The novel KIT D816V inhibitor elenestinib (BLU-263) has the potential to offer a new treatment option for patients with indolent systemic mastocytosis (ISM) with an enhanced safety profile compared with first-generation KIT inhibitors such as avapritinib (Ayvakit), according to Tsewang Tashi, MD.

“Elenestinib is a novel KIT inhibitor that’s still in clinical trials—specifically, the [phase 2/3] HARBOR trial [NCT04910685] that’s ongoing for [patients with] ISM or non-advanced systemic mastocytosis,” Tashi said in an interview with 

®. “One of the main differentiating factors [of this agent compared] with avapritinib is that elenestinib does not cross the blood-brain barrier. Avapritinib [can lead to] intracranial bleeds in [patients with] advanced systemic mastocytosis. It’s expected that elenestinib may [be able to] mitigate that risk.”

Tashi is the leader of the Mastocytosis Program at the University of Utah Huntsman Cancer Institute in Salt Lake City.

HARBOR is a randomized, double-blind study that is comparing elenestinib plus symptom-directed therapy (SDT) with placebo plus SDT for the treatment of patients with ISM whose symptoms are not adequately controlled by SDT.

 The primary end points in part 1 are the rate of treatment-emergent adverse effects (AEs) and changes in the mean ISM-Symptom in Assessment Form (ISM-SAF) Total Symptom Score (TSS) from baseline. In parts 2 and 3, the primary end point is change in mean ISM-SAF TSS from baseline; AEs are also a primary end point in part 3.

In the interview, Tashi discussed the historical limitations of first-generations KIT inhibitors, how elenestinib aims to address these limitations, and the future of elenestinib in patients with ISM.

: What are the key limitations of first-generation KIT inhibitors such as imatinib (Gleevec) and avapritinib in managing ISM symptom burden and modifying its disease course?

: Imatinib is used mainly in [patients with] 

 D816V–unmutated systemic mastocytosis, as well as for those with unknown 

 mutation [status]. That was the initial FDA-approved indication. That’s [approximately] 5% of all [patients with] systemic mastocytosis, and it is not effective for [those with disease harboring the]

 D816V mutation, so we don’t use it in that setting at all.

The response rate for imatinib in these non–D816V mutated systemic mastocytosis cases is not high—it’s [approximately] 40% to 50%. We also sometimes use it in [patients with] wild-type 

. It is a good drug to consider if [the patient doesn’t] have the 

Avapritinib is a selective and potent KIT inhibitor that has recently been approved for both advanced systemic mastocytosis and ISM and it’s an excellent drug, as we saw in the [phase 2] PIONEER study [NCT03731260]. It has a robust safety profile too, especially in [patients with] ISM. Avapritinib decreases all the objective markers of mast cell disease, [such as] tryptase level, 

 mutational burden, and mast cell burden in the bone marrow.

Now of course, if you talk about the limitations—we’re still learning a lot about this disease, because avapritinib hasn’t been out there that long. We saw in PIONEER that approximately 25% of patients ultimately needed to increase their dose to 50 mg, and there are some patients who may need a higher dose. 

It’s still an open question as to how these patients can be identified early on—who are the patients who need a higher dose and [which ones] don’t? That’s an ongoing discussion. Also, avapritinib is indicated for those patients who are already on best supportive therapy with antihistamines and mast cell stabilizers, and who are still symptomatic despite all those medications.

Determining how symptomatic the patient is can be challenging. It’s sometimes subjective because it’s based on patient-reported symptoms. You must assess whether the symptoms are from systemic mastocytosis or if they could be coming from other comorbidities. It takes a lot of expertise and experience to clearly delineate which symptoms are from systemic mastocytosis vs not. These are all challenges we still face in this rare disease population.

In the advanced systemic mastocytosis clinical trials, avapritinib [led to] some cases of intracranial bleeding. [These events were] mainly in patients with advanced systemic mastocytosis, especially those with low platelet counts. When patients do their own research on the internet they also come across this warning. They have concerns and questions about it. Some patients may have reservations about using this drug—even in ISM—although the risk is much lower in that setting. But it’s still a concern that the general population will always have.

How might the selectivity and pharmacokinetic profile of elenestinib address the shortcomings of avapritinib beyond the improvement in intracranial bleeding risk?

When we used avapritinib in patients with systemic mastocytosis, early on in the clinical trial some patients had substantial cognitive symptoms. Whether these are from the disease or from avapritinib is an ongoing debate, but there was likely some worsening of neurocognitive symptoms seen with avapritinib. It’s an issue that we see patients complain about. If that’s indeed from avapritinib, then we believe elenestinib—because it does not cross the blood-brain barrier—should not be causing any neurocognitive symptoms.

Of course, there are other differences in off-target effects that we still don’t fully know about. As the HARBOR trial matures and we get more data, we’ll be able to see in detail what the real differences are between elenestinib and avapritinib. In [patients with] systemic mastocytosis, it’s not only the symptoms—there are also other disease manifestations, including mast cell burden and risk of osteoporosis. It also remains to be seen how elenestinib affects these complications [and] whether it’s able to change the natural course of osteoporosis compared with avapritinib. These are still being evaluated, and we’re eagerly awaiting the study results.

What should investigators look for in the primary end points of HARBOR to be convinced of elenestinib’s disease-modifying potential?

The primary end point is symptom improvement. When we enroll patients in the HARBOR trial, only those above a certain threshold of symptoms—despite taking best supportive therapy—are included. With that in mind, we also look at objective markers. Do the symptom improvements correlate with objective decreases in mast cell disease burden?

If you see sustained decreases in tryptase values, bone marrow mast cells, and 

 variant allele frequency, and if that correlates with symptom improvement, then that clearly indicates a disease-modifying effect by inhibiting the 

 mutation. That’s the same thing we saw with other KIT inhibitors, such as avapritinib. The main thing we look for in the primary and secondary end points is whether it’s a disease-modifying agent.

What should be known about the safety profile of elenestinib considering long-term needs such as quality of life improvements and limiting the risk for osteoporosis in ISM?

ISM is a risk factor for premature osteoporosis. If [a patient] has osteoporosis or osteopenia with ISM, we still need to treat them with vitamin D and calcium supplements. If needed, they may require bisphosphonates or other anabolic treatments for bone health. That’s the standard way of addressing the bone effects from ISM. We hope that KIT inhibitors reduce the risk of worsening osteoporosis by treating the disease.

As for the long-term effects of these KIT inhibitors—only time will tell, because these drugs haven’t been out that long, and some are still under investigation. We don’t have long-term data yet, but so far the safety profile of elenestinib looks great. In part 1 [of the] study, the safety profile was excellent—no grade 3 or 4 AEs were noted, and no patients had to discontinue the drug due to AEs.

What role should validated clinical outcome assessments such as the ISM-SAF TSS play in interpreting HARBOR results and ultimately in guiding therapy decisions in practice?

Validated total symptom scores such as the ISM-SAF are important because they allow us to objectively assess patients’ subjective symptoms. If you have a validated scoring tool, it can be applied uniformly across different practices and clinical trials, setting a standard. Right now, all these KIT inhibitor trials, including PIONEER and HARBOR, use some kind of clinically validated symptom assessment score [and] patients who exceed a certain threshold are enrolled in the trials. This helps us assess patients uniformly across studies.

It takes effort and experience to parse out what symptoms are from which condition. Patients may have different comorbidities or preexisting conditions that contribute to symptoms. Sometimes these unrelated conditions can exacerbate systemic mastocytosis symptoms, which makes it even harder. [Therefore], a validated clinical symptom score is very important.

Do you foresee a role for combining elenestinib with complementary agents or using molecular tools like single-cell genomics to stratify patients who will derive the most benefit—or is monotherapy likely to define the therapeutic niche?

We’re still learning a lot about systemic mastocytosis, including ISM. ISM is a very heterogeneous disease—some patients are not symptomatic at all, and others have debilitating symptoms. Some patients have diffuse skin involvement, some don’t. Some have frequent anaphylactic reactions, and others have never had one. Although we call them all ISM, the clinical spectrum is very broad.

We’re still learning why there is such variability as well as who needs treatment vs who doesn’t. We don’t have a good way to differentiate these patients yet, although research is ongoing. We’re also trying to understand who might progress to smoldering or advanced systemic mastocytosis and who might not. These are all open questions.

So far, monotherapy with avapritinib has been practice-changing, but we must remember that patients can still have symptoms even during KIT inhibitor therapy. KIT inhibition is not the complete answer to all symptoms—it may blunt or reduce them but it doesn’t eliminate them completely.

We expect something similar with elenestinib —it will likely be very effective in treating patients with systemic mastocytosis but it will not be curative. Although monotherapy has been a paradigm shift in systemic mastocytosis treatment, in the future, as we learn more about the disease’s heterogeneity, we may identify patients who need combination treatments. The best answer is that time will tell.

Castells M, Livideanu CB, Hermine O, et al. HARBOR: an ongoing phase 2/3 study of elenestinib in patients with indolent systemic mastocytosis. 

. 2025;155(suppl 2):AB170. doi:10.1016/j.jaci.2024.12.538

(HARBOR) study to evaluate efficacy and safety of BLU-263 versus placebo in patients with indolent systemic mastocytosis. ClinicalTrials.gov. Updated April 30, 2025. Accessed September 3, 2025. https://clinicaltrials.gov/study/NCT04910685

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“As the HARBOR trial matures and we get more data, we’ll be able to see in detail the real differences between elenestinib and avapritinib.”

Tsewang Tashi, MD, a hematologist/oncologist and an associate professor in the Division of Hematology & Hematologic Malignancies at the University of Utah Huntsman Cancer Institute and leader of the Mastocytosis Program at the Huntsman Cancer Hospital, discussed ​ways that elenestinib (BLU-263) might uniquely address unmet needs for patients with indolent systemic mastocytosis (SM).

Elenestinib is a novel KIT inhibitor currently under investigation in the phase 2/3 HARBOR trial (NCT04910685) for patients with indolent SM, Tashi began. One of the principal distinctions between elenestinib and avapritinib (Ayvakit) is that elenestinib does not cross the blood-brain barrier, he said. This characteristic carries potential clinical implications, he noted. Specifically, avapritinib has been associated with intracranial hemorrhage in patients with advanced SM, he explained. It is anticipated that elenestinib may mitigate this risk due to its limited central nervous system penetration, he contextualized.

Another relevant consideration in the management of SM concerns neurocognitive effects, according to Tashi. In earlier avapritinib studies for SM, a proportion of patients reported significant cognitive disturbances, often described as “brain fog,” he reported. Whether these symptoms were directly attributable to avapritinib or represented manifestations of the underlying disease remains uncertain, he stated. However, some evidence suggested a potential exacerbation of neurocognitive symptoms with avapritinib initiation, he cautioned. If these adverse effects are drug-related, elenestinib’s inability to cross the blood-brain barrier suggests that such neurocognitive complications would be less likely with the use of this agent, representing a notable therapeutic advantage in the paradigm, particularly given that neurocognitive impairment itself is a symptom of SM that requires management, he emphasized.

Additional off-target differences between the 2 agents are not yet fully characterized, Tashi noted. As the HARBOR trial progresses and more data emerge, clearer delineations between elenestinib and avapritinib are expected to become evident, he predicted. Importantly, in SM, disease manifestations extend beyond symptomatic burden and include complications like increased mast cell burden and risk of osteoporosis, he added. Whether elenestinib alters the natural course of these disease-related complications, including skeletal health, remains under active investigation, he concluded.

Videos

Tsewang Tashi, MD, discusses ​the aspects of elenestinib that differentiate it from avapritinib in the management of indolent systemic mastocytosis.


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