PATHFINDER: Avapritinib Induces Rapid Responses in Advanced Systemic Mastocytosis

Three-quarters of patients with advanced systemic mastocytosis (SM) responded to treatment with the oral KIT D816V inhibitor avapritinib, according to interim results from the PATHFINDER trial presented at the American Association for Cancer Research’s 2021 virtual meeting. The findings were presented by Daniel J. DeAngelo, MD, PhD, from Dana-Farber Cancer Institute in Boston, Massachusetts.

SM is a clonal, hematologic neoplasm driven by KIT D816V mutation in more than 90% of cases, with limited treatment options, Dr. DeAngelo noted during his presentation. He described the responses seen with avapritinib as “rapid, durable, and improving.”

The open-label, single-arm, phase II trial enrolled 62 adults with advanced SM. Participants received avapritinib primarily at 200 mg once daily. Participants’ median age was 69 years (range = 31-88) and 31% had Eastern Cooperative Oncology Group performance score of 2 or 3. Sixty-eight percent had received prior systemic treatment; the most common treatment approach was midostaurin (55%). SM with an associated hematologic neoplasm was the most common disease subtype in this population (81%), followed by mast cell leukemia (13%) and aggressive SM (6%). At baseline, patients’ median bone marrow mast cell burden was 50%, and the median baseline serum tryptase levels was 293 ng/mL.

After a median follow-up of 10.4 months, 52 patients (84%) remained on treatment and 32 patients were considered evaluable for response (the study’s primary endpoint). However, a large portion of patients (92%) required dose reductions from 200 mg to 100 mg or less.

In the interim analysis, the overall response rate (ORR) among the 32 patients was 75%. This included 19% who experienced a complete response (CR) with full or partial hematologic recovery. The median time to response was two months, and the median time to CR with partial hematologic recovery was 5.6 months. Dr. DeAngelo noted that responses deepened over time.

The investigators also noted that there was no difference in ORR between patients with previously treated and de novo disease (78% vs. 74%), but the rates of CR with partial hematologic recovery appeared to be higher among those with de novo disease (13% vs. 33%).

Dr. DeAngelo reported that most patients (87%) experienced a ≥50% reduction in baseline serum tryptase levels.

He also highlighted improvements in symptom burden with avapritinib treatment, with a mean reduction of 7.7 points after six months of treatment.

The most common adverse events (AEs; occurring in ≥25% of patients) included peripheral (50%) and periorbital (35%) edema, thrombocytopenia (32%), and anemia (29%). Overall, 5% of patients discontinued due to a treatment-related AE and 5% due to disease progression.

Median overall survival (OS) was not reached at the time of analysis, and the estimated 12-month OS was 87%. Three patients died during treatment; all deaths were considered unrelated to treatment.

“The pivotal PATHFINDER study showed that avapritinib 200 mg once daily induced rapid responses … and improved symptoms in patients with advanced SM,” the authors concluded, however, the lack of a comparator arm limits the implications of this analysis.

Study authors report relationships with Blueprint Medicines Corporation, which sponsored this trial.


DeAngelo DJ, Reiter A, Radia D, et al. CT023 – PATHFINDER: Interim analysis of avapritinib (ava) in patients (pts) with advanced systemic mastocytosis (AdvSM). Abstract #CT023. Presented at the 2021 American Association for Cancer Research Annual Meeting, April 11, 2021.