Dr Tashi on Differentiating Characteristics of Elenestinib in Indolent Systemic Mastocytosis

“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.