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Gastrointestinal Stromal Tumor (GIST)

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Therapies

Antineoplastics

Antineoplastics, anticancer drugs encompassing a diverse and large group of medications, mostly have some degree of hepatotoxicity. Antineoplastic agents may be classified by what they treat, the mechanism of action, chemical structure, cytotoxic vs noncytotoxic, or nonspecific versus targeted. The antineoplastic agents, which target gastrointestinal stromal tumors (GISTs), are classified under protein kinase inhibitors.1

Protein kinase inhibitors specifically target the altered protein kinases within cancer cells that contribute to their abnormal growth.2 Protein kinases are proteins found either on the surface of the cell or within the cell. These kinases participate in cell signaling pathways involved in cellular growth and proliferation, metabolism, and inflammatory responses. These protein kinases are  “activated” when a phosphate group attaches to a specific amino acid site on the protein.2 There are more than 500 protein kinases encoded by the human genome. They are classified as tyrosine, serine-threonine, or nonspecific (both), depending on specificity of their amino acids.2 The specific type of protein kinase inhibitors to target GISTs are classified as tyrosine kinase inhibitors.    

Tyrosine Kinase Inhibitors

GISTs respond in diverse ways to tyrosine kinase inhibitors. The European Society for Medical Oncology (ESMO) advises evaluation of both tumor size and density via computer tomography (CT) scan, MRI, or ultrasound to visualize consistent tumor changes and to thereby determine tumor response to treatment.3 If the GIST demonstrates tumor progression absence after a 6-month course of treatment, this is also counted as a positive tumor response. ESMO recommends KIT, PDGFRA, and SDH mutation genotyping to guide treatment decision-making using tyrosine kinase inhibitors.3 

Imatinib mesylate (Gleevec) is a first-line tyrosine kinase inhibitor used both in adjuvant and neoadjuvant treatment of GIST. Adjuvant therapy means that imatinib is used following the primary treatment of surgical resection to prevent GIST recurrence. In neoadjuvant therapy,  imatinib is used prior to primary treatment of surgical resection to some previous treatments that had been tried in the past were strong recommendations against their use by the 2015 ATS/ERS/JRS/ALAT guidelines.

These treatments include the anticoagulant, warfarin; the selective endothelin receptor antagonist, ambrisentan; the tyrosine kinase receptor, imatinib; and the combination therapy of prednisone, azathioprine, and N-acetylcysteine (NAC).2 Conditional recommendations against the use of the phosphodiesterase-5 inhibitor, sildenafil, as well as NAC monotherapy, and the dual endothelin receptor antagonists macitentan and bosentan.2 These decisions were made based on inconclusive or negative results from studies.

Shrink GISTs that are classified as borderline or marginally resectable are considered too dangerous to resect due to their large size or their location near blood vessels or other vital structures which render the operation risky.4 

Patients with GISTs caused by the mutation in exon 11 of the KIT gene demonstrate the highest response to use of imatinib (90%) due to increased activity levels of the medication in these tumors. Patients with GISTs caused by KIT exon 9 Ala502_Tyr503dup mutations that predominantly develop in the intestines demonstrate less responsiveness to imatinib (50%). For these individuals, it is recommended to increase imatinib dosage from the standard 400 mg daily to 800 mg daily over a month as long as the patient tolerates the graduated increase.5 

Individuals with GISTs caused by the PDGFRA gene mutation respond well to imatinib, except in cases of D842V mutation. Providers agree that patients with the PDGFRA D842V mutation should not receive imatinib due to the lack of responsiveness in this genotype.5 

When imatinib is not well tolerated by the patient or is ineffective against advanced GIST progression, treatment using other tyrosine kinase inhibitors is considered in a specific order. 

Sunitinib (Sutent) is less targeted than imatinib. The FDA approved sunitinib in 2006 as a second-line therapy for advanced GIST.4 Sunitinib slowed tumor progression by 27 weeks compared with 6 weeks in individuals who did not receive the therapy.5 GISTs caused by secondary mutations in exons 13 and 14 are most responsive to sunitinib. Additionally, sunitinib demonstrates marked activity against GISTs caused by primary mutations in exon 11.6 

Regorafenib for Advanced GIST

Regorafenib (Stivarga) is a third-line drug therapy for advanced GIST in individuals no longer responding to imatinib or sunitinib. Regorafenib demonstrated an improved progression-free survival (PFS) of 4.8 months compared with the 0.9-month PFS of the placebo group in phase III trials.4,7 Regorafenib demonstrates activity against primary KIT exon 11 mutations coupled with secondary mutations in exons 14, 17, and 18.6 

Three fourth-line agents have obtained FDA approval for treatment of advanced GIST, including avapritinib (Ayvakit), nilotinib (Tasigna), and ripretinib (Qinlock). The FDA approved Avapritinib in January of 2020. Avapritinib targets GISTs caused by PDGFRA and PDGFRA D842 mutations in addition to multiple KIT exon 11, exon 17, and a mix of exon 11 and 17 mutations.5 Avapritinib is especially indicated for use in treating individuals with unresectable or metastatic GISTs caused by PDGFRA exon 18 mutations, including the PDGFRA D842V mutations, which are deemed unresponsive to imatinib.5 61% of patients with PDGFRA exon 18 mutations responded to avapritinib for at least 6 months or longer.8 

Nilotinib is designed specifically to overcome imatinib resistance by binding more tightly than imatinib to the KIT and PDGFRA kinase proteins in GIST. A study conducted in 2009 investigated nilotinib efficacy in patients who had progressive GIST despite imatinib or sunitinib treatments (96%). The remaining 4% of participants were intolerant to imatinib or sunitinib. Out of 52 patients in the study, 5 responded to nilotinib and 19 achieved GIST stabilization, proving that nilotinib is active in GIST that is resistant to imatinib and sunitinib. Median PFS of nilotinib treatment was 12 weeks and median overall survival was 34 weeks.9  

Ripretinib obtained FDA approval in May, 2020 for use in patients with unresectable, locally advanced, or metastatic GIST. Ripretinib demonstrated a 6.3-month PFS compared with the 1-month PFS in the placebo group in clinical trials.4,5

Sorafenib (Nexavar) and dasatinib (Sprycel) are investigational fourth-line therapies for advanced GIST.4 Patients with advanced, imatinib/sunitinib-resistant GIST benefited from sorafenib, demonstrating a 1-year overall survival rate of 23% and a median progression-free survival of 7.7 months.10 

In a prospective multicenter phase II study, dasatinib showed modest anticancer activity in patients who had metastatic GIST which failed to respond to imatinib and sunitinib therapies. Primary and secondary gene mutations are not predictive of GIST responsiveness to dasatinib. The 3-month PFS rate was 53.4% and the median overall survival was 14 months.11   

Individuals with GISTs caused by SDH gene mutations demonstrate overall resistance to treatment with tyrosine kinase inhibitors. Therefore, surgical intervention is the treatment of choice for these patients despite frequent recurrence. Clinical trials testing the safety and efficacy of systemic agents that treat SDH-deficient GIST are in progress.12 

References

  1. Antineoplastic agents. In: LiverTox: Clinical and Research Information on Drug-Induced Liver Injury. National Institute of Diabetes and Digestive and Kidney Diseases; 2012. Accessed June 22, 2021.
  2.  LiverTox: clinical and research information on drug-induced liver injury. National Institute of Diabetes and Digestive and Kidney Diseases; 2012. Accessed June 27, 2021.
  3. Casali PG, Abecassis N, Bauer S, et al. Gastrointestinal stromal tumours: ESMO–EURACAN clinical practice guidelines for diagnosis, treatment and follow-up. Annals of Oncology. 2018; 29:iv68-iv78. doi:10.1093/annonc/mdy095
  4. Choti, MA. Gastrointestinal stromal tumors (GISTs): practice essentials, background, pathophysiology. Medscape. Published online April 3, 2021. Accessed June 22, 2021.
  5. Choti, MA. Gastrointestinal stromal tumors (GISTs) treatment and management: medical care. Medscape. Accessed June 23, 2021.
  6. Napolitano A, Vincenzi B. Secondary KIT mutations: the GIST of drug resistance and sensitivity. Br J Cancer. 2019; 120(6):577-578. doi:10.1038/s41416-019-0388-7 
  7. Demetri GD, Reichardt P, Kang Y-K, et al. Efficacy and safety of regorafenib for advanced gastrointestinal stromal tumours after failure of imatinib and sunitinib: an international, multicentre, prospective, randomised, placebo-controlled phase 3 trial (GRID). Lancet. 2013; 381(9863):10.1016/S0140-6736(12)61857-1. doi:10.1016/S0140-6736(12)61857-1
  8. Heinrich M, von Mehren M, Jones RL, et al. Avapritinib is highly active and well-tolerated in patients with advanced GIST driven by a diverse variety of oncogenic mutations in KIT and PDGFRA. Presented at: Connective Tissue Oncology Society 2018 Annual Meeting; November 15, 2018; Rome, Italy. Accessed June 27, 2021.
  9. Montemurro M, Schöffski P, Reichardt P, et al. Nilotinib in the treatment of advanced gastrointestinal stromal tumours resistant to both imatinib and sunitinib. Eur J Cancer. 2009; 45(13):2293-2297. doi:10.1016/j.ejca.2009.04.030 
  10. Rutkowski P, Jagielska B, Andrzejuk J, et al. The analysis of the long-term outcomes of sorafenib therapy in routine practice in imatinib and sunitinib resistant gastrointestinal stromal tumors (GIST). Contemp Oncol (Pozn). 2017; 21(4):285-289. doi:10.5114/wo.2017.72393
  11. Zhou Y, Zhang X, Wu X, et al. A prospective multicenter phase II study on the efficacy and safety of dasatinib in the treatment of metastatic gastrointestinal stromal tumors failed by imatinib and sunitinib and analysis of NGS in peripheral blood. Cancer Med. 2020; 9(17):6225-6233. doi:10.1002/cam4.3319
  12. Neppala P, Banerjee S, Fanta PT, et al. Current management of succinate dehydrogenase deficient gastrointestinal stromal tumors.Cancer Metastasis Rev. 2019; 38(3):525-535. doi:10.1007/s10555-019-09818-0

Reviewed by Kyle Habet, MD, on 7/1/2021.

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