Inotuzumab ozogamicin (1) – Besponsa®

Adults with relapsed or refractory CD22-positive B-precursor ALL (acute lymphoblastic leukaemia) and adults with Philadelphia chromosome-positive (Ph+) relapsed or refractory B-progenitor ALL, who have previously undergone unsuccessful treatment with at least one tyrosine kinase inhibitor

• In summary, the additional benefit of inotuzumab ozogamicin is assessed as follows: for adult patients with relapsed or refractory CD22-positive B-precursor ALL (acute lymphoblastic leukaemia) and adults with Philadelphia chromosome-positive (Ph+) relapsed or refractory B-precursor ALL who have previously undergone unsuccessful treatment with at least one tyrosine kinase inhibitor, there is a minor additional benefit.
• The G-BA therefore classifies the extent of the additional benefit of inotuzumab ozogamicin as minor, based on 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 treating the disease.
• mortality
  • In the INO-VATE ALL trial, overall survival was defined as the time from randomisation to death from any cause.
  • Treatment with inotuzumab ozogamicin results in a statistically significant advantage in overall survival compared with chemotherapy (hazard ratio (HR) 0.75; 97.5% confidence interval (CI) [0.57; 0.99]; p = 0.011).
  • The median survival time for patients in the inotuzumab ozogamicin arm was 7.7 months, which was 1.5 months longer than the 6.2 months observed in the control arm.
  • Overall, treatment with inotuzumab ozogamicin results in an advantage in overall survival compared with chemotherapy. The prolongation in survival achieved is considered a relevant improvement rather than a merely minor one.
• Morbidity – Complete remission (CR, CR/CRi)
  • The results for the combined endpoint comprising complete remission (CR) and complete remission with incomplete haematological recovery (CRi) show a statistically significant advantage for treatment with inotuzumab ozogamicin.
  • It is evident that 88 patients (80.7%) achieved CR/CRi whilst receiving inotuzumab ozogamicin. This compares with 32 patients (29.4%) in the chemotherapy arm. There is a statistically significant advantage for inotuzumab ozogamicin (difference in CR/CRi rate (%) 51.4; 97.5% CI [38.4; 64.3]; p < 0.001).
  • The CR endpoint is an important prognostic factor and is relevant to treatment decisions. A CR associated with a reduction in disease symptoms that is noticeable to the patient is, in principle, relevant to the benefit assessment.
  • The endpoints were therefore assessed not on the basis of symptoms, but on the basis of laboratory tests.
  • There is no validation of CR as a surrogate parameter for patient-relevant endpoints, e.g. mortality. Furthermore, it is unclear whether achieving CRi has comparable clinical relevance to achieving CR. The endpoints CR and CR/CRi are therefore classified in this assessment as endpoints of unclear relevance and are presented only as supplementary information. No conclusion can be drawn regarding the extent of the additional benefit.
• quality of life
  • Health-related quality of life was assessed using the EORTC QLQ-C30, based on the scale for general health status/quality of life, the functional scales and the question on financial hardship.
  • The response rates for the EORTC QLQ-C30 used to assess health-related quality of life are comparable to those for the symptom scales of the EORTC QLQ-C30. For this reason, the results for health-related quality of life are, in line with the comments in the ‘Symptoms’ section, not considered usable overall.
• Side effects – Serious adverse events (SAEs), severe adverse events (CTCAE grade ≥ 3) and therapy discontinuation due to adverse events
  • Adverse events (AEs) occurred in almost all patients. No differences were observed between the treatment arms with regard to SAE and AEs leading to therapy discontinuation.
  • For severe AEs, there was a statistically significant difference between the treatment arms (HR 0.74; 95% CI [0.59; 0.94]; p = 0.01), with an advantage favouring treatment with inotuzumab ozogamicin. Severe AEs occurred in 90.9% of patients in the inotuzumab ozogamicin arm and in 96.5% of patients in the chemotherapy arm.
• Overall assessment
  • Compared with chemotherapy, inotuzumab ozogamicin results in a 1.5-month prolongation of median survival (7.7 months vs. 6.2 months), thereby achieving a significant prolongation of overall survival.
  • No meaningful data are available for either the morbidity endpoint category or the health-related quality of life, as information was not available for a high proportion of patients at the early analysis time points. It is therefore not possible to assess the impact of inotuzumab ozogamicin on disease-specific symptoms and health-related quality of life. Findings regarding quality of life and morbidity are considered particularly important in the present treatment context.
  • With regard to side effects, inotuzumab ozogamicin leads to a reduction in severe adverse events (CTCAE grade ≥ 3) as well as in the incidence of febrile neutropenia and hospitalisations compared with chemotherapy.
  • The only disadvantages of inotuzumab ozogamicin compared with chemotherapy relate to the occurrence of potential venous occlusive liver disease (VOD)/sinusoidal obstruction syndrome (SOS).
  • Overall, the positive effects outweigh the side effects, meaning that an advantage of treatment with inotuzumab ozogamicin over chemotherapy is identified.
  • In summary, a moderate—and not merely minor—improvement in treatment-related benefit, which has not been achieved previously, is observed, as a significant prolongation of survival and a significant reduction in side effects are achieved. However, uncertainties remain due to the lack of meaningful data on morbidity and quality of life.

Courtesy translation only, please refer to the German original.