Safety and efficacy of avapritinib in advanced systemic mastocytosis: the phase 1 EXPLORER trial

Abstract

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.

Midostaurin therapy for advanced systemic mastocytosis: Mayo Clinic experience in 33 consecutive cases

“…Interim analysis of an ongoing phase 2 trial of avapritinib in adv‐SM ( n = 62) was recently communicated with an OR rate of 75% in 32 response‐evaluable patients (19% with CR with full or partial hematologic recovery) 7 ; a >50% reduction in BM MCs, serum tryptase level, and KIT D816V allele burden were reported in 88%, 93% and 60% of patients, respectively; adverse events included grade ≥3 neutropenia (24%), thrombocytopenia (16%), and any grade periorbital edema (45%), peripheral edema (42%), diarrhea (11%), and vomiting (10%). Of concern, cognitive impairment and intracranial bleeding were reported in 11% and 2% of patients, respectively, as was also the case in an accompanying report of a phase‐1 trial of avapritinib where the corresponding incidence rates were 30% and 13%, among 69 patients with adv‐SM 16 …”

“…Of concern, cognitive impairment and intracranial bleeding were reported in 11% and 2% of patients, respectively, as was also the case in an accompanying report of a phase-1 trial of avapritinib where the corresponding incidence rates were 30% and 13%, among 69 patients with adv-SM. 16 It is important to note that the above-discussed three treatment options have not been compared head-to-head and one should not rely on retrospective comparisons, which are marred by differences in patient selection and research methodology, including the application of different response criteria. At the same time, we are enamored by the possibility of deeper anti-clonal activity from avapritinib therapy, while being fully aware of substantial drug toxicity, as outlined above.…”

Superior Efficacy of Midostaurin Over Cladribine in Advanced Systemic Mastocytosis: A Registry-Based Analysis

“…The serial measurement of (minimal/measurable) residual disease through high-sensitivity assays such as quantitative real-time polymerase chain reaction or digital-droplet polymerase chain reaction and reported either as relative reduction of the allele burden at certain time points or as absence (below detection level) of the mutation in terms of complete molecular remission may become as relevant and recommendable as it is already in practice in many other hematologic neoplasms. Within the phase-I trial (EXPLORER, NCT02561988 50 ) and an interim analysis of the phase-II clinical trial (PATHFINDER, NCT03580655 51 ), avapritinib, a highly selective KIT inhibitor, produced an ORR of approximately 75% according to IWG-MRT-ECNM criteria including marked responses in BM MC burden, serum tryptase, and splenomegaly. In addition, molecular remissions with KIT D816V variant allele frequency < 1% were reported in 30% (in BM) and 35% (in peripheral blood) of patients with AdvSM, respectively.…”

“…Some patients exhibit mutations in the juxtamembrane region of KIT . c On the basis of results from EXPLORER 49 and PATHFINDER 50 trials. Before and during treatment with avapritinib, the platelet count should be > 50 × 10 9 /L to mitigate the potential for intracranial bleeding.…”

How I diagnose and treat chronic myelomonocytic leukemia

“…SM-CMML patients have several exciting KIT-directed targeted therapies for the SM component (e.g. midostaurin and avapritinib) and given that in SM-CMML, neoplastic monocytes are also often KIT mutated 57 , these drugs can sometimes effectively decrease monocyte counts and infiltrative disease burden 58 . JAK2V617F mutant CMML usually gives rise to a pCMML subtype with higher hemoglobin levels and AMC, with monocyte repartitioning by flow being a useful tool to distinguish this entity from MPN with monocytosis 59 .…”