Avapritinib (3) – Ayvakyt®

• Clinical trials
  • PIONEER is an ongoing Phase II trial divided into three parts.
  • The second part of the trial comprises the double-blind, randomised phase in which avapritinib was compared with placebo, in each case in combination with best supportive care (BSC), over a period of 24 weeks.

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

• Indication 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.
• Overall, the level of evidence is classified as ‘indication’.
• 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)
  • The responder analysis of the ISM-SAF shows a statistically significant difference in the skin domain symptom score in favour of avapritinib.
  • The ISM-SAF total score, as well as the ‘gastrointestinal symptoms’ and ‘neurocognitive symptom cluster’ domains, show no statistically significant differences between the treatment arms.
  • Both the lead symptom and the lead domain show a significant improvement in the mean difference in the avapritinib arm.
  • The 95% confidence interval of the standardised mean difference (Hedges’ g) for the lead 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; therefore, 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)/Patient Global Impression of Change (PGIC)
  • For the PGIS, there is a statistically significant advantage for avapritinib.
  • For the PGIC, there is no statistically significant difference between the two treatment arms.
• Morbidity – Health Status (EQ-5D VAS) (visual analogue scale of the European Quality of Life Questionnaire – 5 Dimensions)
  • The responder analysis of the EQ-5D VAS shows a statistically significant effect in favour of avapritinib.
• Conclusion on the morbidity endpoint category
  • An overall analysis of the endpoints relating to symptoms and health status suggests an overall advantage for avapritinib.
  • The responder analysis for the ISM-SAF endpoint indicates an advantage with regard to skin symptoms. However, the responder analysis shows no improvements in the other domains or in the overall score.
  • The improvement in symptoms for each individual patient is captured by the assessment of the individual lead symptom and the lead domain of the ISM-SAF. However, only the lead domain shows an effect size of clinical relevance.
  • The PGIS and the EQ-5D VAS were assessed as further endpoints in the morbidity category; a significant advantage for avapritinib was observed for both endpoints.
• Health-related quality of life – Short Form-12 Health Survey Version 2 (SF-12)
  • The responder analysis of the SF-12 shows a statistically significant effect in favour of avapritinib for the PCS. No significant difference was observed for the MCS.
• Health-related quality of life – Mastocytosis Quality of Life Questionnaire (MC-QoL)
  • A statistically significant advantage for avapritinib is observed in terms of the mean differences for both the total score and the domain scores.
  • However, the 95% confidence interval for the standardised mean difference (Hedges’ g) lies within the irrelevance threshold (-0.2 to 0.2), meaning it cannot be concluded with sufficient certainty that the observed effect is clinically relevant.
• Conclusion on the ‘health-related quality of life’ endpoint category
  • Results from the SF-12 and the MC-QoL are available for the health-related quality of life endpoint category. The Physical Component Summary of the SF-12 endpoint shows an advantage for avapritinib. Given the differences observed in the MC-QoL, it cannot be concluded with sufficient certainty that the observed effect is clinically relevant.
• Side effects – Total adverse events (AEs)
  • Adverse events (AEs) occurred in almost all study participants.
• Side effects – serious AEs (SAEs), severe AEs (CTCAE grade ≥ 3) and therapy discontinuations due to AEs
  • There were no statistically significant differences between the treatment arms for SAEs, severe AEs (CTCAE grade ≥ 3) and therapy discontinuations due to AEs.
• Overall assessment
  • Results from the double-blind, randomised comparison with best supportive care in the PIONEER trial are available for the assessment of the additional benefit of avapritinib across the endpoint categories of mortality, morbidity, health-related quality of life and side effects.
  • With regard to overall survival, no deaths occurred in either treatment arm. The available data therefore show no relevant difference.
  • In the morbidity endpoint category, results are available on patient-reported symptoms (ISM-SAF, PGIS) and health status (EQ-5D VAS).
  • The results of the responder analysis of the ISM-SAF show a clinically relevant advantage for treatment with avapritinib in terms of skin symptoms. However, no difference was observed with regard to other relevant symptoms in the gastrointestinal and neurocognitive domains. In the analysis of the individual key domain, avapritinib demonstrates a clinically relevant advantage.
  • An advantage of treatment with avapritinib is also evident in the PGIS and EQ-5D VAS endpoints.
  • The advantages in the morbidity endpoint category are, on the whole, assessed as a moderate – and not merely minor – improvement in treatment-related benefit that has not been achieved before.
  • For the health-related quality of life endpoint category, results from the SF-12 and the MC-QoL are available. The Physical Component Summary of the SF-12 endpoint shows an advantage for avapritinib. Given the differences observed in the MC-QoL, it cannot be concluded with sufficient certainty that the observed effect is clinically relevant.
  • 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. Therefore, these results are assessed overall as a relevant improvement in symptoms, which, in the overall assessment, justifies a minor but not a considerable additional benefit. This assessment of the extent of the additional benefit is also supported by the results on health-related quality of life.

Courtesy translation only, please refer to the German original.