Gastrointestinal stromal tumors (GISTs) are rare tumors of the gastrointestinal 
(GI) tract yet represent the most common GI sarcomas. Most GISTs are driven by 
activating mutations of the KIT and/or PDGFRA genes. Prior to the development of 
tyrosine kinase inhibitors (TKIs), GISTs were associated with a poor prognosis 
because conventional cytotoxic chemotherapy was relatively ineffective. However, 
TKIs that inhibit the most common driver mutations in KIT or PDGFRA have 
revolutionized the treatment of GISTs over the past two decades. 
Notwithstanding, ongoing management challenges relate to the development of 
secondary mutations in these genes, resulting in tumor progression. Due to both 
the intra- and inter-patient heterogeneity of these secondary mutations in 
GISTs, optimal treatment requires an agent that blocks as many mutant genes as 
possible. Ripretinib - a novel switch-control TKI - inhibits many of the most 
common primary and secondary activating KIT and PDGFRA mutants involved in GIST 
progression through a dual mechanism of action. In the pivotal INVICTUS 
phase III trial, patients with advanced GIST that had progressed on at least 
imatinib, sunitinib, and regorafenib and who received ripretinib experienced 
significantly longer progression-free survival (primary endpoint) as well as 
prolongation of overall survival, compared with those receiving placebo. 
Treatment with ripretinib was associated with durable improvements in 
quality-of-life indices and a manageable toxicity profile. The most frequent 
side effects were common to the class of TKIs used in the management of GIST. 
These results led to the approval of ripretinib for treatment of advanced GIST 
in adults who have received three or more TKIs, including imatinib. Ripretinib 
is also under investigation in the second-line treatment of advanced GIST in a 
phase III trial (INTRIGUE) comparing ripretinib with sunitinib in patients with 
advanced GIST after treatment with imatinib.
PLAIN LANGUAGE SUMMARY: Use of ripretinib for the treatment of gastrointestinal 
stromal tumors (GISTs) Gastrointestinal stromal tumors (GISTs) are a rare type 
of tumor most commonly located in the stomach and small intestine but can 
develop anywhere throughout the gastrointestinal tract. The symptoms of GISTs 
vary in extent depending on location of the primary tumor and include a feeling 
of fullness, abdominal pain, intestinal bleeding, and fatigue. Since these 
symptoms are nonspecific, making a diagnosis can be challenging. Most GISTs 
carry initial mutations in genes that control specific enzymes called tyrosine 
kinases. Historically, treatment of GISTs was limited because traditional 
chemotherapy is ineffective against these tumors. However, with the introduction 
of drugs that inhibit tyrosine kinases [i.e., tyrosine kinase inhibitors 
(TKIs)], survival has been extended substantially. However, many GISTs go on to 
develop secondary mutations that render them resistant to a given TKI. Prior to 
the approval of ripretinib, four TKIs were available for the treatment of GIST: 
imatinib; sunitinib; regorafenib; and, recently, avapritinib. Each drug is used 
until resistance develops or patients are unable to tolerate the side effects of 
treatment, after which the next drug is started. Ripretinib was recently 
approved by the FDA as the fourth drug in the usual treatment sequence 
recommended for patients with advanced GIST who have progressed (or are 
treatment intolerant) after receiving three or more TKIs, including imatinib. 
Approval of ripretinib was based on the results of the INVICTUS trial, which 
demonstrated that the drug significantly improves the time patients have without 
progression of the disease or death compared with placebo. The most common side 
effects related to ripretinib were hair loss, muscle pain, nausea, fatigue, 
hand-foot syndrome, and diarrhea, although most events were not very severe. 
Ripretinib is being further studied as the second TKI used in patients with GIST 
who have progressed on or could not tolerate first-line treatment with imatinib.