Tsewang Tashi, MD, discusses long-term avapritinib data in indolent systemic mastocytosis from part 3 of the PIONEER trial.
Long-term data position avapritinib (Ayvakit) as a favorable treatment option for patients with indolent systemic mastocytosis (SM), supporting the continued use of this agent, which was
In part 3 of the phase 2 PIONEER trial (NCT03731260), data from which were presented at the
PIONEER: Avapritinib Showed Durable Findings at Over 2 Years of Follow-Up in Indolent SM
“Going forward, it will be important to see whether we can identify which patients might benefit from 50 mg and which will benefit from staying on 25 mg,” Tashi, a hematologist/oncologist at the University of Utah Huntsman Cancer Institute in Salt Lake City, said in an interview with OncLive®.
In the interview, Tashi dove into the long-term efficacy and safety data from part 3 of the PIONEER trial on a granular level, noting how these data will affect the current and future state of KIT inhibitor–based indolent SM treatments.
Tashi: The PIONEER trial was the first trial to be conducted for patients with indolent SM using selective KIT inhibitors. Prior to [the PIONEER trial], there were no effective treatments [for indolent SM].
The PIONEER study was designed as different parts: parts 1, 2, and 3.2 Part 1 was a dose-finding phase where patients were randomly assigned to receive different dose levels [of avapritinib or] a placebo. The optimal dose was determined based on [findings from] part 1.
In part 2 of the trial, patients were randomly assigned between the optimal dose and placebo. Patients were blinded for 24 weeks, which was the primary duration of part 2. After that, patients were unblinded, and those who were in the placebo arm went on to receive avapritinib in part 3.
The main finding from the 24-week part 2 of the PIONEER study, data from which were published in 2023, was that there was a substantial improvement in the primary end point, which was symptom improvement. Patients who received avapritinib [in part 2] had a TSS reduction of [15.6] points [95% CI, –18.6 to –12.6] compared with [9.2] points [95% CI, –13.1 to –5.2] for patients who were randomly assigned to receive placebo.4 [There were also] significant reductions in objective markers for [indolent SM], including serum tryptase levels, KIT mutation variant allele frequency, and bone marrow mast cell burden; all [these] had substantial decreases with avapritinib compared with placebo. Based on these impressive data, the FDA approved avapritinib for indolent SM, and the optimal dose chosen was 25 mg. The protocol allowed an increase [of avapritinib] to 50 mg in part 3 of the trial if patients had higher burden of disease or if symptoms were not well controlled at 25 mg.
It now has been 2 additional years since the 24-week [part 2] PIONEER study data were published in 2023. Part 3 is still ongoing, and the total study time [has been approximately] 5 years for the patients. The data we presented at ASH 2025 were long-term efficacy at a median follow-up of 3 years.
These long-term follow up data show that the symptom improvement [with avapritinib] in patients is deep and sustained even at 2 or 3 years. Patients [who received the agent] experienced TSS improvements of [–17.51 (SD, 22.25)] and [–19.39] points, at 2 and 3 years, respectively, [compared with baseline; these findings are] comparable with what patients had achieved at 24 weeks.2 These data show that avapritinib is good at keeping sustained responses in symptom improvement for these patients.
The safety findings were also consistent with what we has already presented in the 24-week manuscript. The main adverse effects [AEs] associated with avapritinib [in part 3] were peripheral edema and periorbital edema. The rest of the AEs were similar to [those seen in] the placebo arm. There were no new safety signals or concerns, no cases of intracranial bleeds, and no cases of liver abnormalities or any other lab abnormalities.
One-third of patients [who received avapritinib] in part 3 of PIONEER had doses increased to 50 mg. Even in those patients, there was no new safety signals. All the safety signals, AEs, and toxicities were consistent with what we already know. Peripheral edema was seen a bit more at 50 mg but was never bad enough that patients had to discontinue treatment.
These long-term data show that avapritinib is good in sustaining responses in the long term. Thirty percent of patients had to increase dosages to 50 mg, and it will be interesting to see the different responses with either 25 mg or 50 mg.
