Avapritinib (1) – Ayvakyt®

• Clinical trials
  • The NAVIGATOR trial is a single-arm, multicentre, international Phase I/II trial investigating avapritinib in 237 patients with GIST and other recurrent or refractory solid tumours.
  • The VOYAGER trial is a randomised Phase III trial investigating treatment with avapritinib compared with regorafenib in people with locally advanced, unresectable or metastatic GIST who have previously received imatinib and one or two other TKIs.

Adult patients with inoperable or metastatic gastrointestinal stromal tumours (GIST) who harbour the platelet-derived growth factor receptor alpha (PDGFRA) D842V mutation

• Hint for a non-quantifiable additional benefit, as the scientific evidence does not permit quantification
• The certainty of the evidence is assessed as a hint because only a single-arm study is available and a comparative assessment is not possible.
• Overall, there is a hint of a non-quantifiable additional benefit for avapritinib, as the scientific evidence does not permit quantification.
• Consequently, the G-BA classifies the extent of the additional benefit of avapritinib for the treatment of adult patients with inoperable or metastatic GIST who carry the thrombocyte growth factor receptor-alpha-D842V mutation, as non-quantifiable due to the limited data available, 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 condition.
• mortality
  • Overall survival is defined as the time from the start of study medication until the time of death or until the patient is censored.
  • As at the data cut-off date of 9 March 2020, following a median follow-up period of 25.5 months, 8 patients in the relevant patient population of the NAVIGATOR study had died (29%), meaning that the median survival time had not yet been reached.
  • In addition, results for the overall survival endpoint are also available from the final data cut-off on 29 January 2021, with a median follow-up period of 33.1 months. At the time of the data cut-off, 9 patients in the relevant patient population had died (32%).
  • Overall, however, the results of the NAVIGATOR study on the endpoint of overall survival do not allow any conclusions to be drawn regarding the extent of the additional benefit for the endpoint category of mortality, as no comparative data are available.
• morbidity
  • PFS was assessed as a secondary endpoint in the NAVIGATOR study and defined as the time from the start of treatment with avapritinib to the date of the first documented disease progression or death from any cause, whichever occurred first.
  • The median PFS was 24 months; no comparative data are available from the NAVIGATOR study.
  • The overall response rate (ORR) ORR) is a primary endpoint of the extension phase (Part II) of the NAVIGATOR study and is defined as the confirmed rate of complete response (CR) or partial response (PR).
  • There is no validation of this endpoint as a surrogate marker for patient-relevant endpoints. In this assessment, the overall response rate is presented only as supplementary information in the resolution.
• quality of life
  • No data are available for the quality of life endpoint category.
• Side effects
  • AE occurred in all study participants. The results are presented only as supplementary information.
  • Serious SAEs occurred in 75% of patients. The most common serious SAEs included ‘Gastrointestinal disorders (SOC)’ and ‘Infections and infestations (SOC)’.
  • Severe AEs (CTCAE grade ≥ 3) occurred in almost all patients (96%). The most common severe AEs included those under the SOCs ‘Blood and lymphatic system disorders’, ‘Investigations’, ‘Metabolism and nutrition disorders’ and ‘Gastrointestinal disorders’.
  • More than a third of patients (36%) discontinued avapritinib treatment due to AEs.
  • AE of particular interest included “cognitive effects” and “intracranial haemorrhages”. Cognitive effects occurred in 68% of patients. These included ‘cognitive impairment’, ‘impaired memory’ and ‘confusion’. ‘Intracranial haemorrhages’ occurred in 7% of patients.
  • Overall, based on the results of the NAVIGATOR study regarding adverse events, no conclusion can be drawn regarding the extent of the additional benefit for the endpoint category ‘side effects’, as no comparative data are available.
• Overall assessment
  • To assess the additional benefit of avapritinib for the treatment of adult patients with inoperable or metastatic gastrointestinal stromal tumours (GIST) harbouring the platelet-derived growth factor receptor alpha (‘Platelet-Derived Growth Factor Receptor Alpha’, PDGFRA) D842V mutation, the single-arm NAVIGATOR study (BLU-285-1101) is used as the basis.
  • Results from the NAVIGATOR study are available for patient-relevant endpoints in the categories of mortality and side effects.
  • However, a comparative assessment of the study results is not possible due to the single-arm design of the NAVIGATOR study.
  • The results of the VOYAGER study (BLU-285-1303) submitted by the pharmaceutical manufacturer for the benefit assessment are not used for the present benefit assessment, as the analyses of the VOYAGER study are deemed not to have been pre-specified.
  • Nor is the propensity score (PS)-adjusted indirect comparison between the NAVIGATOR study and the retrospective observational study BLU-285-1002 taken into account for the present benefit assessment. A key factor in this regard is, in particular, the choice of the starting point of the observation period for the event-time analysis in the external control group.
  • Consequently, it is not possible to carry out a quantitative assessment of the extent of the effect or to quantify the additional benefit on the basis of the data provided.

Courtesy translation only, please refer to the German original.