Gastrointestinal Stromal Tumor (GIST)

Gastrointestinal stromal tumors (GISTs) are the most common sarcomas of the digestive system. Before the advent of tyrosine kinase inhibitor (TKI) drug therapy, patients with advanced or metastatic GISTs had an overall survival rate of 10 to 20 months without this treatment. Emergence of TKI treatment occurred during the last 2 decades, and clinical guidelines stipulate a drug therapy sequence for patients with advanced GISTs. This sequence includes imatinib as the first-line TKI therapy, sunitinib as the second-line TKI therapy, and regorafenib as the third-line TKI therapy. The most recent developments include two TKI treatments: ripretinib as a fourth-line therapy and avapritinib as a first-line therapy for individuals with platelet-derived growth factor receptor alpha (PDGFRA) exon 18 D842V mutations.1  

There are several experimental therapies under clinical investigation that can progress care of patients with advanced GIST, each with different efficacy and safety profiles. These current investigational therapies include targeted kinase inhibitor (KI) therapies approved for other forms of cancer, immunotherapies, combination therapies, and alternating or cycling therapies.1 

Cabozantinib GIST
Cabozantinib is orally available kinase inhibitor and antineoplastic agent that is used in treatment of advanced, metastatic medullary thyroid cancer Credit: PubChem

Experimental Targeted Kinase Inhibitor Therapies 

Cabozantinib is a KI approved for use in thyroid cancer, renal cell carcinoma, and hepatocellular carcinoma being tested as a third-line therapy for advanced GIST. The progression-free survival (PFS) at 12 weeks is 60% with 80% of patients achieving a partial response or stable disease. The median PFS is 6 months. Diarrhea, hypertension, fatigue, and palmar-plantar erythrodysesthesia syndrome (PPES).1

Sorafenib is a KI approved for use in kidney, liver, and thyroid cancer being tested for fourth-line, but possibly third-line therapy for advanced GIST. The mean PFS was 7.2 months, and 40% of patients achieved a partial response or stable disease; 72% of patients reported adverse events but none discontinued use.1 

Nilotinib is a KI approved to treat Philadelphia chromosome chronic myeloid leukemia (CML) being tested as a second- or third-line, possibly first-line therapy for advanced GIST. Comparison studies showed imatinib with a 59.2% efficacy and nilotinib with a 51.6% efficacy as a first-line therapy. Nilotinib resulted in a PFS of 24 months. 8% of participants in the study discontinued use of nilotinib, while only 5% discontinued imatinib. Adverse events of nilotinib included abdominal pain, nausea, and rashes. In the study which investigated nilotinib as a second- or third-line therapy, 4 of 12 patients achieved stable disease. The most common adverse events were anemia, fatigue, and anorexia.1 

Dasatinib is a KI approved to treat CML and acute lymphocytic leukemia (ALL) being tested as a second-line GIST therapy. Median PFS is 2.9 months with partial response reported in 25% of patients. Serious adverse events such as pleural effusion, nausea and vomiting, and muscle weakness occurred in 24% of patients taking dasatinib.1 

Pazopanib is a vascular endothelial growth factor receptor and c-KIT and PDGF-R kinase inhibitor approved to treat advanced renal cell cancer and metastatic soft tissue sarcomas. It is being tested as a third-line GIST therapy. Median PFS was 3.4 months compared to 2.3 months with supportive care only. The most common adverse effect was hypertension, and 72% of patients reported grade 3 or higher adverse events.1,2 

Pazopanib GIST
Pazopanib is a pyrimidine that is 5-(pyrimidin-2-yl}amino-2-methylbenzenesulfonamide substituted at position 4 by a (2,3-dimethylindazol-6-yl)(methyl)amino group. It has a role as an antineoplastic agent, a tyrosine kinase inhibitor, a vascular endothelial growth factor receptor antagonist and an angiogenesis modulating agent. Credit: PubChem

Ponatinib is a TKI approved to treat CML and ALL being tested as a third-line GIST therapy. Clinical benefit rate (CBR) was 55% at greater than or equal to 16 weeks for patients with a primary KIT exon 11 mutation and 22% for those without a primary KIT exon 11 mutation. The most common adverse events included rash, myalgia, dry skin, and fatigue.1,2

Crenolanib is a PDGFRA inhibitor undergoing Phase III clinical trials who have advanced or metastatic GIST with a D842V mutation in the PDGFRA gene without published results.2

Vandetanib is a VEGFR2 inhibitor which has been explored in a soon-to-be-published completed phase II clinical trial for children and adults. Only nine participants had wild-type GIST.2

Famitinib is a receptor tyrosine kinase (RTK) inhibitor which targets c-KIT, PDGFRA, VEGFR2, VEGFR3, and Flt3 being tested as a second-line therapy against GIST after imatinib and comparing its efficacy with sunitinib. No results have been published.2 

Anlotinib is an RTK inhibitor which targets VEGFR2 and VEGFR3. There is a phase III clinical trial without published results studying the efficacy of anlotinib in patients with advanced GIST after imatinib failure.2 

Other alternative TKI therapies targeting imatinib refractory GIST include masitinib, dovitinib, vatalanib, and linsitinib.3,4 

Masitinib demonstrated a median PFS of 3.7 months compared with 1.9 months in the control group of patients taking sunitinib. Median overall survival of the masitinib group was 29.8 months compared with the 17.4 months in the sunitinib group.3

Dovitinib demonstrated a median PFS of 3.6 months and a median overall survival of 9.7 months.3 

Vatalanib demonstrated a median time to progression of 4.5 months.3 

Linsitinib demonstrated a median PFS of 9.1 months.4 

Experimental Immunotherapies

Immunotherapeutic agents used in these clinical trials are anti-programmed cell death protein-1 (PD-1/PDL 1) molecules as well as cytotoxic T-lymphocyte-associated antigen 4 (CTLA4).2

Pembrolizumab is an anti-PD-1 humanized monoclonal immunoglobulin IgG4 antibody approved to treat multiple cancers. In GIST treatment, 11% of patients demonstrated a 6-month non progression rate with mild adverse events such as diarrhea, anemia, and fatigue.1,2 

Nivolumab and ipilimumab combine to form an anti-PD-1 antibody treatment for multiple cancers and this treatment is being tested as a third-line, possibly second-line GIST therapy. Nivolumab is a human immunoglobulin IgG4 monoclonal antibody which targets PD-1 and PDL-1.2 Ipilimumab is a recombinant human immunoglobulin IgG1 monoclonal antibody directed against CTLA4.2 This combination treatment demonstrated a median PFS of 8.43 weeks compared to only 8 weeks with nivolumab alone. One patient experienced grade 3 fatigue in the nivolumab-only group and 1 patient experienced diarrhea in the nivolumab + ipilimumab group.1

Seventeen clinical trials are ongoing to determine the efficacy of the following experimental immunotherapies for GIST treatment: spartalizumab, avelumab, and PDR001 as well as the pembrolizumab, nivolumab, and ipilimumab.2 

Spartalizumab is a humanized monoclonal antibody which targets PD-1. A phase Ib clinical trial testing spartalizumab in combination with ribociclib has yet to recruit patients.2 

Avelumab is a humanized monoclonal antibody which targets PD-1. An ongoing clinical trial is testing avelumab with axitinib in patients with unresectable or metastatic GIST after failure of standard TKI therapies. Another trial combines avelumab with regorafenib in patients with solid tumors and GIST. There are no published results yet from these clinical trials.2 

PDR001 is a monoclonal antibody which targets PD-1. There are two clinical trials (Phase I and Phase II) combining imatinib with PDR001 without any published results at present.2 

Olaratumab is a human IgG1 monoclonal antibody which targets PDGFRA. In a phase II clinical trial treating patients with unresectable or metastatic GIST, results demonstrated no apparent effect on PFS in patients who did not have PDGFRA mutations, but patients with PDGFRA D842V GIST mutations achieved longer disease control compared with past data for this genotype.2

Experimental Combination Therapies

Only four drugs, imatinib, dasatinib, axitinib, and ribociclib have been used in combination with immunotherapy agents in clinical trials, indicating potential for a diverse field of research in combination therapies.2

Imatinib with peginterferon α-2b is a combination therapy where interferon is administered to promote antitumor activity. This combination therapy is approved to treat hepatitis C and melanoma and is being tested as a possible third- or -fourth line GIST therapy. All 7 patients (100%) experienced a complete response or partial response to treatment with 100% overall survival at follow-up. All patients had the adverse effect of flu-like symptoms including low-grade fever. Three patients had grade 3 neutropenia and 2 patients had skin rash.1 

Imatinib with buparlisib is a phosphoinositide 3-kinase inhibitor combination therapy approved to treat breast cancer being tested as a third-line GIST therapy. There was no partial or complete response with a median PFS of 3.5 months. Adverse events were reported in 98.3% of patients with 45% being grade 3 or 4 adverse events such as nausea and fatigue.1

Imatinib with binimetinib is a combination therapy with a mitogen-activated protein kinase (MAPK) inhibitor approved to treat metastatic melanoma being tested as a first-line GIST therapy. Of 38 patients, 26 had a partial response with the best objective response rate of 68.4%. Grade 3 and 4 toxicities included creatinine phosphokinase (CPK) elevations, neutrophil decreases, anemia, and rash.1 

Binimetinib is a MEK1/2 inhibitor undergoing Phase Ib/II clinical trials for patients with advanced GIST in combination with imatinib without published results. Another clinical trial yet to begin will study the effects of the combination binimetinib with pexidartinib on GIST.2

Axitinib is a PDGFR inhibitor used in a phase II trial combined with avelumab to treat unresectable or metastatic GIST as a second-line treatment without published results.2

Alvocidib is a cyclin-dependent kinase (CDK) inhibitor which demonstrated poor results in a trial treating patients with metastatic or recurrent GISTs when combined with doxorubicin.2 

Ribociclib is another CDK inhibitor which is currently being investigated in a phase Ib multicenter open label study combined with spartalizumab without published results.2 

Pexidartinib is a TKI inhibitor which will be studied in a phase I clinical trial in combination with binimetinib to treat patients with advanced GIST.2

Experimental Alternating or Cycling Therapies

Imatinib/regorafenib (ALT-GIST) is an alternating regimen for GIST with the patient taking imatinib for 21 to 25 days with a 3-to-7-day washout, then initiating regorafenib for 21 days with a 7-day washout. This alternating therapy is being tested as a first-line GIST therapy. Responses to imatinib and the alternating therapy were similar. One patient on the alternating therapy had a complete response. Twenty-three patients had a partial response and 15 attained stable disease. The PFS at 1 year was 86%. Seven patients discontinued the alternating therapy regimen due to toxicity while 38% of patients on the alternating therapy regimen had serious adverse events.1 

Sunitinib/regorafenib is an alternating therapy regimen with the patient taking sunitinib for 3 days and then regorafenib for 4 days without any washouts. This cycling therapy is being tested as a fourth-line GIST therapy. Four patients achieved stable disease. The median PFS was 1.9 months with the median overall survival of 10.8 months. All patients experienced treatment-related adverse events, but most were mild in nature (grades 1 and 2). Four patients reported grade 3 adverse events of hypertension or PPES.1  

Imatinib rechallenge (RIGHT) is a rechallenge for patients who demonstrated disease progression while taking imatinib and sunitinib. This is being tested as a third-line GIST therapy. The median PFS with imatinib was 1.8 months compared with 0.9 months in the placebo group. Adverse events included fatigue, anemia, and hyperbilirubinemia. Imatinib rechallenge improved PFS in advanced GIST patients, but the rechallenge was not as efficacious as regorafenib as a third-line GIST TKI therapy.1  

Other Experimental GIST Therapies 

Monoclonal antibodies and small-molecule inhibitors which target specific signaling pathways involved in the formation of GISTs or proteins associated with resistance to existing TKI therapies are being investigated as alternative GIST therapies. Researchers are also investigating additional targeted approaches involving inhibition of the regulators of protein folding, chromatin packaging, and cell-cycle regulation.5 

Secondary resistance develops in about 50% of individuals receiving imatinib over a 2-year period. Specific gene mutations and metastatic capacity for specific areas of the body are associated with this secondary resistance. GIST metastasis occurs in the liver (28%), mesentery and omentum (30%), lungs (7%), subcutaneous tissues (4.7%), lymph nodes (4.7%), and bone (2.3%).2 Recent research reveals the role of fibroblast growth factor (FGF) ligands lessening the therapeutic effect of imatinib on GISTs. A potential therapeutic area of study may investigate inhibitors for the FGF family to overcome imatinib resistance. A recent study demonstrates that c-KIT independent GISTs expressed epidermal growth factor receptor (EGFR), while in c-KIT positive GISTs, EGFR was not expressed. There is a reasonable hypothesis that EGFR expression is related to imatinib resistance; however, there is conflicting evidence from experimentation using gefitinib to prove this hypothesis. Further research on the relationship of EGFRs to imatinib resistance is needed to improve understanding of the molecular mechanisms involved in secondary resistance development.2 

The main mechanism of imatinib resistance and tumor progression involves complex molecular pathways associated with secondary mutations. Cellular signaling pathways responsible for imatinib resistance include the Hippo pathway, MAPK, BET, PTEN, PI3K, PRKCQ, and JUN. Future research should target these pathways to target secondary resistance.2 

Several studies recommend the novel approach using liquid biopsy of circulating tumor DNA instead of requiring multiple tumor tissue biopsies to monitor resistance and response of GIST to TKI treatment. The argument is that the tissue biopsy only provides a static picture of disease progression which overlooks the inter- and intra-metastatic molecular heterogeneity and typifies most GIST. Further, liquid biopsy can theoretically overcome all the limitations of tissue biopsies as tumor tissue in formalin-fixed paraffin-embedded blocks is not optimal for wide genome analysis. It requires high-throughput technologies for which fresh DNA is more suitable’.GIST may provide the optimal field for research using this challenging method.6,7

Molecular profiling of high-risk GISTs will increase understanding of GIST and lead to development of specific drugs that target resistance mutations. Solutions for NF1 and BRAF mutations and SDH-deficient GIST have also not been researched.8 


  1. Patel SR, Reichardt P. An updated review of the treatment landscape for advanced gastrointestinal stromal tumors. Cancer. 2021; 127(13):2187-2195. doi:10.1002/cncr.33630
  2. Vallilas C, Sarantis P, Kyriazoglou A, et al. Gastrointestinal stromal tumors (GISTs): novel therapeutic strategies with immunotherapy and small molecules. Int J Mol Sci. 2021; 22(2):E493. doi:10.3390/ijms22020493
  3. Kelly CM, Gutierrez Sainz L, Chi P. The management of metastatic GIST: current standard and investigational therapeutics. J Hematol Oncol. 2021; 14:2. doi:10.1186/s13045-020-01026-6
  4. A phase 2 study of linsitinib (OSI-906) in pediatric and adult wild type gastrointestinal stromal tumors. National Cancer Institute (NCI). 2018. Accessed June 29, 2021. 
  5. Sankhala KK. Clinical development landscape in GIST: from novel agents that target accessory pathways to revisiting non-targeted therapies. Expert Opin Investig Drugs. 2017; 26(4):427-443. doi:10.1080/13543784.2017.1303045
  6. Nannini M, Astolfi A, Urbini M, Biasco G, Pantaleo MA. Liquid biopsy in gastrointestinal stromal tumors: a novel approach. J Transl Med. 2014; 12:210. doi:10.1186/1479-5876-12-210
  7. Wozniak A, Gebreyohannes YK, Debiec-Rychter M, Schöffski P. New targets and therapies for gastrointestinal stromal tumors. Expert Rev Anticancer Ther. 2017; 17(12):1117-1129. doi:10.1080/14737140.2017.1400386
  8. Mohammadi M, Gelderblom H. Systemic therapy of advanced/metastatic gastrointestinal stromal tumors: an update on progress beyond imatinib, sunitinib, and regorafenib. Expert Opinion on Investigational Drugs. 2021; 30(2):143-152. doi:10.1080/13543784.2021.1857363

Article reviewed by Debjyoti Talukdar, MD, on July 1, 2021.