The potent KITD816V inhibitor induced durable responses that deepened over time in patients with this disease, regardless of prior therapy or the presented subtype
A provisional and pre-specified analysis of PATHFINDER (NCT03580655), a phase II, open-label and single-arm trial that evaluated avapritinib in patients with advanced systemic mastocytosis, a hematological clonal neoplasm induced by the KITD816V mutation in more than 90% of cases, whose treatment options are limited, was presented at the 2021 Annual Meeting of the American Association for Cancer Research (AACR).
In this analysis, 32 patients assessable for response aged 18 ≥ were included. The primary endpoint was the overall response rate (ORR) per modified criteria from the International Working Group-Myeloproliferative Neoplasms Research and Treatment and the European Competence Network on Mastocytosis. The secondary endpoints included mean change from baseline in TSS (AdvSM-Symptom Assessment Form Total Symptom Score) and safety.
On June 23, 2020, 62 patients with advanced systemic mastocytosis received 200 mg orally once daily. The average age was 69 years, 31% had ECOG between 2 and 3, and 68% of the participants received prior systemic treatment (55% with midostaurin).
At the mean follow-up of 10.4 months, 84% of the patients remained in treatment. ORR was 75% (95% CI: 57 – 89; P = 1.6×10-9) in 32 participants assessable for response. Complete remission with total or partial hematological recovery occurred in 19%. The average response time was two months and the answers deepened over time.
Median overall survival has not achieved. The estimated overall survival at 12 months was 87%. There were reductions ≥ 50% of baseline serum tryptase (87%; n = 54), bone marrow mast cells clustering (71%; n = 44) and KITD816V allele fraction (53%; n = 33).
The mean TSS at baseline (n = 56) was 18.3. Fatigue, spotting, itching, flushing and abdominal pain were the most severe symptoms. The mean change in TSS was -7.7 (P< 0.001) after six months of treatment (n = 36).
Common adverse events, including all grades and grade ≥ 3, respectively, included: peripheral (50%, 3%), periorbital edema (35%, 3%), thrombocytopenia (32%, 8%) and anemia (29%, 16%). Overall, 5% of patients discontinued therapy due to treatment-related adverse events and 5% due to disease progression.
There were three (5%) deaths, all unrelated to treatment. Seven (11%) patients had cognitive effect adverse events (all grade 1 to 2). One participant with severe thrombocytopenia prior to treatment (platelets < 50×109/L) presented a grade 4 subdural hematoma. Subsequent patients with severe pre-treatment thrombocytopenia were excluded, platelet level monitoring was intensified, and dose interruption for severe thrombocytopenia was recommended. No intracranial bleeding event occurred in 57 patients without severe thrombocytopenia prior to treatment.
The researchers concluded that the PATHFINDER trial showed that avapritinib 200mg a day induced rapid responses, which deepened throughout treatment, and improved symptoms in patients with advanced systemic mastocytosis. The medication was generally well–tolerated and had a manageable safety profile, including effectively reduction in the risk of thrombocytopenia.
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