The European Commission has expanded the current indication for avapritinib to include use as a single agent in adult patients with aggressive systemic mastocytosis, systemic mastocytosis with an associated hematologic neoplasm, or mast cell leukemia, following at least 1 systemic treatment.
The European Commission has expanded the current indication for avapritinib (Ayvakyt) to include use as a single agent in adult patients with aggressive systemic mastocytosis, systemic mastocytosis with an associated hematologic neoplasm, or mast cell leukemia, following at least 1 systemic treatment.1
The regulatory decision follows the positive opinion issued by the European Medicines Agency’s Committee for Medicinal Products for Human Use in January 2022.2 The recommendation is based on findings from the phase 1 EXPLORER trial (NCT02561988) and the phase 2 PATHFINDER trial (NCT03580655), in which avapritinib showcased durable clinical efficacy in this population, spanning disease subtypes, along with an acceptable toxicity profile.
Among all patients determined to be evaluable in both trials (n = 53), the agent was found to produce an objective response rate (ORR) of 57% (95% CI, 42%-70%), which was comprised of a 28% complete remission rate and a 28% partial remission rate. Moreover, the median time to response with avapritinib was 2.1 months, and the median duration of response was 38.3 months (95% CI, 19–not estimable).
The phase 1 EXPLORER trial enrolled 86 patients with advanced systemic mastocytosis, 69 of whom had centrally confirmed disease.3 The trial was comprised of 2 portions; in the dose-escalation portion (n = 32), the agent was evaluated at once daily doses that ranged from 30 mg to 400 mg, and in the dose-expansion portion (n = 54), they were given avapritinib at a once-daily dose of 300 mg or 200 mg.
The primary end points of the trial were maximum tolerated dose (MTD), recommended phase 2 dose (RP2D), and safety. Secondary end points included ORR and changes in measures of mast cell burden.
Among the 86 study participants, the median age was 64 years (range, 34-83). Fifty-three percent of patients were male, 74% had an ECOG performance status of 0 or 1, 59% previously received antineoplastic therapy in the form of midostaurin, and 14% previously received cladribine. Moreover, 52% of patients had tumors that harbored at least 1 mutation in the SRSF2, ASXL1, or RUNX1 genes—all of which have been associated with poor prognosis.
Investigators did not identify the MTD of avapritinib. In the first portion of the trial, 1 participant experienced a dose-limiting toxicity in the form of grade 4 vomiting; this patient had received the agent a once-daily dose of 400 mg. A once-daily dose of 300 mg was determined to be the RP2D, and it was initially selected for investigation in the second portion of the research. However, because dose reductions to 200 mg once daily proved to be common, a second expansion cohort was added.
A total of 15 patients received avapritinib at less than 200 mg once daily, and 21 patients started treatment with the agent at the once-daily, 200-mg dose. Moreover, 43 patients started avapritinib at 300 mg once daily, and 7 initiated avapritinib at 400-mg, once-daily dose.
Among the 53 patients evaluable for response, the agent elicited an ORR of 75% (95% CI, 62%-86%). Notably, 36% of patients experienced a CR with full hematologic recovery or CR with partial hematologic recovery (CRh), and 34% had a PR. Six percent of patients experienced clinical improvement with avapritinib.
In a subset of patients who were naïve to midostaurin (n = 36), avapritinib elicited an ORR of 83% (95% CI, 67%-94%) compared with 59% (95% CI, 33%-82%) in the subset of patients who previously received the agent (n = 17). Moreover, in those who were midostaurin naïve, the CR/CRh rate was 44% vs 18% of those who had prior exposure; in those who previously received the agent, these rates were 12% and 6%, respectively.
The most common toxicities experienced by the total population with avapritinib included fatigue (9%), vomiting (5%), nausea (3%), arthralgia (3%), hypokalemia (3%), dizziness (2%), diarrhea (1%), hair color changes (1%), reduced appetite (1%), constipation (1%), abdominal pain (1%), headache (1%), upper respiratory tract infection (1%), cognitive disorder (1%), insomnia (1%), and urinary tract infection (1%).
A total of 62 patients with advanced systemic mastocytosis were enrolled to the phase 2 PATHFINDER trial.4 The majority of these patients received avapritinib at a starting dose of 200 mg once daily, although 2 patients started the agent at a once-daily dose of 100 mg.
The primary end point of the trial was ORR, and 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.
Among the 32 patients determined to be evaluable for response, the median age was 68 years (range, 37-85). Additionally, 56% of patients were male, 66% had an ECOG performance status of 0 or 1, 53% received prior midostaurin, and 13% previously received cladribine.
At a median follow-up of 10.4 months, avapritinib induced an ORR of 75% (95% CI, 57%-89%; P = 1.6 x 10-9), which was comprised of a 19% CRh rate and a 31% PR rate. Notably, 25% of patients experienced clinical improvement with avapritinib. Responses were observed in all subsets analyzed, regardless of prior therapy exposure. Moreover, the median time to response was 2.0 months (range, 0.3-12.2) and they improved with time. The median time to CRh was 5.6 months (range, 1.8-6.1).
In the subset of patients with S/A/R mutations, the ORR achieved with avapritinib was 71% (95% CI, 44%-90%); in those without these mutations, the ORR with the agent was slightly higher, at 80% (95% CI, 52%-96%).
The most frequent non-hematologic toxicities that were grade 3 or higher in severity and determined to be linked with avapritinib included peripheral edema (2%), periorbital edema (3%), fatigue (3%), diarrhea (2%), vomiting (2%), and increased blood alkaline phosphatase (2%). Grade 3 or higher hematologic adverse effects 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 hematologic neoplasm, and mast cell leukemia based on findings from EXPLORER and PATHFINDER.5