11  TKIs for Systemic Mastocytosis

11.1 Midostaurin

• 100 mg BID

• Only TKI we can use for plt <50

• International, multi-centre open label study of oral midostaurin in 89 patients with advanced disease (ASM n = 16, SMAHN n = 57, MCL n = 16) demonstrated an overall response rate of 60% regardless of the subtype. (Gotlib J, NEJM 2016).

• The important thing when you look at the, the New England Journal paper is there were no crs and there were no C. There were all partial remissions or clinical improvement.

The median overall survival was 28.7 months (44 months amongst responders) and progression free survival was 14.1 months amongst all patients, with 77% of patients demonstrating a reduction in spleen size

11.2 Avapritinib

• For ASM patients

11.2.1 EXPLORER DeAngelo et al. (2021)

• Phase 1 study
• N= 86
• In this trial no limitations on the platelet count

11.2.2 PATHFINDER Gotlib et al. (2021)

• Phase 2
• N=107
• Only accrued patients with Plt>50

Side effects of avapritinib

1. Not be given with platelet counts <50,000/microL due to an increased potential risk of intracranial hemorrhage.

2. Grade ≥3 cytopenias (~25% of pts)

3. facial/periorbital edema (any grade) (~50% of pts). Periorbital edema can get better with cold compresses.

4. Cognitive changes

5. Worsening of hypertension

The avapritinib medicine can cause your kidney function to look falsely low based on normal labs, and so the cystatin C test helps us to have a better understand the true kidney function

11.2.3 POINEER Study (ISM patients only) Gotlib et al. (2023)

• Gotlib NEJM Evidence
• a randomized double-blind placebo-controlled trial of 251 patients with ISM, studied avapritinib, a KITD816V-specific inhibitor

11.3 Bezuclastinib

• 150 mg OD

• Does not cross the blood-brain barrier

11.3.1 APEX trial

• N=32
• Advanced SM patients
• ASH 2024 DeAngelo et al. (2024)

11.3.2 SUMMIT trial

• Non-adv SM patients

Side effects

• Change in hair color (normal KIT causes melanin deposition)

11.4 Elenestinib

• non-brain penetrant
• potently and selectively inhibits KIT D816V

11.4.1 HARBOR trial (ISM patients only)

11.4.2 AZURE trial DeAngelo et al. (2022)

• Closed

• Andrew K trial is ongoing

DeAngelo, Daniel J., Jason Gotlib, Vinod Pullarkat, et al. 2024. “Apex Part 1: Updated Assessment of Bezuclastinib (CGT9486), a Selective KIT D816V Tyrosine Kinase Inhibitor, in Patients with Advanced Systemic Mastocytosis (AdvSM).” Blood 144 (Supplement 1): 659–59. https://doi.org/10.1182/blood-2024-193678.

DeAngelo, Daniel J., Deepti H. Radia, Tracy I. George, et al. 2021. “Safety and Efficacy of Avapritinib in Advanced Systemic Mastocytosis: The Phase 1 EXPLORER Trial.” Nature Medicine 27 (12): 2183–91. https://doi.org/10.1038/s41591-021-01538-9.

DeAngelo, Daniel J., Andreas Reiter, Tracy I. George, et al. 2022. “AZURE: A Phase 1/2 Study of Blu-263 as Monotherapy and in Combination with Azacitidine in Patients with Advanced Systemic Mastocytosis.” Blood 140 (Supplement 1): 6877–78. https://doi.org/10.1182/blood-2022-167410.

Gotlib, Jason, Mariana Castells, Hanneke Oude Elberink, et al. 2023. “Avapritinib Versus Placebo in Indolent Systemic Mastocytosis.” NEJM Evidence 2 (6). https://doi.org/10.1056/evidoa2200339.

Gotlib, Jason, Andreas Reiter, Deepti H. Radia, et al. 2021. “Efficacy and Safety of Avapritinib in Advanced Systemic Mastocytosis: Interim Analysis of the Phase 2 PATHFINDER Trial.” Nature Medicine 27 (12): 2192–99. https://doi.org/10.1038/s41591-021-01539-8.