Phase I Trial Shows “Exciting” Results With Avapritinib in Advanced Systemic Mastocytosis

The oral KIT D816V inhibitor avapritinib (formerly known as BLU-285) could provide an alternative treatment option for patients with advanced systemic mastocytosis (SM), including those whose disease progressed after treatment with midostaurin, according to results from an ongoing phase I trial presented as a plenary abstract at the 2017 ASH Annual Meeting.

“We are seeing a high rate of rapid and durable responses, with a very low rate of adverse side effects, in patients with an advanced or aggressive form of the disease,” said lead study author and presenter Daniel J. DeAngelo, MD, PhD, director of clinical and translational research at the Dana-Farber Cancer Institute in Boston, Massachusetts. “All patients had some response, which is really exciting in a phase I clinical trial.”

As of November 27, 2017 (data cutoff), 32 adult patients (median age = 63 years; range = 34-83 years) with SM (28 of whom had advanced SM per World Health Organization [WHO] diagnostic criteria) were evaluated in a 3+3 dose-escalation and -expansion design to establish the safety and maximum tolerated dose (MTD; primary endpoint) of avapritinib.

Twenty-eight patients had a KIT mutation (88%), and 14 had high-risk mutations, defined as one or more co-occurring mutations in the bone marrow (BM), the most frequent of which ASXL1, SRSF2, and RUNX1.

Most patients (n=22; 69%) had received a prior antineoplastic therapy, including four (13%) whose disease progressed after receiving midostaurin – the only U.S. Food and Drug Administration–approved treatment for SM.

Patients were treated in seven dosing cohorts ranging from 30 to 400 mg once-daily in four-week cycles.

Unlike the multikinase inhibitor midostaurin, which “hits a lot of targets and has some off-target toxicity,” Dr. DeAngelo explained to ASH Clinical News, avapritinib is a highly selective and highly potent inhibitor of KIT activation loop mutants, including D816V.

The specificity may have contributed to the low toxicity observed in this trial. “Thirty of 32 patients remain on study after a median treatment duration of nine months [range = 4-19 months], which is kind of unusual for patients in a phase I study,” he added. Two patients discontinued treatment because of progressive disease (acute myeloid leukemia) and investigator decision.

The most common non-hematologic adverse events (AEs) were:

  • periorbital edema (any-grade, n=19 [52%] and grade ≥3, n=2 [6%])
  • fatigue (any-grade, n=13 [41%] and grade ≥3, n=2 [6%])
  • peripheral edema (any-grade, n=11 [34%])

Hematologic AEs included:

  • anemia (any-grade, n=9 [28%] and grade ≥3, n=3 [9%])
  • thrombocytopenia (any-grade, n=9 [28%] and grade ≥3, n=2 [6%])
  • neutropenia (any-grade, n=4 [13%] and grade ≥3, n=4 [13%])

Overall, 16 patients (50%) experienced grade ≥3 AEs, and there were no deaths on study. “Most of the toxicities were lower-grade (grade 1 or 2) and were easily controlled with dose delays or reductions,” Dr. DeAngelo said.

No dose-limiting toxicities were observed and the MTD was not reached. Based on the results from the dose-escalation phase, the recommended phase II dose is avapritinib 300 mg once-daily.

Ten patients with advanced SM were excluded from the efficacy analysis for not meeting WHO diagnostic criteria, and 18 patients with advanced SM were evaluable for response (measured by International Working Group criteria).

The preliminary overall response rate was 72 percent, including two complete responses (11%), eight partial responses (44%), and three “clinical improvements” (17%). Seventeen of these patients remain on treatment.

“Avapritinib demonstrated significant clinical activity across all dose levels, with rapid and durable reductions in mast cell (MC) burden and D816V mutant allele fraction relative to baseline,” the authors noted (see TABLE).

They observed reductions in MC burden, and D816V mutant allele fraction were durable in 28 of the 30 patients who remain on study, seven of whom have completed one or more years of treatment. These observations occurred regardless of advanced SM subtype, prior therapy, concomitant mutations, and performance status. Marked reductions in MC burden were noted in two patients with mantle cell lymphoma whose disease had progressed on midostaurin and in two patients with advanced SM who were intolerant to midostaurin. These four patients are still on therapy at five, 12, seven, and 14 months, respectively.

In a secondary analysis of neoplastic activity among patients treated with avapritinib, all patients achieved at least a 50 percent reduction in serum tryptase levels from baseline. “[Serum tryptase] is a good marker of MC burden,” Dr. DeAngelo explained. “To our excitement, 60 percent of patients had complete remission with respect to their marrow disease.”

All 25 patients with splenomegaly at baseline also experienced a decrease in spleen volume, including 15 patients (60%) who achieved a reduction of at least 35 percent from baseline.

“The KIT D816V mutation is present in 90 percent of patients with advanced SM, and these data validate this as a key disease driver,” Dr. DeAngelo said. The data are preliminary, and safety and efficacy will need to be confirmed in dose-expansion cohorts, he noted. There are several planned investigations of avapritinib, including in indolent and smoldering SM.

The corresponding authors report receiving financial support from Bristol-Myers Squibb, Incyte, Immunogen, Blueprint Medicines, ARIAD, Shire, Glycomimetics, Celgene, Novartis Pharmaceuticals Corporation, Amgen, Pfizer Inc., and Takeda Pharmaceuticals U.S.A., Inc.


DeAngelo DJ, Quiery AT, Radia D, et al. Clinical activity in a phase 1 study of Blu-285, a potent, highly-selective inhibitor of KIT D816V in advanced systemic mastocytosis (AdvSM). Abstract #2. Presented at the 2017 American Society of Hematology Annual Meeting, Atlanta, GA, December 10, 2017.