Avelumab (4) – Bavencio®

• Clinical trials
  • For the benefit assessment, the pharmaceutical manufacturer has submitted the results of the open-label, randomised, controlled JAVELIN Bladder 100 trial comparing avelumab plus best supportive care (BSC) with BSC alone.

Adults with locally advanced or metastatic urothelial carcinoma who are progression-free following platinum-based chemotherapy; first-line maintenance therapy

• Consequently, the G-BA has determined that there is a hint of considerable additional benefit for avelumab compared with the appropriate comparator therapy.
• Due to relevant uncertainties, the certainty of the evidence for the established additional benefit is classified overall as ‘hint’.
• mortality
  • In the JAVELIN Bladder 100 trial, overall survival was defined as the time from randomisation to death from any cause.
  • For the endpoint of overall survival, treatment with avelumab + BSC resulted in a significant prolongation of overall survival compared with BSC alone.
  • The extent of the prolongation in overall survival achieved is assessed as a marked improvement.
• Morbidity – Progression-free survival
  • Radiological progression-free survival (PFS) was defined in the JAVELIN Bladder 100 study as the time to the first documented disease progression or to death, regardless of the underlying cause of death.
  • The results show a statistically significant prolongation of PFS with treatment with avelumab + BSC compared with BSC.
  • The morbidity component was not assessed on the basis of symptoms, but exclusively by means of imaging procedures (radiologically determined disease progression according to the RECIST criteria).
  • Taking the above aspects into account, there are differing views within the G-BA regarding the clinical relevance of the PFS endpoint to patients.
• Morbidity – Symptoms (NFB1SI-18)
  • The ‘NCCN/FACT Bladder Symptom Index-18’ (NFB1SI-18) forms part of the FACT questionnaire system and assesses symptoms in patients with bladder cancer.
  • The two subscales, ‘Disease-related Symptoms – Physical’ (DRS-P) and ‘Treatment Side Effects’ (TSE), can be categorised under symptoms.
  • Overall, there are no significant differences in morbidity between the treatment groups.
• Morbidity – Health Status (EQ-5D VAS)
  • In the JAVELIN Bladder 100 study, health status was assessed using the visual analogue scale (VAS) of the EQ-5D questionnaire.
  • The results show no statistically significant difference between the treatment groups.
• quality of life
  • To assess quality of life, the pharmaceutical manufacturer presents the ‘NCCN/FACT Bladder Symptom Index-18’ (NFB1SI-18); however, this is not suitable for measuring health-related quality of life.
  • As no other instruments for assessing health-related quality of life were used in the JAVELIN Bladder 100 study, there are no suitable data available for this endpoint category to assess the additional benefit.
• Side effects – Adverse events
  • The results for the endpoint ‘Total Adverse Events’ are presented for supplementary purposes only.
  • In the JAVELIN Bladder 100 study, 98.3% of patients in the intervention arm and 78.8% of patients in the comparator arm experienced an adverse event.
• Side effects – serious AEs
  • No statistically significant difference was observed between the two treatment arms with regard to serious adverse events.
• Side effects – Severe AEs (CTCAE grade ≥ 3)
  • With regard to the time to onset of severe adverse events with a CTCAE grade of ≥ 3, a statistically significant difference was observed between the treatment arms, with a disadvantage for avelumab + BSC.
• Side effects – Discontinuation due to AEs
  • No usable data are available on therapy discontinuation due to an AE.
• Side effects – Specific AEs
  • A detailed analysis of specific AE reveals the following for the specific AE ‘hypothyroidism’ (PT, AE), ‘gastrointestinal disorders’ (SOC, AE), ‘infections and infestations’ (SOC, AE), ‘arthralgia’ (PT, AE), ‘respiratory, thoracic and mediastinal disorders’ (SOC, AE), ‘skin and subcutaneous tissue disorders’ (SOC, AE) ‘Elevated lipase’ (PT, severe AEs), ‘Elevated amylase’ (PT, severe AEs), ‘Metabolic and nutritional disorders’ (SOC, severe AEs), in each case a statistically significant disadvantage for avelumab + BSC.
  • For the endpoint ‘Benign, malignant and unspecified neoplasms, including cysts and polyps’ (SOC, severe AEs), there was a statistically significant advantage for avelumab + BSC compared with BSC.
  • No usable data are available for the endpoint ‘Infusion-related reactions’.
  • For the endpoint ‘Immune-mediated severe adverse events’, there was a statistically significant difference between the treatment groups in favor of avelumab + BSC, with a disadvantage for avelumab.
  • In the overall assessment of the side effect endpoints, avelumab shows statistically significant disadvantages for the endpoint ‘severe AEs’ and, in detail, predominantly for the specific AEs.
  • Overall, a disadvantage for treatment with avelumab + BSC compared with BSC is observed in the area of adverse events.
• Overall assessment
  • For the overall survival endpoint, there is a statistically significant advantage of avelumab, the extent of which is assessed as a marked improvement.
  • In the morbidity endpoint category, no differences relevant to the benefit assessment are evident.
  • No suitable data are available regarding health-related quality of life.
  • In the side effects category, there are overall disadvantages for avelumab in terms of severe AEs, and, in detail, predominantly also for specific AEs.
  • An overall review of the available results shows a marked improvement in overall survival. With regard to disease symptoms, there is neither an advantage nor a disadvantage for avelumab. No suitable data on health-related quality of life are available. With regard to side effects, disadvantages are evident for serious AEs, and, in detail, predominantly also for specific AEs. However, the extent of these disadvantages is not considered so severe as to justify a downgrading of the extent of the additional benefit in the overall assessment.
  • Consequently, a considerable additional benefit is identified for avelumab plus best supportive care compared with best supportive care alone.

Courtesy translation only, please refer to the German original.