4-Year Data Underscore Durable Efficacy With Avapritinib in Advanced Systemic Mastocytosis

Long-term data from the phase 2 PATHFINDER trial (NCT03580655) have underscored the durability of response achieved with avapritinib (Ayvakit) in patients with advanced systemic mastocytosis, according to Deepti Radia, MBBS, BSc, MRCPI, FRCPath, MSc Med Ed, who also noted that the data point to potential bone health improvement for this patient population.

"[This] is the first time we've seen these wonderful, deep responses in the clinic. The depth of complete responses [CRs] and partial responses [PRs] is significant, but we need to be aware of the myelosuppression and the adverse effect [AE] profile," Radia said. "The data now show that patients [previously] exposed to a TKI still have good responses. Those patients who have not been exposed [to a TKI] and [received avapritinib] in the first line had deeper responses.”

Findings from PATHFINDER trial presented at the 2025 ASH Annual Meeting and Exposition showed that at a median follow-up of approximately 4 years, response-evaluable patients (n = 83) achieved an overall response rate (ORR) of 73% (95% CI, 63%-83%), including a CR or CR with incomplete hematologic recovery (CRh) rate of 30% and a PR rate of 39%.¹ Treatment with avapritinib in the overall population was also associated with clearance of bone marrow mast cell aggregates (74%), reductions in serum tryptase levels to below 20 ng/mL (65%), reductions in KIT D816V variant allele frequency (VAF) to less than 1% (64%), and clinical resolution of palpable spleens (78%).

Notably, in June 2021, the FDA approved avapritinib for adult patients with advanced systemic mastocytosis, including those with aggressive systemic mastocytosis, systemic mastocytosis with an associated hematological neoplasm (AHN), and mast cell leukemia, based on data from the phase 1 EXPLORER trial (NCT02561988) and PATHFINDER.²

In an interview with OncLive®, Radia provided background on the PATHFINDER study, broke down the key efficacy data presented in the trial’s final analysis, and detailed potential bone health improvements associated with avapritinib.

Radia is a consultant hematologist, chair of the London Specialist Training Committee, and chair of the National Specialist Advisory Committee in Haematology at Guy's and St Thomas' NHS Foundation Trust in London, United Kingdom.

OncLive: What was the rationale and design behind the PATHFINDER trial and the clinical questions it was seeking to answer?

Radia: PATHFINDER was designed to look at the efficacy and safety of avapritinib, which is a potent KIT D816V inhibitor, in patients with advanced systemic mastocytosis. PATHFINDER was the follow-up trial to EXPLORER, which was the initial phase 1 trial. The dose that was identified in the EXPLORER trial was 200 mg once daily. The patients eligible for [PATHFINDER] were those with advanced systemic mastocytosis—either aggressive systemic mastocytosis, mast cell leukemia, or advanced systemic mastocytosis with an AHN, [the latter of] which make up most patients in clinical practice. Those with very high–risk AHN or acute myeloid leukemia were excluded. [Inclusion criteria also had] the usual [criteria] of being over the age of 18 and an ECOG performance status of less [than 4].

The primary end point was to look at the efficacy and the safety of avapritinib in improving the C-findings. Patients had screening done, and their marrows were centrally adjudicated, as were their responses by a central committee, to make sure there was an improvement of some C-findings [compared with baseline]. [The goal of PATHFINDER] was to see if what we saw in EXPLORER, which was an excellent response for patients with advanced systemic mastocytosis [treated] with avapritinib, bore out in the phase 2 trial.

The findings shared at ASH 2025 [had a data cutoff] of March 2025, and 107 patients were enrolled altogether. [The dataset] shared at ASH [included] patients receiving first-line therapy—those who were naive to previous TKIs. There were 38 patients enrolled [in the first-line population], and 30 of those were evaluable per International Working Group-Myeloproliferative Neoplasms Research and Treatment and European Competence Network on Mastocytosis [IWG-MRD-ECNM] criteria. Those familiar with systemic mastocytosis will understand those criteria, but essentially, a centrally adjudicated committee looked at the bone marrow as a response for the pathological improvement of symptoms, [improvement of] mast cell disease burden, and the reversal of C-findings, which you find in patients with advanced systemic mastocytosis.

What 4-year efficacy data were presented for patients with advanced systemic mastocytosis treated with avapritinib in PATHFINDER?

In terms of responses for those patients treated in the first line...the ORR was still 87% [95% CI, 69%-96%] with 4 years of follow-up; the CR/CRh rate was 43%, and the PR [rate was] 43%.¹ Time to response [in the first-line setting] was quick at 3.1 months [95% CI, 0.3-15.0], and the median progression-free survival and overall survival were not reached with first-line treatment.

The bottom-line message was that patients who were TKI naive did well with avapritinib at a starting dose of 200 mg once daily. However, there was a median [daily] dose of 106 mg [range, 27-240] at the end of 4 years, with very good decreases in mast cell disease burden. Additionally, [84% of patients treated in the first line] had a drop in their mast cell bone marrow burden, [79%] had serum tryptase levels [drop below 20 ng/mL], and [67%] had a reduction in [KIT D816V] VAF [to less than 1%]. [Therefore], very good results carried over with 4 years [of follow-up].

What was uncovered about the bone health findings from this analysis?

[Emerging data from] both the advanced and indolent [systemic mastocytosis] trials [signal] that there might be an improvement in bone health [with avapritinib]. Now, that could be because of the disease-modifying impact of avapritinib and the reduction in those mast cell [levels], but we need to investigate this more.

A small proportion of patients had serial dual-energy X-ray absorptiometry [DXA] scans [n = 56] to compare baseline [bone density] with follow-up [densities], and bone turnover markers [were also evaluated in a proportion of patients (n = 47)]. There seemed to be an improvement in [bone density and bone turnover markers] from baseline with follow-up in a very small cohort of patients, suggesting that there might be an improvement in bone health over time if patients are exposed to a TKI. However, this is a complex dynamic, so it's the first signal that we saw that there might be an improvement [in bone health].

What did 4-year data show regarding the safety of avapritinib in patients with advanced systemic mastocytosis?

Overall, 107 patients were enrolled onto PATHFINDER. [Notably], part of the eligibility criteria was that you needed a platelet count above 50 x 10⁹/L, which was very important. In EXPLORER, we had a safety signal of intracranial hemorrhages. Since that [platelet count criterion] was amended in PATHFINDER, the important message is that no further intracranial hemorrhages were seen [in PATHFINDER].

There were very few grade 3 [or higher] AEs. Among the most common [any-grade] AEs were periorbital and peripheral edema, which we are used to seeing. We can manage those, and they get better with dose reductions. There was some myelosuppression with anemia and thrombocytopenia, which could be managed with dose reductions and adjustments. Therefore, the overall safety profile was maintained for [avapritinib]. It was reasonably well tolerated for patients with the dose adjustment, usually with most of the patients ending up [receiving dose density of] just over 100 mg and having this depth of response. The most important message is to make sure [a patient's] platelet count is above 50 x 10⁹/L before initiating therapy.

References

1. Reiter A, George T, Radia D, et al. Avapritinib treatment of patients with advanced systemic mastocytosis: 4-year safety, effect on bone and first-line efficacy results of the pathfinder clinical study. Blood. 2025;146(suppl 1):1022. doi:10.1182/blood-2025-1022
2. FDA approves avapritinib for advanced systemic mastocytosis. News release. FDA. June 16, 2021. Accessed February 12, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-avapritinib-advanced-systemic-mastocytosis