Avapritinib Leads a Charge of Novel Targeted Therapies for Indolent Systemic Mastocytosis

Tsewang Tashi, MD

Targeted therapies have revolutionized treatment patterns for patients with symptomatic indolent systemic mastocytosis, according to Tsewang Tashi, MD, who emphasized that the KIT inhibitor avapritinib (Ayvakit) has become a mainstay in the treatment paradigm due to its ability to improve patient symptoms and its tolerable safety profile at low indicated doses.

Avapritinib was FDA approved in 2023 for the treatment of adult patients with indolent systemic mastocytosis.1 In the pivotal phase 2 PIONEER trial (NCT03731260), among patients with indolent systemic mastocytosis and moderate-to-severe symptom burden despite prior treatment with best supportive care (BSC), the mean change in total symptom score at 24 weeks significantly favored the arm of patients who received avapritinib in addition to BSC (n = 141) compared with the arm of those who received placebo plus BSC (n = 71; P = .003).2

“With these improved therapy options, it's important to correctly diagnose these patients in the first place,” Tashi said in an interview with OncLive®.

In the interview, Tashi discussed the efficacy and tolerability benefits of targeted therapies like avapritinib for patients with indolent systemic mastocytosis, factors to consider before treating patients with avapritinib, and future directions for targeted therapy development in this disease.

Tashi is an associate professor in the Division of Hematology & Hematologic Malignancies at the Huntsman Cancer Institute at the University of Utah in Salt Lake City.

OncLive: How has the emergence and development of targeted therapies affected the indolent systemic mastocytosis treatment paradigm?

Tashi: [Targeted therapy] is a big step forward in this disease field. [Indolent systemic mastocytosis is] no longer the orphan disease [we considered it to be] in the past with no effective treatments. We can now provide better and more effective treatment [that is associated] with fewer adverse effects [AEs] and is more tolerable to the patients [than treatment options that were available historically]. For patients, [targeted therapies] also come with a sense of validation that we can now offer treatments that will effectively address and improve their years of enduring symptoms, frustration, and helplessness. That is a positive step in this field.

What is the role of avapritinib in indolent systemic mastocytosis?

In patients with indolent systemic mastocytosis, the symptoms [fall on] a large spectrum. There are many patients who have minimal symptoms, and on the other side of the spectrum, there are patients who have debilitating symptoms. Avapritinib [was FDA] approved based on [findings from] the PIONEER clinical trial for patients who have increased symptoms despite receiving all the best available therapies.

The treatment goals in these patients are improvement of symptoms and quality of life. It is important to assess patients individually to maximize and optimize their best available and BSC therapies first. If their symptoms are still not well controlled, then avapritinib is a legitimate option.

What patient characteristics and disease factors do you consider when determining whether a patient should receive avapritinib in addition of BSC?

[I would consider adding avapritinib to a patient's treatment regimen] if they have significant symptoms—despite receiving antihistamines or mast cell stabilizers—such as anaphylaxis that is frequent and requires EpiPens and [emergency room care]. [I would also consider using avapritinib in patients with] signs that their disease may be progressing, [such as if] their tryptase levels are gradually increasing, or if their KIT mutation allele burden or mast cell counts are increasing compared with those levels at diagnosis.

The avapritinib prescribing information does not indicate this agent for patients with indolent systemic mastocytosis who have platelet counts lower than 50 x 109/L.3 How prevalent are low platelet counts in this patient population?

Low platelet counts are not usually seen in indolent systemic mastocytosis, so that is not a major concern. Low platelet counts are seen more in advanced systemic mastocytosis or in mastocytosis with associated hematologic malignancies. Additionally, in clinical trials, the concern with low platelet counts [that were potentially] associated with intracranial bleeding were [only] seen in the subset of patients who did not have indolent mastocytosis.

Furthermore, in indolent systemic mastocytosis, we use a lower dose of avapritinib. The FDA-approved dose [for patients with indolent systemic mastocytosis] is 25 mg, and this may be increased to 50 mg if needed. At those 2 low doses, we have not seen intracranial bleeds or reported any major complications. Those lower doses are well tolerated. Overall, in indolent systemic mastocytosis, low platelet counts and other major complications are not a major concern.

How might the indolent systemic mastocytosis treatment paradigm evolve as more novel KIT inhibitors progress through development and become available for clinical use?

We'll have more options [as research continues]. Avapritinib [has only been clinically available] for a few years, so we're still learning [about its] long-term effects. Some subsets of patients with indolent systemic mastocytosis start treatment with 25 mg of avapritinib and subsequently need higher doses. Those may be some of the patients in whom lower doses of avapritinib may not be adequate. Additionally, we don't know whether there might be a subset of patients who may develop resistance or have rare, intolerable AEs. Those are all possibilities we're learning about as we go into the future.

Other KIT inhibitors as options are always good. Bezuclastinib and elenestinib [BLU-263] are doing well in clinical trials. One of the [aspects of these agents] that separates them from avapritinib is that their ability to cross the blood-brain barrier is lower, and therefore, [these drugs] may have less [of an effect on patients'] neurocognitive symptoms [than avapritinib].

Beyond KIT, what other potential targets might be investigated in indolent systemic mastocytosis?

There are other targets, and there are a few clinical trials ongoing [investigating agents directed at these targets]. A BTK inhibitor trial is ongoing. Early-phase clinical trials have been conducted with anti-Siglec antibodies with good results. There are [agents directed at] other targets, such as different interleukin [IL] antibodies, that we already use in clinical settings, like IL-4– and IL-5–directed antibodies. All these agents can be evaluated in combination with other targeted therapies and are potential options for future investigation.

Given what is currently available and all of the ongoing research, how do you see the indolent systemic mastocytosis paradigm evolving in the future?

There may be a lot of patients who receive questionable diagnoses of mastocytosis. Given that there are effective treatments [for this disease], it's important to identify these patients and correctly diagnose them. If they need to be referred to centers of excellence with [oncologists who have] expertise in [managing] mastocytosis, that would be a great option. Because this is a rare disease, you need to have an expert to [assess the patient in the clinic, as well as the pathology of their] bone marrow biopsies. If patients are symptomatic, it's important [that they are] optimized on best available and BSC therapy. Then, [you can] consider targeted therapies or enroll the patients in a clinical trial whenever possible.

References

1. FDA approves Ayvakit (avapritinib) as the first and only treatment for indolent systemic mastocytosis. News release. Blueprint Medicines Corporation. May 22, 2023. Accessed March 19, 2025. https://ir.blueprintmedicines.com/news-releases/news-release-details/fda-approves-ayvakitr-avapritinib-first-and-only-treatment
2. Blueprint Medicines announces positive top-line results from PIONEER trial of Ayvakit (avapritinib) in patients with non-advanced mastocytosis achieving primary and all key secondary endpoints. News release. Blueprint Medicines Corporation. August 17, 2022. Accessed March 19, 2024. https://ir.blueprintmedicines.com/news-releases/news-release-details/blueprint-medicines-announces-positive-top-line-results-pioneer
4. Prescribing information. Avapritinib. Blueprint Medicines. Updated November 2024. Accessed March 19, 2025. https://www.blueprintmedicines.com/wp-content/uploads/uspi/AYVAKIT.pdf