Avapritinib: novel hope for patients with metastatic gist with PDGFRA exon 18 mutation

Abstract

Gastrointestinal stromal tumors (GISTs) are mesenchymal neoplasms of the gastrointestinal tract associated with high rates of malignant transformation. The activating mutations in platelet-derived growth factor receptor A (PDGFRA) have been linked to the development of GISTs, and up to approximately 10% of GIST cases involve mutations of this gene. Current treatment options for metastatic GIST are minimal, mainly trusting on tyrosine kinase inhibitors (TKIs) such as Imatinib, Sunitinib and Regorafenib. However, eventually, most patients develop resistance to TKIs, usually due to the acquisition of secondary mutations. Moreover, 5-6% of patients with unresectable of metastatic GIST have the primary PDGFRA D842V mutation, which makes it resistant to all approved treatment options. Avapritinib, a potent and selective TKI of KIT and PDGFRA activation loop mutants. The drug demonstrates anti-tumor activity by inhibiting the autophosphorylation of KIT D816V and PDGFRA D842V, thereby terminating the downstream signalling. The drug is available in oral formulation with a recommended dosage of 300 mg once daily. The onset of Avapritinib is fast, shows rapid absorption and linear pharmacokinetics. Most common adverse reactions seen are edema, fatigue, abdominal pain, and neurocognitive defects. Clinical trials for Avapritinib have been positive, and results suggest that the drug may be a new safe and effective option for metastatic GIST treatment. With Blueprint Medicines having already received US FDA approval in January 2020, Avapritinib may soon be an addition to the mounting armoury of drugs against metastatic GIST harbouring PDGFRA exon 18 mutation.

Treatment of Gastrointestinal Stromal Tumors (GISTs): A Focus on Younger Patients

“…In total, 49% of patients required dose modifications (reduction or treatment discontinuation). In total, 48% of participants treated with avapritinib experienced grade 1–3 cognitive impairment [ 90 ].…”

Treatment of Metastatic Gastrointestinal Stromal Tumors (GIST): A Focus on Older Patients

“…Dose modification effectively managed the grade 2 cognitive impairment. The median time to improvement was 12.0 days for any intervention and 32.5 days for no intervention [ 113 ]. The cognitive disturbances may be AEs of special importance in older patients during avapritinib therapy.…”