from the categories of mortality and morbidity.
  • The ‘mortality’ component of this endpoint is already assessed as a standalone endpoint via the secondary endpoint of overall survival.
  • Taking the aforementioned aspects into account, there are differing views within the G-BA regarding the clinical relevance of the IRC-defined PFS endpoint.
  • The endpoint ‘duration of absence of all B-symptoms’ is defined only for patients who exhibited at least one B-symptom at the time of inclusion in the study.
  • As this approach means the groups are no longer comparable, a high potential for bias must be assumed for this endpoint.
  • It is also unknown whether B-symptoms first appeared during treatment with GClb or RClb.
  • It is therefore not possible to make a statement on the extent of the additional benefit for this endpoint, even taking the commenting procedure into account.
• Health-related quality of life
  • The EORTC-QLQ-C30 questionnaire was used in the CLL11 study to assess quality of life and symptoms.
  • With regard to the health-related quality of life endpoint, there is no evidence of an advantage of obinutuzumab over rituximab, in each case in combination with chlorambucil.
  • No statistically significant differences were demonstrated for either the overall quality of life or the individual functional scales or symptom scales of the EORTC-QLQ-C30.
• Side effects
  • The overall rates of adverse events of CTCAE grade ≥ 3 were statistically significantly higher in the GClb group compared with the RClb group (69.9% versus 55.1%; RR: 1.27; 95% CI [1.12; 1.43]).
  • No significant differences were observed between the intervention group and the control group for the endpoints of adverse events, serious adverse events, CTCAE Grade 5 adverse events and therapy discontinuations due to adverse events.
  • Neutropenia occurred statistically significantly more frequently with obinutuzumab than with rituximab (42.0% versus 33.0%; RR: 1.27; 95% CI [1.04; 1.55]).
  • The proportion of patients with thrombocytopenia was statistically significantly higher in the GClb group than in the RClb group (15.8% versus 6.9%; RR: 2.30; 95% CI [1.43; 3.69]).
  • In most cases, patients with thrombocytopenia had risk factors such as anticoagulant therapy or a history of bleeding events.
  • No clear association between the occurrence of thrombocytopenia and haemorrhagic events could be established.
  • Infusion-related reactions (IRRs) occurred statistically significantly more frequently with obinutuzumab than with rituximab (65.8% versus 37.7%; RR: 1.74; 95% CI [1.49; 2.05]).
  • Whilst 65% of patients on obinutuzumab experienced an IRR at the first dose, the incidence was 3% at the second dose and only 1% for subsequent doses.
  • No tumour lysis syndrome occurred in the rituximab arm. Among patients receiving obinutuzumab, 14 (4.2%) developed tumour lysis syndrome.
  • With regard to the assessment of the side effect endpoint, whilst there are indications of a greater potential for harm with obinutuzumab compared with rituximab, there are uncertainties regarding the interpretation of this endpoint due to numerous protocol amendments designed to reduce side effects by intensifying premedication.
  • Overall, in the present case scenario, no conclusion can be drawn regarding the extent of the additional benefit in terms of side effects.
• Overall assessment
  • On balance, it is not possible, on the basis of the data presented, to carry out a quantitative assessment of the extent of the treatment effect or to quantify the additional benefit of obinutuzumab into one of the categories ‘minor’, ‘considerable’ or ‘major’.

Courtesy translation only, please refer to the German original.