Gemtuzumab Ozogamicin (1) – Mylotarg®

• Clinical trials
  • The pivotal ALFA-0701 trial was taken into account to demonstrate additional benefit. The open-label, randomised and actively controlled trial was conducted between 2008 and 2013 at 26 French centres.

Patients aged 15 years and over with untreated, newly diagnosed CD33-positive acute myeloid leukaemia (AML), excluding acute promyelocytic leukaemia (APL)

• The G-BA assesses the extent of the additional benefit of gemtuzumab ozogamicin—which, from a purely legal perspective, is to be classified 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 treating 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
  • In the ALFA-0701 study, overall survival was defined as the time from randomisation to the patient’s death, regardless of the underlying cause of death.
  • In the registration trial, treatment with GO in combination with DNR and AraC did not result in a statistically significant prolongation of overall survival compared with treatment with DNR and AraC. The median overall survival was 27.5 months in the intervention arm and 21.8 months in the control arm.
  • Based on the results of the ALFA-0701 study, there is no additional benefit in the endpoint category of mortality.
• Morbidity – Relapse-free survival (RFS)
  • Recurrence-free survival was defined as the time between complete remission and recurrence or death from any cause, with recurrence defined as more than 5% blasts in the bone marrow, blasts in the blood count or evidence of extramedullary disease.
  • As the inclusion of only those patients who achieved complete remission following induction therapy constituted a breach of the initial randomisation, the results are potentially highly biased.
  • Recurrence-free survival was 9.6 months longer in the intervention arm than in the control arm (21.7 months vs. 12.1 months).
  • Given the curative intent of the treatment regimen used in the ALFA-0701 study (induction combined with consolidation) for the treatment of previously untreated acute myeloid leukaemia, relapses or relapse-free survival are patient-relevant endpoints indicating the failure of the primary therapeutic approach and thus the potential cure of the disease.
  • There are also uncertainties, as further therapeutic options are available to patients following relapse, including those with a curative intent. Thus, following the completion of the study medication, 71.1% (intervention arm) and 80.1% (control arm) of patients, respectively, received at least one follow-up treatment.
  • Consequently, the result for recurrence-free survival—which shows a statistically significant advantage for the intervention (hazard ratio (HR): 0.66 [95% confidence interval (CI): 0.47; 0.92]; p-value 0.0144), is used only as supplementary evidence in the overall assessment.
• Health-related quality of life
  • No data on health-related quality of life were collected in the ALFA-0701 study.
• Side effects
  • Side effects were recorded in the ALFA-0701 study using a predefined, non-exhaustive checklist. There was no open-ended survey of all events that occurred. Adverse events (AEs) classified as CTCAE Grade 1 and 2 were not considered at all.
  • Statistically significant disadvantages for the intervention arm were observed in a retrospective analysis of therapy discontinuations due to AEs (31.3% vs. 7.3%, RR: 4.29 [2.32; 8.92]; p-value < 0.0001), as well as with regard to serious adverse events (SAEs, 53.4% vs. 40.1%, RR: 1.33 [95% CI: 1.02; 1.74]; p-value 0.0313).
  • Severe adverse events with a CTCAE grade of ≥ 3 did not differ statistically significantly between the study arms with regard to the predefined AEs categories (RR: 1.06 [95% CI: 0.95; 1.17]; p-value 0.3121).
  • With regard to adverse events of particular interest, which were grouped under CTCAE grade ≥ 3, GO in combination with DNR and AraC showed exclusively disadvantages in the mucosal AE categories (16.0% vs. 6.6%, RR: 2.44 [95% CI: 1.18; 5.96]; p-value 0.0145), pain (14.5% vs. 3.6%, RR: 3.97 [95% CI: 1.61; 12.47]; p-value 0.0018) and haemorrhages (22.9% vs. 9.5%; RR: 2.41 [95% CI: 1.33; 4.45]; p-value 0.0044).
  • Given the exclusively negative effects, and taking into account the uncertainties mentioned, there is a disadvantage associated with GO in the endpoint category of side effects.
• Overall assessment
  • Results are available for the endpoint categories of mortality, morbidity and side effects for the comparison of GO in combination with DNR and AraC with the chemotherapy regimen of DNR and AraC.
  • No statistically significant prolongation of overall survival was observed in the ALFA-0701 study. Disadvantages in terms of adverse events are offset by positive effects on morbidity. However, there are significant uncertainties regarding data collection and interpretation.
  • Having weighed up the positive and negative effects, and taking into account the limited statistical power of the results as well as the lack of findings regarding quality of life, the G-BA, from a purely legal perspective pursuant to Section 35a(1), sentence 11, first clause of SGB V, determines that there is a non-quantifiable additional benefit of GO in combination with DNR and AraC.

Courtesy translation only, please refer to the German original.