Gastrointestinal Stromal Tumors: Management of Advanced Disease

Third-line Therapy

Patients who have progressed on prior imatinib and sunitinib can receive third-line regorafenib, a multi-TKI that differs chemically from sorafenib by a fluorouracil group (fluoro-sorafenib). FDA approval of regorafenib was based on the phase 3 GRID (GIST Regorafenib In progressive Disease) multicenter international trial.²⁰ This trial randomly assigned 199 patients in a 2:1 fashion to receive regorafenib 160 mg daily for 21 days out of 28-day cycles plus best supportive care (BSC) versus placebo plus BSC. Cross-over was allowed. Regorafenib significantly reduced the hazard risk of progression by 73% compared with placebo (4.8 vs 0.9 months; HR, 0.27; P < 0.001). There was no difference in OS, which may be because of cross-over (median OS, 17.4 months in both arms). As a result, regorafenib is now considered standard third-line treatment for patients with metastatic GISTs. It has a less favorable toxicity profile than imatinib, with hand-foot syndrome, transaminitis, hypertension and fatigue being the most common treatment toxicities. In order to avoid noncompliance, it is recommended to start at 80 mg and carefully titrate upwards to the 160 mg dose.

A list of landmark studies for advanced GISTs is provided in Table 1.

A summary of FDA-approved drugs for treating GISTs is provided in Table 2.

Clinical Trials

Clinical trial enrollment should be considered for all patients with advanced or unresectable GISTs throughout their treatment continuum. Owing to significant advances in genomic profiling through next-generation sequencing, multiple driver mutations have recently been identified, and targeted therapies are being explored in clinical trials.²¹ For example, the neurotrophic receptor tyrosine kinase (NTRK) gene appears to be mutated in a small number of advanced GISTs, and these can respond to the highly selective TRK inhibitor larotrectinib.²² Additionally, ongoing studies are assessing immunotherapies for sporadic GISTs and treatment for familial GISTs (Table 3). Some notable studies include those assessing the efficacy of agents that target KIT and PDGFR secondary mutations, including avapritinib (BLU-285) and DCC-2618, MEK inhibitors, and the multi-kinase inhibitor crenolanib for GISTs harboring the imatinib-resistant PDGFRA D842V mutation. There are also studies utilizing checkpoint inhibitors alone or in combination with imatinib.

Case Conclusion

Given the patient’s progression on imatinib, he is started on second-line sunitinib malate. He experiences grade 1 fatigue and hand-foot syndrome, which are managed supportively. After he has been on sunitinib for approximately 8 months, his disease progresses. He subsequently undergoes genomic profiling of his tumor and starts BLU-285 on a clinical trial.

Key Points

• For advanced and metastatic disease, TKIs have substantially improved the prognosis of KIT mutated GISTs, with 3 FDA-approved drugs: imatinib, sunitinib, and regorafenib. Imatinib 400 mg is the standard-of-care frontline therapy for locally advanced, unresectable, or metastatic imatinib-sensitive GISTs. If a patient has a KIT exon 9 mutation and 400 mg is well-tolerated, increasing to 800 mg is recommended. Imatinib should be continued indefinitely unless there is intolerance, a specific patient request for interruption, or progression of disease.
• When there is progression of disease in a patient with a sensitive mutation on 400 mg of imatinib, the dose can be increased to 800 mg.
• For patients who are imatinib-intolerant or have progression, standard second line is sunitinib.
• For patients who further progress or are sunitinib-intolerant, regorafenib is the standard third-line treatment.
• There needs to be close attention to side effects, drug and food interactions, and patient copay costs in order to maintain patient compliance while on TKI therapy.
• There are still major limitations in the systemic treatment of GISTs marked by their inherent genetic heterogeneity and secondary resistance. Continued translational and clinical research is needed in order to improve treatment for patients who develop secondary resistance or who have less common primary resistant mutations. Patients are encouraged to participate in clinical trials of new therapies.

Summary

GISTs are the most common mesenchymal tumors of the GI tract. They comprise an expanding landscape of tumors that are heterogenous in terms of natural history, mutations, and response to systemic treatments. The mainstay of treatment for localized GISTs is surgical resection followed by at least 3-years of adjuvant imatinib for patients with high-risk features who are imatinib-sensitive. Patients with GISTs harboring resistance mutations such as PDGFRA D842V or with SDH-deficient or NF1-associated GISTs should not receive adjuvant imatinib. Patients with more advanced GISTs and/or in difficult to resect sites harboring a sensitive mutation can be considered for neoadjuvant imatinib. Those with metastatic GISTs can receive first-, second-, and third-line imatinib, sunitinib, or regorafenib, respectively. Clinical trial enrollment should be encouraged for patients whose GISTs harbor primary imatinib-resistant mutations, and those with advanced or unresectable GISTs with secondary resistance.