Gastrointestinal stromal tumor (GIST) is the most common gastrointestinal cancer of mesenchymal origin. It is mostly driven by oncogenic KIT and PDGFRA gain-of-function mutations. This disease is most prevalent among adults aged between 60 and 65 years.

There are a number of possible treatment strategies for patients with advanced GIST. Surgery is the treatment of choice when the tumor is still small and localized. In advanced GIST, surgery is rarely the first-line therapy; nonetheless, a number of studies have indicated that surgery in patients with metastatic GIST is safe. 

The first-line therapy for advanced GIST, regardless of whether a decision has been made on surgery, is a tyrosine kinase inhibitor (TKI), such as imatinib. Imatinib was approved by the US Food and Drug Administration (FDA) in 2002 for the treatment of advanced GIST. The approval process was relatively quick due to the availability of studies that demonstrated the efficacy of imatinib at 2 doses in patients with advanced GIST. 


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However, imatinib does not necessarily improve clinical outcomes across the board. Research indicates that recovery from GIST is driven by multiple factors.

“The more appropriate predictor of clinical outcomes is frailty,“ Dudzisz‐Śledź and colleagues wrote in Drugs and Aging. “Additionally, the age of 65 years has been identified, along with multimorbidity and polypharmacy, as a significant risk factor for adverse drug reactions.” 

Read more about GIST etiology 

The primary mechanism of imatinib failure is the rise of secondary mutations in KIT among certain populations. Patients who are resistant to imatinib treatment are usually prescribed another TKI, such as sunitinib or ripretinib. Studies have indicated both of these drugs are efficacious in improving clinical outcomes, compared to placebo.

In a paper recently published in the American Society of Clinical Oncology Educational Book, Schaefer and colleagues detailed recent progress in treating advanced GIST. They wrote that, although the contours of treatment protocols remain as described, new TKIs have the potential to become significant game-changers in the treatment of advanced GIST. 

Two Novel Therapeutic Options

Schaefer et al’s study examined 2 of these TKIs: ripretinib and avapritinib. Ripretinib is a broad KIT/PDGFRA inhibitor; it was designed to better target primary and secondary mutations in KIT and PDGFRA. Blay and colleagues conducted a study that demonstrated the drug significantly improved the median progression-free survival time of patients with advanced GIST, compared to placebo. In addition, ripretinib achieved disease stabilization in roughly half of the treatment group. Blay and colleagues also found it had an acceptable safety profile and was well-tolerated overall. 

All TKIs currently targeting KIT and PDGFRA are type II inhibitors, except for avapritinib, which is a selective type I inhibitor. Schaefer and colleagues called avapritinib “a milestone in cancer treatment.” This is due to studies revealing a disease control rate of 100% at all doses, as well as an overall response rate of 91%. Avapritinib is commonly used for the treatment of advanced GIST harboring any PDGFRA exon 18 mutation. 

However, these novel therapies also raise questions that need to be answered. First, how do they impact disease progression? This information is crucial; the last thing we want is for broad TKIs like ripretinib to indirectly trigger KIT-independent mechanisms of progression. 

Read more about GIST treatment 

Second, do we have a backup plan should these therapies fail? Because TKIs such as ripretinib and avapritinib are newer, they are more likely to be used as third- or fourth-line therapies, after the more commonly recommended TKIs have failed. Drug resistance is a common problem everywhere; there is no reason to believe ripretinib and avapritinib will be spared.

“Although multikinase inhibitors such as sunitinib and regorafenib might have some activity, there is a lack of truly effective treatments after avapritinib progression,” Schaefer et al wrote. This makes it more likely for patients to be continued on these medications even if they fail, since there are no alternatives.

The Potential of Molecular Classification

Another potential way forward in GIST therapy is the determination of GIST molecular subtypes—with the view of tailoring treatment to the individual molecular profile of the patient.

“The determination of specific molecular subtypes is the cornerstone for the clinical management of GIST from localized to metastatic disease, given their relevance to predicting the clinical behavior and the response to molecularly targeted agents,” Schaefer et al wrote. 

We already know a fair amount about the molecular classification of GIST. For example, we know that around 80% of GISTs harbor gain-of-function KIT mutations. The most common mutation occurs on KIT exon 11, followed by KIT exon 9. Around 10% of GISTs are KIT and PDGFRA wild-types associated with genetic mutations in the RAS-MAPK pathway. 

“Knowledge of the molecular landscape in GIST is important because it provides prognostic information but also guides therapeutic selection,” Kelly and colleagues wrote in the Journal of Hematology & Oncology.

It is imperative that clinical trials are designed in such a way as to allow for the development of therapies according to the different molecular subtypes of GIST. This would be an investment toward the vision of increasingly personalized medicine in the future. 

One practical way to improve care now is to do so in a multidisciplinary setting. This is important given the need for radiological, surgical, and oncological expertise in the management of GIST. In the case of GIST, multidisciplinary care is best conducted within a dedicated sarcoma center.

References

Kelly CM, Gutierrez Sainz L, Chi P. The management of metastatic GIST: current standard and investigational therapeuticsJ Hematol Oncol. 2021;14(1):2. doi:10.1186/s13045-020-01026-6

Schaefer IM, DeMatteo RP, Serrano C. The GIST of advances in treatment of advanced gastrointestinal stromal tumorAm Soc Clin Oncol Educ Book. 2022;42:1-15. doi:10.1200/EDBK_351231

Dudzisz-Śledź M, Bylina E, Teterycz P, Rutkowski P. Treatment of metastatic gastrointestinal stromal tumors (GIST): a focus on older patientsDrugs Aging. 2021;38(5):375-396. doi:10.1007/s40266-021-00841-x

Blay JY, Serrano C, Heinrich MC, et al. Ripretinib in patients with advanced gastrointestinal stromal tumours (INVICTUS): a double-blind, randomised, placebo-controlled, phase 3 trialLancet Oncol. 2020;21(7):923-934. doi:10.1016/S1470-2045(20)30168-6