First- and Later-Line Avapritinib Prolongs OS, DOT in Advanced Systemic Mastocytosis

Treatment with avapritinib (Ayvakit) demonstrated a significant improvement in overall survival (OS) and duration of treatment (DOT) vs midostaurin in the first-line setting and best available therapy (BAT) in the second- and later-line settings for patients with advanced systemic mastocytosis in standard clinical practice, according to results from a retrospective analysis of the phase 2 PATHFINDER study (NCT03580655) and a real-world retrospective chart review (NCT04695431) presented during the 2024 ASH Annual Meeting.

In the first-line analysis, death occurred in 10.5% and 56.9% of patients treated with avapritinib (n = 38) vs midostaurin (n = 58), respectively, during the follow-up period. The unweighted median OS was not reached (NR; 95% CI, not estimable [NE]-NE) in the avapritinib cohort vs 28.6 months (95% CI, 18.2-49.8) in the midostaurin cohort (P < .001). Unweighted median DOT was 41.3 months (95% CI, 33.9-NE) in the avapritinib cohort vs 11.6 months (95% CI, 7.5-22.1) in the midostaurin cohort. However, in the inverse probability of treatment weighting (IPTW) Cox analysis, treatment with avapritinib significantly prolonged both OS (HR, 0.19; 95% CI, 0.06-0.57; P =.003) and DOT (HR, 0.37; 95% CI, 0.19, 0.70; P = .002) vs midostaurin.

In the second- and later-line analysis, death during the follow-up period occurred in 25.4% and 68.5% of patients in the avapritinib (n = 67) and BAT cohorts (n = 73). The unweighted median OS was NR (95% CI, NE-NE) with avapritinib vs 20.3 months (95% CI, 14.9-33.9) in the BAT cohort (P < .001).The unweighted median DOT was 24.0 months (95% CI, 20.8-NE) with avapritinib vs 5.2 months (95% CI, 3.1-8.1) with BAT. According to the IPTW-weighted Cox analysis, avapritinib significantly increased OS (HR, 0.34; 95% CI, 0.16-0.75; P = .008) and DOT (HR, 0.35; 95% CI, 0.21-0.58; P < .001) vs BAT.

Notably, DOT analysis comprised 97 lines of therapy, of which 7 lines were excluded due to unknown discontinuation date and unknown last known prescription date.

“This study supports the use of avapritinib as first-line treatment for advanced systemic mastocytosis and also supports the use of avapritinib in the second line [and later],” lead study author Andreas Reiter, MD, of the University Medical Centre in Mannheim, Germany, and colleagues reported in a poster presentation of the data. “In the absence of a randomized controlled trial, these data offer important insights on the superior efficacy and suggest good tolerability of avapritinib as compared with midostaurin and other available therapies for patients with advanced systemic mastocytosis and may help inform treatment decisions.”

Background and Study Overview

The majority of patients with systemic mastocytosis harbor a KIT D816V mutation, making KIT inhibition a key therapeutic strategy. Avapritinib, a selective inhibitor of KIT D816V mutations, is approved for the management of advanced systemic mastocytosis in Europe (following prior systemic therapy) and in the United States based on findings from the single-arm, phase 1 EXPLORER (NCT02561988) and PATHFINDER trials. However, no randomized controlled trials have compared avapritinib with BAT in systemic mastocytosis.

The current analysis built on prior research by comparing OS and DOT outcomes in patients with advanced systemic mastocytosis who received the 200-mg daily starting dose of avapritinib in the safety population of the PATHFINDER study vs those treated with BAT in the observational, retrospective chart review study conducted across 6 global sites.

The data cutoff in PATHFINDER was September 9, 2022, and the median follow-up was 26.3 months. Real-world data from eligible patients treated with BAT in the retrospective chart review were collected from March 26, 2021, to October 4, 2021.

Patients 18 years or age or older were included in the study if they had a diagnosis of advanced systemic mastocytosis documented in their chart and received 1 or more lines of systemic therapy at a participating study site on or after January 1, 2009. For patients receiving multiple lines of therapy, data on all available therapies were collected and analyzed.

Patients were excluded from the study if they had a history of another primary malignancy that was diagnosed or required therapy within 3 years prior to the index date, except for completely resected basal cell and squamous cell skin cancer; curatively treated localized prostate cancer; and completely resected carcinoma in situ in any site. Receipt of avapritinib as the first therapy for advanced systemic mastocytosis at a participating site was also not permitted.

In the first line, avapritinib was compared with midostaurin. In the second line or later, avapritinib was compared with all BATs used in real-world clinical practice, including midostaurin and cladribine.

Study end points included OS, defined as time from treatment initiation to death from any cause; and DOT, defined as time from treatment initiation to last dose date with avapritinib or discontinuation of BAT for any reason.

Baseline Characteristics

The first-line analysis comprised 38 patients treated with avapritinib and 58 patients treated with midostaurin. The mean age at treatment initiation (68.3 in avapritinib arm; 67.4 in midostaurin) was comparable between the avapritinib and midostaurin cohorts. Notably, a higher proportion of patients in the avapritinib vs midostaurin cohorts had 1 or more mutated genes in the SRSF2/ASXL1/RUNX1 panel. At baseline, the percentage of patients with elevated serum tryptase levels above 125 ng/mL was also comparable between arms (71.1%; 69.0%).

The second-line analysis comprised 67 patients treated with avapritinib and 73 patients treated with BAT. Within the BAT group, patients underwent a total of 104 lines of therapy. Between the avapritinib and BAT cohorts, the mean age at treatment initiation (66.6; 11.7) was also similar. Information on agents administered as BAT was available for 89 lines of therapy. Commonly administered agents in the second line or later included midostaurin (46.1%), cladribine (32.6%), and hydroxyurea (7.9%).

At baseline, a greater proportion of patients treated with avapritinib vs BAT had elevated serum tryptase (80.6%; 65.4%) and received prior treatment with TKIs (89.6%; 48.1%). However, more patients in the BAT arm had 1 or more mutated genes in the SRSF2/ASXL1/RUNX1 panel vs the avapritinib cohort.

Reference

Reiter A, Gotlib J, Alvarez-Twose I, et al. Overall survival and duration of treatment in patients with advanced systemic mastocytosis receiving avapritinib versus midostaurin or best available therapy in a real-world setting. Blood. 2024;144(suppl 1):1801. doi:10.1182/blood-2024-204015