TY - JOUR
T1 - Safety and efficacy of avapritinib in advanced systemic mastocytosis
T2 - the phase 1 EXPLORER trial
AU - DeAngelo, Daniel J.
AU - Radia, Deepti H.
AU - George, Tracy I.
AU - Robinson, William A.
AU - Quiery, Albert T.
AU - Drummond, Mark W.
AU - Bose, Prithviraj
AU - Hexner, Elizabeth O.
AU - Winton, Elliott F.
AU - Horny, Hans Peter
AU - Tugnait, Meera
AU - Schmidt-Kittler, Oleg
AU - Evans, Erica K.
AU - Lin, Hui Min
AU - Mar, Brenton G.
AU - Verstovsek, Srdan
AU - Deininger, Michael W.
AU - Gotlib, Jason
N1 - Publisher Copyright:
© 2021, The Author(s).
PY - 2021/12
Y1 - 2021/12
N2 - Advanced systemic mastocytosis (AdvSM) is a rare hematologic neoplasm driven by the KIT D816V mutation and associated with poor survival. This phase 1 study (NCT02561988) evaluated avapritinib (BLU-285), a selective KIT D816V inhibitor, in patients with AdvSM. The primary endpoints were the maximum tolerated dose, recommended phase 2 dose and safety of avapritinib. Secondary endpoints included overall response rate and changes in measures of mast cell burden. Avapritinib was evaluated at doses of 30–400 mg once daily in 86 patients, 69 with centrally confirmed AdvSM. Maximum tolerated dose was not reached, and 200 mg and 300 mg daily were studied in dose-expansion cohorts. The most frequent adverse events observed were periorbital edema (69%), anemia (55%), diarrhea (45%), thrombocytopenia (44%) and nausea (44%). Intracranial bleeding occurred in 13% overall, but in only 1% of patients without severe thrombocytopenia (platelets <50 × 109/l). In 53 response-evaluable patients, the overall response rate was 75%. The complete remission rate was 36%. Avapritinib elicited ≥50% reductions in marrow mast cells and serum tryptase in 92% and 99% of patients, respectively. Avapritinib induced deep and durable responses, including molecular remission of KIT D816V in patients with AdvSM, and was well tolerated at the recommended phase 2 dose of 200 mg daily.
AB - Advanced systemic mastocytosis (AdvSM) is a rare hematologic neoplasm driven by the KIT D816V mutation and associated with poor survival. This phase 1 study (NCT02561988) evaluated avapritinib (BLU-285), a selective KIT D816V inhibitor, in patients with AdvSM. The primary endpoints were the maximum tolerated dose, recommended phase 2 dose and safety of avapritinib. Secondary endpoints included overall response rate and changes in measures of mast cell burden. Avapritinib was evaluated at doses of 30–400 mg once daily in 86 patients, 69 with centrally confirmed AdvSM. Maximum tolerated dose was not reached, and 200 mg and 300 mg daily were studied in dose-expansion cohorts. The most frequent adverse events observed were periorbital edema (69%), anemia (55%), diarrhea (45%), thrombocytopenia (44%) and nausea (44%). Intracranial bleeding occurred in 13% overall, but in only 1% of patients without severe thrombocytopenia (platelets <50 × 109/l). In 53 response-evaluable patients, the overall response rate was 75%. The complete remission rate was 36%. Avapritinib elicited ≥50% reductions in marrow mast cells and serum tryptase in 92% and 99% of patients, respectively. Avapritinib induced deep and durable responses, including molecular remission of KIT D816V in patients with AdvSM, and was well tolerated at the recommended phase 2 dose of 200 mg daily.
UR - http://www.scopus.com/inward/record.url?scp=85120695709&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85120695709&partnerID=8YFLogxK
U2 - 10.1038/s41591-021-01538-9
DO - 10.1038/s41591-021-01538-9
M3 - Article
C2 - 34873347
AN - SCOPUS:85120695709
SN - 1078-8956
VL - 27
SP - 2183
EP - 2191
JO - Nature medicine
JF - Nature medicine
IS - 12
ER -