Better understanding of the molecular and genetic characteristics that underlie the aberrant behavior of GIST has increased the accuracy of its diagnosis, and allowed for the identification of distinct genetic hallmarks, prognostic groups, and treatment strategies. Collectively, this has resulted in the development of targeted tyrosine kinase inhibitors, imatinib and sunitinib, and continues to prompt studies of novel agents for primary and metastatic disease. Ongoing research will define the optimal duration of imatinib, as well as the role of sunitinib and emerging novel therapies in overcoming treatment-resistant GIST.

The 5-year overall survival (OS) rate for individuals with primary gastrointestinal stromal tumors (GISTs) undergoing macroscopically complete resections was only 54% prior to the advent of targeted therapy for this rare sarcoma.  The risk of recurrence may now be predicted based on 3 key prognostic factors. They are size, mitotic count, and site of origin.  The success of targeted therapy with imatinib and sunitinib in patients with advanced GISTs has led to the investigation of imatinib as an adjuvant and neoadjuvant agent in patients with resectable primary GIST in an effort to improve resectability, recurrence-free survival (RFS), and OS. 

The ACOSOG Z9001 phase III trial randomized patients with resected GIST at least 3 cm in size to receive one year of imatinib or placebo postoperatively.  One year of imatinib improved RFS but there was no evidence of improved OS.  Nevertheless, the RFS benefit was sufficient to change the standard of care, and imatinib was approved by the FDA as an adjuvant therapy for at least 1 year following resection of primary GISTs at least 3 cm in size.  Earlier this year, at the ASCO Annual Meeting, investigators reported the results of the SSGXVIII/AIO phase III trial randomizing patients with operable GIST with a high risk of recurrence to 1 versus 3 years of imatinib.

Imatinib has also been evaluated as a neoadjuvant agent in patients with large, borderline resectable GIST.  The RTOG 0132 phase II trial reported that neoadjuvant therapy with imatinib is a safe and feasible approach. This presentation will discuss these concepts along with recent clinical trial data and emerging paradigms will be reinforced using patient case studies.

Gastrointestinal stromal tumors (GISTs) are characterized by activating mutations in KIT (80-85%) or PDGFRA (7.5%) that can be treated by small molecule tyrosine kinase inhibitors that target KIT/PDGFRA. Imatinib mesylate is FDA-approved as 1st line therapy.  The majority, 70-80%, of GISTs respond to imatinib, primarily with stable disease. Approximately 20% of GISTs exhibit primary imatinib resistance. Responsive GISTs tend to have KIT exon 11 mutations while primary resistance correlates predominantly with KIT exon 9, KIT exon 17, and PDGFRA exon 18 D842V mutations. KIT exon 9 mutations can be rescued therapeutically by increasing the imatinib dose to 800mg daily. Because genotypic correlates of primary imatinib resistance are known, the question of whether the KIT/PDGFRA genotype of recurrent/metastatic disease should be determined has been raised. Currently, NCCN guidelines suggest that mutational analysis should be considered for metastatic/advanced disease.

Secondary/acquired resistance arises within 2 years of the initiation of therapy in approximately 50% of GISTs that initially respond to imatinib. Secondary resistance correlates with the acquisition of second-site, intra-allelic KIT mutations that interfere with imatinib binding or render KIT insensitive to imatinib. The most common KIT V654A and T670I mutations are sensitive to sunitinib malate, which is FDA-approved as 2nd  line therapy for imatinib-resistant GISTs or imatinib-intolerant patients.

There is currently no FDA approved 3rd line therapy. Several novel KIT/PDGFRA inhibitors are being tested. Furthermore, a variety of other therapies are being considered including those that destabilize KIT, those that interfere with downstream KIT signaling, immune-based therapies, and those therapies that disrupt cell survival pathways.

Gastrointestinal stromal tumors (GISTs), the most common mesenchymal tumors of the gastrointestinal tract, represent neoplasms that are far more common than recognized prior to the 21st century.  The clinical presentation of GIST spans a remarkable spectrum from tiny, benign growths to life-threatening, aggressively malignant cancers.  Prior to the advent of rationally-designed tyrosine kinase inhibitors (TKIs), GIST was recognized as a form of sarcoma that is absolutely resistant to traditional cytotoxic chemotherapy and radiation treatment. While surgery remains the primary treatment modality for patients with GIST, advanced GIST remains incurable for patients with metastatic or unresectable disease. The standard of care for diagnosing and managing patients with GIST rapidly changed after the introduction of effective TKI therapies, such as imatinib and sunitinib that address the fundamental mutations which are drivers of disease in the majority of GIST patients.

Imatinib, the first TKI targeting the mutant oncogene products of KIT and PDGFRA, has improved the median survival of patients with metastatic GIST from less than 6 months to nearly 5 years, with some patients still benefitting from disease control more than 11 years on continuous imatinib dosing from the initial US trial. This research has advanced the treatment paradigm by defining molecularly distinct subsets of GIST that exhibit different clinical behavior, with implications for decision-making.  For example, data support the fact that patients with GIST driven by the KIT exon 9 mutation may benefit from doses of imatinib higher than 400 mg daily. Sunitinib, a structurally distinct inhibitor of KIT, PDGFR and VEGFR kinases, was able to show benefit in terms of disease control for GIST patients following failure of imatinib after drug resistance and disease progression. Other new kinase inhibitors, such as the investigational new agent regorafenib, are being tested in phase 3 trials for GIST patients, with early data documenting what appears to be unique activity in GIST.  Research has also translated these advances from late-stage disease into early adjuvant therapy with great impact to prevent early recurrences of GIST with benefits in overall survival.

The rationally targeted approach to understanding GIST and developing new therapeutics serves as a paradigm for the development of similar approaches to other more common gastrointestinal tumors, as well as other forms of cancer. This presentation will expand this concept of GIST as an ideal model for the discovery and development of mechanistically justified targeted therapies in human cancer.