Avapritinib (4) – Ayvakyt®

Adults with indolent systemic mastocytosis (ISM) presenting with moderate to severe symptoms, in whom adequate control cannot be achieved with symptomatic treatment

• Hints of a minor additional benefit.
• The G-BA therefore classifies the extent of the additional benefit of avapritinib for the treatment of adults with indolent systemic mastocytosis (ISM) with moderate to severe symptoms, in whom adequate control cannot be achieved with symptomatic treatment, as minor.
• The certainty of the evidence is classified as ‘hint’. This is based on uncertainty regarding the implementation of the BSC in the PIONEER study, resulting from a restriction on glucocorticoid therapy during the course of the study.
• mortality
  • No deaths occurred in the second part of the PIONEER study.
• Morbidity – symptoms measured using the Indolent Systemic Mastocytosis Symptom Assessment Form (ISM-SAF)
  • For the ISM-SAF endpoint, a statistically significant difference in favour of avapritinib was observed in the skin domain. No statistically significant differences were observed between the study arms in the TSS or in the gastrointestinal and neurocognitive symptom domains.
  • Both the lead symptom and the lead domain showed a significant improvement in the mean difference in the avapritinib arm. The 95% confidence interval of the standardised mean difference (Hedges’ g) for the key domain lies outside the irrelevance threshold (-0.2 to 0.2), meaning that the effect is classified as clinically relevant. This is not the case for the primary symptom; consequently, it cannot be concluded with sufficient certainty that the observed effect for the primary symptom is clinically relevant.
• Morbidity – Patient Global Impression of Symptom Severity (PGIS)
  • For the PGIS, there is a statistically significant difference in favour of avapritinib.
• Morbidity – Patient Global Impression of Change (PGIC)
  • For the PGIC, there is no statistically significant difference between the study arms.
• Conclusion on the morbidity endpoint category
  • For the ISM-SAF endpoint, a statistically significant difference in favour of avapritinib was observed in the skin domain. No statistically significant differences were observed between the study arms in the TSS, or in the gastrointestinal and neurocognitive symptom domains.
  • Changes in individual symptoms are assessed by evaluating the individual lead symptom and lead domain using the ISM-SAF. The analysis of the individual lead domain shows a clinically relevant advantage for avapritinib.
  • Symptoms were also assessed using the PGIS, and health status using the EQ-5D VAS and PGIC. A statistically significant difference in favour of avapritinib was observed for both the PGIS and EQ-5D VAS endpoints. No statistically significant difference was observed between the study arms for the PGIC.
• Quality of life – Mastocytosis Quality of Life Questionnaire (MC-QoL)
  • For the MC-QoL endpoint, statistically significant differences in favour of avapritinib were observed in the overall score as well as in the domains of symptoms, emotions and social life/functional ability. In the skin domain, no statistically significant difference was observed between the study arms.
• Side effects – Serious AEs (SAEs). Severe AEs (CTCAE grade ≥ 3) and therapy discontinuations due to AEs
  • For the endpoints SAEs, severe AEs and therapy discontinuations due to AEs, no statistically significant difference was observed between the study arms in any case.
• Overall assessment
  • To assess the additional benefit of avapritinib for the treatment of adults with ISM with moderate to severe symptoms, in whom adequate control cannot be achieved with symptomatic treatment, the pharmaceutical manufacturer presents the results of the PIONEER study. In the completed, double-blind, randomised second part of the study, avapritinib was compared with placebo, in each case in combination with best supportive care (BSC), over 24 weeks. Results are available for the endpoint categories of mortality, morbidity, quality of life and side effects.
  • With regard to overall survival, no deaths occurred in either study arm. The available data therefore show no relevant difference.
  • In the morbidity endpoint category, results are available for symptoms (ISM-SAF, PGIS) and health status (EQ-5D VAS, PGIC).
  • For the ISM-SAF endpoint, a statistically significant difference in favour of avapritinib was observed in the skin domain. No statistically significant differences were observed between the study arms in the TSS or in the domains of gastrointestinal and neurocognitive symptoms.
  • Changes in individual symptoms are assessed by evaluating the individual lead symptom and lead domain using the ISM-SAF. The analysis of the individual lead domain reveals a clinically relevant advantage for avapritinib.
  • Symptoms were also assessed using the PGIS, and health status using the EQ-5D VAS and PGIC. Statistically significant differences in favour of avapritinib were observed in the PGIS and EQ-5D VAS. No statistically significant difference was observed between the study arms for the PGIC.
  • The advantages in the morbidity endpoint category are overall assessed as a moderate—and not merely minor—improvement in treatment-related benefit, which has not been achieved before.
  • In the quality of life endpoint category, results are available for the MC-QoL and the SF-12.
  • For the MC-QoL endpoint, statistically significant differences in favour of avapritinib were observed in the total score as well as in the domains of symptoms, emotions and social life/functionality. In the skin domain, no statistically significant difference was observed between the study arms.
  • For the PCS of the SF-12, a statistically significant difference was observed in favour of avapritinib. For the MCS of the SF-12, no statistically significant difference was observed between the study arms.
  • With regard to side effects, the results show no differences relevant to the assessment.
  • Overall, treatment with avapritinib compared with best supportive care shows a relevant improvement in skin symptoms, but not in other significant symptoms. Significant improvements were also observed in the quality of life endpoint category. Overall, these results are assessed as a significant improvement, which, in the overall assessment, justifies a minor additional benefit.

Courtesy translation only, please refer to the German original.