EXPLORER
EXPLORER was the first human study of avapritinib, a pill designed to block the KIT D816V mutation that drives almost every case of advanced systemic mastocytosis; three quarters of evaluable patients responded and a third went into complete remission, and the drug was approved for the disease in 2021.
Overview
EXPLORER was a phase 1 dose-escalation and expansion study of avapritinib (BLU-285), a selective inhibitor of KIT D816V, in 86 patients with advanced systemic mastocytosis or relapsed myeloid malignancies, 69 of whom had centrally confirmed advanced systemic mastocytosis. The primary endpoints were the maximum tolerated dose, the recommended phase 2 dose and safety; response rate and measures of mast cell burden were secondary.
The maximum tolerated dose was not reached and 200 mg and 300 mg daily were studied in expansion. Among 53 response-evaluable patients the overall response rate was 75 percent with a complete remission rate of 36 percent, and avapritinib halved marrow mast cells and serum tryptase in almost every patient. Periorbital oedema, anaemia, diarrhoea and thrombocytopenia were the common adverse events; intracranial bleeding occurred in 13 percent overall but in 1 percent of patients without severe thrombocytopenia, which is why the label requires a platelet count of 50 x 10^9/L or more. Together with the phase 2 PATHFINDER trial it supported approval of avapritinib for advanced systemic mastocytosis in the United States in June 2021.
- 75 out of 100 people had their tumour shrink with Avapritinib 30 to 400 mg daily.
- There was no comparison group, so this number cannot tell you how much of the effect is due to the treatment.
- A response rate counts how many people had their tumours shrink by a set amount; shrinking is encouraging but does not by itself show that people live longer or feel better.
- 36 out of 100 people had no sign of cancer on scans or tests with Avapritinib 30 to 400 mg daily.
- There was no comparison group, so this number cannot tell you how much of the effect is due to the treatment.
- This is a surrogate endpoint: it measures the cancer being controlled or absent on scans and tests, which often, but not always, translates into living longer.
- 99 out of 100 people reached this endpoint with Avapritinib 30 to 400 mg daily.
- There was no comparison group, so this number cannot tell you how much of the effect is due to the treatment.
- This endpoint is not one of the standard survival or response measures; read it alongside the trial's primary result.
- 13 vs 1 out of 100 reached this endpoint with Avapritinib, all patients compared with Avapritinib, patients without severe thrombocytopenia; 12 more per 100.
- Roughly one extra person helped for every 8 treated. That is a rough figure taken from the two percentages, not a guarantee for any one person.
- This endpoint is not one of the standard survival or response measures; read it alongside the trial's primary result.
- 69 out of 100 people reached this endpoint with Avapritinib 30 to 400 mg daily.
- There was no comparison group, so this number cannot tell you how much of the effect is due to the treatment.
- This endpoint is not one of the standard survival or response measures; read it alongside the trial's primary result.
- These results apply to the people the trial enrolled: Advanced systemic mastocytosis (aggressive systemic mastocytosis, mastocytosis with an associated haematological neoplasm, mast cell leukaemia) and relapsed myeloid malignancies: first-in-human dose escalation and expansion of the selective KIT D816V inhibitor avapritinib at 30 to 400 mg daily. People in a different situation may not see the same effect.
- Only 86 people took part, so the numbers are less certain than in a large trial.
Numbers are from the trial as recorded here; see the source links in the table below. This is orientation, not medical advice: ask your team how closely the trial population matches you.
86 enrolled.
| Endpoint | Arm | n | Value | HR (95% CI) | p | Source |
|---|---|---|---|---|---|---|
| Overall response rate (response-evaluable advanced systemic mastocytosis) | Avapritinib 30 to 400 mg daily | 53 | 75% | - | - | link |
| Complete remission rate (response-evaluable advanced systemic mastocytosis) | Avapritinib 30 to 400 mg daily | 53 | 36% | - | - | link |
| Reduction of 50% or more in serum tryptase | Avapritinib 30 to 400 mg daily | - | 99% | - | - | link |
| Intracranial bleeding | Avapritinib, all patients | 86 | 13% | - | - | link |
| Avapritinib, patients without severe thrombocytopenia | - | 1% | ||||
| Periorbital oedema (any grade) | Avapritinib 30 to 400 mg daily | 86 | 69% | - | - | link |
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