FDA approves first targeted therapy to treat a rare mutation in patients with gastrointestinal stromal tumours

The US Food and Drug Administration (FDA) has approved Ayvakit (avapritinib) for the treatment of adults with unresectable (unable to be removed with surgery) or metastatic (when cancer cells spread to other parts of the body) gastrointestinal stromal tumor (GIST) – a type of tumor that occurs in the gastrointestinal tract, most commonly in the stomach or small intestine – harbouring a platelet-derived growth factor receptor alpha (PDGFRA) exon 18 mutation. This approval includes GIST that harbours a PDGFRA D842V mutation, which is the most common exon 18 mutation. Ayvakit is a kinase inhibitor, meaning it blocks a type of enzyme called a kinase and helps keep the cancer cells from growing.

“GIST harbouring a PDGFRA exon 18 mutation does not respond to standard therapies for GIST. However, this approval provides patients with the first drug specifically approved for GIST harbouring this mutation,” said Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence and acting director of the Office of Oncologic Diseases in the FDA’s Center for Drug Evaluation and Research. “Clinical trials showed a high response rate with almost 85 per cent of patients experiencing tumor shrinkage with this targeted drug.”

GISTs arise from specialised nerve cells found in the walls of the gastrointestinal tract. One or more mutations in the DNA of one of these cells may lead to the development of GIST. These cells aid in the movement of food through the intestines and control various digestive processes. More than half of GISTs start in the stomach. Most of the others start in the small intestine, but GISTs can start anywhere along the gastrointestinal tract. The activating mutations in PDGFRA have been linked to the development of GISTs, and up to approximately 10 per cent of GIST cases involve mutations of this gene.

The FDA approved Ayvakit based on the results of a clinical trial involving 43 patients with GIST harbouring a PDGFRA exon 18 mutation, including 38 patients with PDGFRA D842V mutation. Patients received Ayvakit 300 mg or 400 mg orally once daily until disease progression or they experienced unacceptable toxicity. The recommended dose was determined to be 300 mg once daily. The trial measured how many patients experienced complete or partial shrinkage (by a certain amount) of their tumors during treatment (overall response rate). For patients harbouring a PDGFRA exon 18 mutation, the overall response rate was 84 per cent, with seven per cent having a complete response and 77 per cent having a partial response. For the subgroup of patients with PDGFRA D842V mutations, the overall response rate was 89 per cent, with eight per cent having a complete response and 82 per cent having a partial response. While the median duration of response was not reached, 61 per cent of the responding patients with exon 18 mutations had a response lasting six months or longer (31 per cent of patients with an ongoing response were followed for less than six months).

Common side effects for patients taking Ayvakit were edema (swelling), nausea, fatigue/asth