EU Panel Recommends Avapritinib for Advanced Systemic Mastocytosis


The European Medicines Agency’s Committee for Medicinal Products for Human Use recommended to expand the current indication for avapritinib to include single-agent use in patients with aggressive systemic mastocytosis, systemic mastocytosis with an associated hematological neoplasm, or mast cell leukemia.

Andreas Reiter, MD

Andreas Reiter, MD

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended to expand the current indication for avapritinib (Ayvakyt) to include use as a single agent in the treatment of adult patients with aggressive systemic mastocytosis, systemic mastocytosis with an associated hematological neoplasm (SM-AHN), or mast cell leukemia, following at least 1 systemic therapy.1

The positive opinion is supported by data from the phase 1 EXPLORER trial (NCT02561988) and the phase 2 PATHFINDER trial (NCT03580655), in which the agent demonstrated durable clinical efficacy in this patient population, across disease subtypes, as well as a favorable safety profile.

Among all 53 evaluable patients in both trials combined, the agent elicited an objective response rate (ORR) of 57% (95% CI, 42%-70%; this included a complete remission rate of 28%, and a partial remission rate of 28%.2 The median duration of response was 38.3 months (95% CI, 19–not estimable) with the agent, and the median time to response was 2.1 months.

The Commission is expected to reach a final decision on the application by early April 2022.

“The positive opinion from the CHMP is a result of nearly a decade of collaboration with the systemic mastocytosis community and a dedication to bring a transformative therapy to treat and manage this rare, life-threatening disease,” Becker Hewes, MD, chief medical officer at Blueprint Medicines, stated in a press release. “Today’s announcement brings patients with advanced systemic mastocytosis in Europe one step closer to accessing [avapritinib], the first specifically designed precision therapy to selectively target the primary driver of their disease.”

EXPLORER enrolled patients with advanced systemic mastocytosis. In a total of 86 participants, 69 of whom had centrally confirmed disease. In the dose-escalation portion of the research, avapritinib was examined at once-daily doses ranging from 30 mg to 400 mg.2 In the dose-expansion portion, patients received the agent at 300 mg or 200 mg once daily.

The primary end points of the trial included maximum tolerated dose (MTD), recommended phase 2 dose (RP2D), and safety. Key secondary end points comprised overall response rate (ORR) and changes in measures of mast cell burden.

Patients were enrolled between March 10, 2016, and March 18, 2020. A total of 103 patients were evaluated for eligibility, and a total of 86 patients were enrolled to the trial; 32 were in the dose escalation portion of the trial and 54 were in the dose expansion portion.

The median age among all 86 enrolled patients was 64 years (range, 34-83), 53% were male, and 74% had an ECOG performance status of 0 or 1. Moreover, 59% of patients received prior antineoplastic therapy in the form of midostaurin, and 14% had received cladribine. Fifty-two percent of patients had at least 1 mutation in the SRSF2, ASXL1, or RUNX1 genes, which are linked with poor prognosis.

No MTD was identified. During part 1 of the research, 1 patient who received the agent at a daily dose of 400 mg reported a dose-limiting toxicity (DLT), which was grade 4 vomiting. The RP2D was determined to be 300 mg once daily, and it was initially chosen for use in part 2.

However, dose reduction to 200 mg once daily was common, especially when patients experienced cytopenias. Because the once-daily 200-mg dose was found to have a similar exposure and time to response, a second expansion cohort was added in a trial amendment. Fifteen patients began treatment at less than 200 mg once daily, and 21 patients started at the 200-mg dose. Forty-three patients started avapritinib at a once-daily dose of 300 mg, and 7 started treatment at a once-daily 400-mg dose.

At the time of data cutoff, 51% of patients had discontinued treatment; 20% did so because of progressive disease, 10% because of toxicities, 9% for reasons unrelated to toxicities, 4% because of withdrawn consent, and 7% because of investigator decision.

A total of 53 patients were found be evaluable for response. Among these patients, avapritinib induced an ORR of 75% (95% CI, 62%-86%), with 36% of patients experiencing a complete remission (CR) with full hematologic recovery or CR with partial hematologic recovery (CRh). Moreover, 34% of patients experienced a partial remission, and 6% had clinical improvement (CI).

In 36 patients who were naïve to midostaurin, the ORR was 83% (95% CI, 67%-94%) vs 59% (95% CI, 33%-82%) in the 17 patients who were previously exposed to the drug. In midostaurin-naïve patients, the CR/CRh rate was 44% and 18% in those with prior exposure. In the midostaurin-naïve subset, the CR rate was 17% and the CRh rate was 28%; in those with prior exposure, these rates were 12% and 6%, respectively.

Among all 86 patients, the most common grade 3 or higher adverse effects (AEs) reported with avapritinib included fatigue (9%), vomiting (5%), nausea (3%), arthralgia (3%), hypokalemia (3%), dizziness (2%), diarrhea (1%), hair color changes (1%), decreased appetite (1%), constipation (1%), abdominal pain (1%), headache (1%), upper respiratory tract infection (1%), cognitive disorder (1%), insomnia (1%), and urinary tract infection (1%).

PATHFINDER enrolled a total of 62 patients with advanced systemic mastocytosis. Patients were enrolled between November 21, 2018, and June 23, 2020.3 Study participants received avapritinib primarily at a starting dose of 200 mg once daily; 2 patients started at a once-daily dose of 100 mg. Treatment was delivered continuously, in 28-day cycles until disease progression, unacceptable toxicity, withdrawal from the investigator, or patient death.

The primary end point of the trial was ORR, and key secondary end points included mean baseline change in AdvSM-Symptom Assessment Form Total Symptom Score and quality of life, time to response, progression-free survival, overall survival, changes in measures of disease burden, and safety.

The median age among the 32 patients evaluable for response at the time of the interim analysis was 68 years (range, 37-85), 56% were male, 66% had an ECOG performance status of 0 or 1, 53% previously received midostaurin, and 13% received prior cladribine.

At a median follow-up of 10.4 months, avapritinib elicited an ORR of 75% (95% CI, 57%-89%; P = 1.6 x 10-9) in the 32 evaluable patients; this included a CRh rate of 19%. Moreover, 31% achieved a partial remission and 25% had CI. Notably, responses were reported in all subgroups, irrespective of exposure to prior therapy.

ORRs in patients with baseline S/A/R mutations and those without proved to be comparable, at 71% (95% CI, 44%-90%) and 80% (95% CI, 52%-96%), respectively. Responses were also found to be rapid, with a median time to response of 2 months (range, 0.3-12.2). These responses were observed to improve with time; the median time to CRh was 5.6 months (range, 1.8-6.1).

At the data cutoff, 84% of the 62 patients were still receiving treatment with avapritinib. The most common reasons for discontinuation included toxicities (n = 6), disease progression per investigator assessment (n = 3), and withdrawn consent (n = 1).

The most common treatment-related, nonhematologic AEs that were grade 3 or higher included peripheral edema (2%), periorbital edema (3%), fatigue (3%), diarrhea (2%), vomiting (2%), and increased blood alkaline phosphatase (2%). Grade 3 or higher hematologic toxicities included neutropenia (23%), thrombocytopenia (15%), anemia (8%), and leukopenia (5%).

In June 2021, the FDA approved avapritinib for the treatment of adult patients with advanced systemic mastocytosis, including those with aggressive systemic mastocytosis, systemic mastocytosis with an associated hematological neoplasm, and mast cell leukemia.4 The decision was supported by data from EXPLORER and PATHFINDER.

“Patients across Europe are waiting for innovative treatment options for advanced systemic mastocytosis, which is associated with organ damage due to mast cell proliferation and poor survival outcomes,” Professor Andreas Reiter, MD, Center of Excellence for Myeloproliferative Neoplasms, University Medicine Mannheim, added in the press release. “A precision therapy associated with potent and selective targeting of the KIT D816V mutation brings the prospect of changing the course of disease and transforming treatment for patients to set a new standard of care in Europe.”


  1. Blueprint Medicines’ AYVAKYT (avapritinib) receives positive CHMP opinion for the treatment of adults with advanced systemic mastocytosis. News release. Blueprint Medicines Corporation; January 28, 2022. Accessed January 31, 2022.
  2. DeAngelo DJ, Radia DH, George TI, et al. Safety and efficacy of avapritinib in advanced systemic mastocytosis: the phase 1 EXPLORER trial. Nat Med. 2021;27(12):2183-2191. doi:10.1038/s41591-021-01538-9
  3. Gotlib J, Reiter A, Radia DH, et al. Efficacy and safety of avapritinib in advanced systemic mastocytosis: interim analysis of the phase 2 PATHFINDER trial. Nat Med. 2021;27(12):2192-2199. doi:10.1038/s41591-021-01539-8
  4. FDA approves avapritinib for advanced systemic mastocytosis. News release. FDA. June 16, 2021. Accessed January 31, 2022.
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