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NCCN Guidelines Version 1.2026

## Gastrointestinal Stromal Tumors

NCCN Guidelines Index Table of Contents Discussion

*Margaret von Mehren, MD/Chair † Fox Chase Cancer Center

*John M. Kane III, MD/Vice-Chair ¶ Roswell Park Comprehensive Cancer Center

Samantha A. Armstrong, MD † Indiana University Melvin and Bren Simon Comprehensive Cancer Center

Tessa Balach, MD †¶ The UChicago Medicine Comprehensive Cancer Center

Andrew J. Bishop, MD § The University of Texas MD Anderson Cancer Center

Darya Buehler, MD ≠ University of Wisconsin Carbone Cancer Center

Shauna R. Campbell, MD § Case Comprehensive Cancer Center/ University Hospitals Seidman Cancer Center and Cleveland Clinic Taussig Cancer Institute

Janai Carr-Ascher, MD, PhD † UC Davis Comprehensive Cancer Center

Edwin Choy, MD, PhD † Mass General Cancer Center

Mary Connolly, MSW ¥ The Ohio State University Comprehensive Cancer Center - James Cancer Hospital and Solove Research Institute

Amanda Dann, MD ¶ UT Southwestern Simmons Comprehensive Cancer Center

Elizabeth J. Davis, MD $\blacktriangleright$† Vanderbilt-Ingram Cancer Center

Sarah Dry, MD ≠ UCLA Jonsson Comprehensive Cancer Center

Vanessa Eulo, MD † O'Neal Comprehensive Cancer Center at UAB

Kristen N. Ganjoo, MD † Stanford Cancer Institute

Ricardo J. Gonzalez, MD ¶ Moffitt Cancer Center

Pedro A. Hermida De Viveiros, MD ‡ Robert H. Lurie Comprehensive Cancer Center of Northwestern University

Ying J. Hitchcock, MD § Huntsman Cancer Institute at the University of Utah

Edward Kim, MD § Fred Hutchinson Cancer Center

Daniel S. Lefler, MD $\blacktriangleright$† Abramson Cancer Center at the University of Pennsylvania

David Liebner, MD $\blacktriangleright$† The Ohio State University Comprehensive Cancer Center - James Cancer Hospital and Solove Research Institute

Martin McCarter, MD ¶ University of Colorado Cancer Center

Sean V. McGarry, MD ¶ Fred & Pamela Buffett Cancer Center

Christian Meyer, MD, PhD † Johns Hopkins Kimmel Cancer Center

Kambiz Motamedi, MD φ UCLA Jonsson Comprehensive Cancer Center Sujana Movva, MD † Memorial Sloan Kettering Cancer Center

NCCN Guidelines Panel Disclosures

Alberto S. Pappo, MD € St. Jude Children's Research Hospital/The University of Tennessee Health Science Center Richard F. Riedel, MD † Duke Cancer Institute Steven Robinson, MBBS † Mayo Clinic Comprehensive Cancer Center Wang Cancer Institute Laura H. Rosenberger, MD, MS † Duke Cancer Institute Scott M. Schuetze, MD, PhD † University of Michigan Rogel Cancer Center

Steven Robinson, MBBS † Mayo Clinic Comprehensive Cancer Center

Laura H. Rosenberger, MD, MS ¶ Duke Cancer Institute

Scott M. Schuetze, MD, PhD † University of Michigan Rogel Cancer Center

Jason K. Sicklick, MD ¶ UC San Diego Moores Cancer Center

William W. Tseng, MD ¶ City of Hope National Medical Center

Mia C. Weiss, MD † Sisteman Cancer Center at Barnes- Jewish Hospital and Washington University School of Medicine

Melissa Zimel, MD T ¶ UCSF Helen Diller Family Comprehensive Cancer Center

NCCN Mary Anne Bergman Vaishnavi Sambandam, PhD

|φ Diagnostic/Interventional radiology|≠ Pathology radiology|≠ Pathology ¥ Patient advocacy € Pediatric oncology § Radiotherapy/Radiation oncology| |---|---|---| |φ Hematology/Hematologic oncology|€ Pediatric oncology § Radiotherapy/Radiation oncology|€ Pediatric oncology § Radiotherapy/Radiation oncology| |β Internal medicine|β Internal medicine ↑ Medical oncology|κ Surgery/Surgical oncology * Discussion writing committee member| |τ Orthopedics/Orthopedic oncology|τ Orthopedics/Orthopedic oncology|★ Discussion writing committee member|

NCCN Guidelines Version 1.2026 Gastrointestinal Stromal Tumors

Version 1.2026, 01/13/26 © 2026 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

NCCN Guidelines Index Table of Contents Discussion

The NCCN Guidelines® are a statement of evidence and consensus of the authors regarding their views of currently accepted approaches to

treatment. Any clinician seeking to apply or consult the NCCN Guidelines is expected to use independent medical judgment in the context of individual clinical circumstances to determine any patient’s care or treatment. The National Comprehensive Cancer Network® (NCCN®) makes no representations or warranties of any kind regarding their content, use or application and disclaims any responsibility for their application or use in any way. The NCCN Guidelines are copyrighted by National Comprehensive Cancer Network®. All rights reserved. The NCCN Guidelines and the illustrations herein may not

NCCN Soft Tissue Sarcoma Panel Members

Summary of the Guidelines Updates

Gastrointestinal Stromal Tumors (GIST)• Workup at Primary Presentation (GIST-1)

• Resectable GIST with Significant Morbidity (GIST-2)

• Postoperative Outcomes and Adjuvant Treatment (GIST-3)

• Unresectable, Recurrent, or Metastatic GIST (GIST-4)

• Treatment for Progressive Disease (GIST-5)

• Principles of Biopsy and Risk Stratification for GIST (GIST-A)

• Principles of Mutation Testing (GIST-B)

• General Principles of Surgery (GIST-C)

• Principles of Interventional Oncology (GIST-D)

• Systemic Therapy Agents and Regimens for GIST (GIST-E)

• Principles of Imaging (GIST-F)

Staging (ST-1)

Abbreviations (ABBR-1)

Find an NCCN Member Institution: https://www.nccn.org/home/memberinstitutions.

NCCN Categories of Evidence and Consensus: All recommendations are category 2A unless otherwise indicated.

See NCCN Categories of Evidence

and Consensus.

NCCN Categories of Preference:

All recommendations are considered appropriate.

See NCCN Categories of Preference.

NCCN Guidelines Version 1.2026 Gastrointestinal Stromal Tumors

NCCN Guidelines Index Table of Contents Discussion

UPDATES

Updates in Version 1.2026 of the NCCN Guidelines for Gastrointestinal Stromal Tumors include:

GIST-2

Neoadjuvant Therapy

• Column 3, modified: For succinate dehydrogenase (SDH)-deficient GIST: Sunitinib or Regorafenib.

GIST-3

Footnote

• w, modified, second sentence: Available data support the use of adjuvant imatinib for high-risk disease for at least 3 years (based on overall survival

benefit) and or at least 6 years (based on disease-free survival benefit).

GIST-4

Follow-up Therapy

• Column 5, flipped Response and Stable disease, added Progression.

• Column 6, off Stable disease, deleted continue TKI.

• Column 7, flipped Resection or Continue TKI if resection not feasible.

GIST-5

Treatment for Progressive Disease

Limited

• Bullet 1, 2nd sub-bullet: deleted procedures.

• Bullet 2, 3rd sub-bullet: new, Palliative radiotherapy if salvage surgical resection of progressive disease and/or ablation is not possible capable.

• Bullet 3, new: If previously treated with avapritinib, consider a switch to an alternate TKI (GIST-E).

GIST-A (1 of 3)

Principles of Biopsy and Risk Stratification for GIST

• Bullet 1, modified: an endoscopic transmural biopsy would be is favored over a percutaneous.

Risk stratification

• Sub-bullet, 1 modified: Pathologic grading by mitotic rate may not be accurate in small biopsies or following neoadjuvant therapy if there is other

evidence of pathologic treatment effect Mitotic rate information might be inaccurate (eg, necrosis, reduced cellularity). If risk stratification is performed on a small biopsy or on a resection specimen following neoadjuvant therapy, there is potential for inaccuracies in the mitotic rate. In this these

situations, risk stratification may...

• Sub-bullet, 3 modified: ...Guidelines for Assessing the Malignant Potential. Deleted the in this instance throughout the guidelines.

GIST-D (1 of 2)

Principles of Interventional Oncology

• Bullet 2, sub-bullet 1, modified:..treatment of liver metastases refractory to targeted therapy imatinib or imatinib and sunitinib.

Patient selection

• Bullet 3, sub-bullet,4 deleted: "Absolute" (Also for GIST-D 2 of 2).

GIST-D (2 of 2)

Patient selection

• Bullet 3, sub-bullet 1, modified: Multidiscipliary discussion can should be performed...

Sub-bullet 3`, modified: ...prohibiting surgical resection can should be considered...

Continued

NCCN Guidelines Version 1.2026 Gastrointestinal Stromal Tumors

NCCN Guidelines Index Table of Contents Discussion

UPDATES

GIST-E (1 of 4)

Systemic Therapy Agents and Regimens for GIST

Neoadjuvant Therapy for Resectable Disease with Significant Morbidity

Preferred

• Bullet 1, modified: Imatinib for KIT or PDGFRA mutations (excluding PDGFRA exon 18 mutations that are insensitive to Imatinib, such as D842V).

Useful in Certain Circumstances

• Bullet 2, sub-bullet 2, new: Regorafenib.

Adjuvant Therapy for Resectable Disease

Preferred

• Bullet 1, modified: Adjuvant Imatinib for patients with significant risk of recurrence, moderate or high risk (category 1 following complete resection with no preoperative imatinib); category 2A following complete resection after preoperative imatinib); see GIST-3.

Footnote

• b, modified,second sentence is new: The optimal duration of adjuvant imatinib is unknown. Available data support the use of adjuvant imatinib for highrisk disease for at least 3 years (based on overall survival benefit) or at least 6 years (based on disease-free survival benefit).

GIST-E 2 of 4

This page has been significiently updated.

GIST-F

Principles of Imaging

Definitively unresectable, recurrent, or metastatic disease

• Bullet 4, sub, sub-bullet 2, modified: In some patients, it may be appropriate to image before "2" 3 months.

Updates in Version 1.2026 of the NCCN Guidelines for Gastrointestinal Stromal Tumors include:

NCCN National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026

Gastrointestinal Stromal Tumors

NCCN Guidelines Index Table of Contents Discussion

WORKUP AT PRIMARY PRESENTATION

MANAGEMENT BASED ON THE RESULTS OF INITIAL DIAGNOSTIC EVALUATION

* All patients should be evaluated and treated by a multidisciplinary team with expertise and experience in gastrointestinal stromal tumors (GIST)

![graph TD\n A1[For very small gastric GIST <2 cm a >Consider endoscopic ultrasound-guided fine-needle aspiration biopsy(EUS-FNAB)b or Endoscopic ultrasound-guided core needle biopsy(EUS-CNB) >Imagingc] --> A2[No high-risk EUS or biopsy features]\n A1 --> A3[High-risk EUSf or biopsy featuresg]\n A1 --> A4[Resectable with minimal morbidity]\n A1 --> A5[Resectable with significant morbidityh,i]\n A1 --> A6[Unresectable or metastatic diseasej]\n A2 --> A7[Consider periodic endoscopic or radiographic surveillancec,l]\n A3 --> A8[Complete surgical resectionm]\n A4 --> A8\n A5 --> A9[If neoadjuvant therapy is planned, biopsyb,k for diagnosis, molecular testing, and(if feasible) risk stratification]\n A6 --> A10[(GIST-4)]\n A8 --> A11[Postoperative Outcomes and Treatment(GIST-3)]\n A9 --> A12[See(GIST-2) for neoadjuvant therapy based on molecular testing to decrease surgical morbidity]\n](1/parseimages/figureca4fe89b17a549438cba0530bdae7dac_0_7.png) a Sepe PS, et al. Nat Rev Gastroenterol Hepatol 2009;6:363-371.

b Principles of Biopsy and Risk Stratification for GIST (GIST-A).

c Principles of Imaging (GIST-F).

d See American Joint Committee on Cancer (AJCC) Staging, 8th Edition (ST-1).

e Mutational analysis may predict response to therapy with tyrosine kinase inhibitors (TKIs) (GIST-B). Tumors with succinate dehydrogenase (SDH) deficiency or NF1 mutations that lack mutations in KIT/PDGFRA may be considered for observation as most, but not all, have more indolent behavior.

f Possible high-risk EUS features include irregular border, cystic spaces, ulceration, echogenic foci, and heterogeneity.

$^{g}$ Possible high-risk pathologic biopsy features include the presence of mitoses and/or tumor necrosis.

Note: All recommendations are category 2A unless otherwise indicated.

$^{1}$ Neoadjuvant therapy for genotype-sensitive disease should be considered for locally advanced GIST in certain anatomical locations, (eg, rectum, esophageal and esophagogastric junction, duodenum), if a multivisceral resection would be required to resect all gross tumor, or in patients who have significant comorbidities and are not fit for surgery.

$^{1}$ Extensive surgery associated with significant morbidity (ie, total gastrectomy to reduce risk of recurrence in stomach) is generally not recommended for SDH-deficient GIST with multifocal disease.

$^{j}$ Consider baseline chest imaging.

* See NCCN Guidelines for Soft Tissue Sarcoma if the pathology results indicate sarcomas of gastrointestinal origin other than GIST.

$^{1}$ Endoscopic ultrasonography surveillance should only be considered after a thorough discussion with the patient regarding the risks and benefits. Evans J, et al. Gastrointest Endosc 2015;82:1-8.

m General Principles of Surgery (GIST-C).

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NCCN Guidelines Index Table of Contents Discussion

![graph TD\n A1[Resectable GIST with significant morbidity] --> A2[Mutational testing⁶ (next-generation sequencing [NGS]) + SDHB immunohistochemistry (IHC)]\n A1 --> A3[NTRK-directed therapies for NTRK fusions For succinate dehydrogenase [SDH]-deficient GIST: Sunitinib or Regorafenib or Observation [category 2B] or Clinical trial BRAF-directed therapies for certain BRAF mutations Forgo neoadjuvant therapy if other mutations [other than listed above)]\n A3 --> A4[Imaging⁵ to assess treatment response⁵ and evaluate patient adherence]\n A4 --> A5[Response⁵ or stable disease⁵]\n A4 --> A6[Progression⁷]\n A5 --> A7[Surgery, if feasible⁸,⁹ after maximal response⁵]\n A5 --> A8[Postoperative Outcomes and Adjuvant Treatment [GIST-3]\n A6 --> A9[Surgery, if feasible⁸,⁸]\n A6 --> A10[If surgery not feasible, see [GIST-5]\n A7 --> A8\n A9 --> A11[Postoperative Outcomes and Adjuvant Treatment [GIST-3]\n](1/parseimages/figuree723a0ab92c24ee7bfea776fd660dede_0_4.png) c Principles of Imaging (GIST-F).

e Mutational analysis may predict response to therapy with TKIs (GIST-B). Tumors with SDH deficiency or NF1 mutations that lack mutations in KIT/PDGFRA may be considered for observation as most, but not all, have more indolent behavior.

m General Principles of Surgery (GIST-C).

n Neoadjuvant therapy for genotype-sensitive disease may prohibit accurate assessment of recurrence risk following resection (GIST-A). Testing tumor for mutation is recommended prior to starting preoperative therapy to ensure tumor has a genotype that is likely to respond to treatment (see above). Consider neoadjuvant therapy only if surgical morbidity could be reduced by downsizing the tumor preoperatively (GIST-E).

° Medical therapy is the usual course of treatment. However, patient may proceed to surgery if bleeding or symptomatic tumor or poor treatment tolerance.

P Maximal response may require treatment for ≥6 months to achieve.

$^{9}$ FDG-PET/CT may give indication of TKI efficacy after 2-4 weeks of therapy when rapid readout of activity is necessary. Frequency of response assessment imaging may be decreased if patient's disease is responding to treatment. See Principles of Imaging (GIST-F).

r Progression may be determined by contrast-enhanced CT or MR imaging with clinical interpretation; FDG-PET/CT scan may be used to clarify if CT or MRI are ambiguous. Increase in tumor size in the presence of decrease in tumor density is consistent with drug efficacy or benefit. See Principles of Imaging (GIST-F).

$^{s}$ Monitor for maximal response if feasible; if maximal response is achieved proceed to surgery.

† Collaboration between medical oncologist and surgeon is necessary to determine the appropriateness and timing of surgery, following major response or sustained stable disease.

Note: All recommendations are category 2A unless otherwise indicated.

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Gastrointestinal Stromal Tumors

NCCN Guidelines Index Table of Contents Discussion

![graph TD\n A1[Gross residual disease(R2 resection) or Preoperative/intraoperative tumor rupturev] --> A2[Should be considered as metastatic disease]\n A2 --> A3[Metastatic disease(GIST-4) For Systemic Therapy(GIST-E)]\n A4[Completely resectedu after neoadjuvant therapy with agent other than imatinib] --> A5[Observe]\n A5 --> A6[History and physical(H&P) and imagingc every 3-6 mo(every 3 mo if high risk) for 5 y, then annuallyx; after 10 y, individualize surveillance]\n A6 --> A7[If Recurrence, see(GIST-4)]\n A8[Completely resectedu(no neoadjuvant therapy)] --> A9[Observe( low-risk disease or non-imatinib-sensitive tumors) or Adjuvant imatinib(category 1) preferred for patients with significant risk of recurrence(moderate or high risk if patient has an imatinib-sensitive mutation)ew(GIST-A)]\n A9 --> A6\n](1/parseimages/figuree4b5103283c645659eaefc28a9058f9f_0_4.png) $^{c}$ Principles of Imaging (GIST-F).

$^{u}$ Completely resected (R0/R1). See GIST-C.

$\bullet$ Some stratification schemes have included tumor rupture, which has been associated with a much higher risk of recurrence. Nishida T, et al. Ann Surg Oncol 2018;25:1961-1969 and Rutkowski P, et al. Ann Surg Oncol 2007;14:2018-2027.

W The optimal duration of adjuvant imatinib is unknown. Available data support the use of adjuvant imatinib for high-risk disease for at least 3 years (based on overall survival benefit) or at least 6 years (based on disease-free survival benefit). The PERSIST study has shown the feasibility of 5-year adjuvant imatinib with no evidence of recurrence in patients with imatinib-sensitive GIST (Raut CP, et al. JAMA Oncol 2018;4:e184060. Other references include Joensuu H, et al. JAMA Oncol 2020;6:1241-6, and Blay J-Y, et al. Ann Oncol 2024;35:1157-1168).

* $X$ Less frequent surveillance may be acceptable for very small tumors (<2 cm), unless they are associated with high mitotic rate.

Note: All recommendations are category 2A unless otherwise indicated.

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Gastrointestinal Stromal Tumors

NCCN Guidelines Index Table of Contents Discussion

![graph TD\n A1[Unresectable primary disease] --> A2[Baseline imagingc,q + Mutational testinge,v (NGS) + SDHB IHC]\n A2 --> A3[Tyrosine kinase inhibitor (TKI)e,y]\n A3 --> A4[Imagingc to assess treatment responseP,q,r and evaluate patient adherence]\n A4 --> A5[Stable disease]\n A4 --> A6[ResponseP]\n A4 --> A7[Progression]\n A5 --> A8[Continue TKIe,y obtain surgical consultation, consider resection]\n A6 --> A9[Resectionm]\n A7 --> A10[(GIST-5)]\n A8 --> A11[Continue TKIe,y if resection not feasible]\n A9 --> A12[Postoperative Outcomes and Adjuvant Treatment (GIST-3)]\n A11 --> A13[H&P and imagingc,r (GIST-F)]\n A14[Recurrent or metastatic disease] --> A15[Life-long systemic therapy is recommended for TKI-sensitive GISTe,y]\n A15 --> A16[Progression]\n A16 --> A10\n](1/parseimages/figuree6e9c8f2845149de922a4da8140265ab_0_4.png) $^{c}$ Principles of Imaging (GIST-F).

m General Principles of Surgery (GIST-C).

P Maximal response may require treatment for ≥6 months to achieve.

$^{q}$ FDG-PET/CT may give indication of TKI efficacy after 2–4 weeks of therapy when rapid readout of activity is necessary. Frequency of response assessment imaging may be decreased if patient's disease is responding to treatment. See Principles of Imaging (GIST-F).

$^{f}$ Progression may be determined by contrast-enhanced CT or MR imaging with clinical interpretation; FDG-PET/CT scan may be used to clarify if CT or MRI are ambiguous. Increase in tumor size in the presence of decrease in tumor density is consistent with drug efficacy or benefit. See [Principles of Imaging (GIST-F)].

† Collaboration between medical oncologist and surgeon is necessary to determine the appropriateness and timing of surgery, following major response or sustained stable disease.

Y Systemic Therapy Agents and Regimens for Unresectable, Progressive, or Metastatic Disease (GIST-E).

Note: All recommendations are category 2A unless otherwise indicated.

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NCCN Guidelines Index Table of Contents Discussion

TREATMENT FOR PROGRESSIVE DISEASE

![graph TD\n A1[Progression] --> A2[Limited]\n A1 --> A3[Generalized （widespread, systemic）]\n A2 --> A4[Continue with the same dose of TKI and consider the following options for lesions progressing on imatinib or avapritinib: > Resection,¹ if feasible⁵a,⁵b > Ablation or embolization, radioembolization, or chemoembolization （GIST-D） > Palliative radiation therapy （RT）（category 2B） for symptomatic lesions]\n A2 --> A5[If previously treated with standard-dose imatinib: > Switch to alternate TKI （GIST-E） > Dose escalation of imatinib as tolerated （if previously treated with standard-dose imatinib; may be most effective for patients with K/IT exon 9 mutation） > Palliative radiotherapy if surgical resection of progressive disease and/or ablation is not possible]\n A2 --> A6[If previously treated with avapritinib, consider a switch to an alternate TKI （GIST-E）]\n A3 --> A7[If disease progression on imatinib or avapritinib: > Switch to alternate TKI （GIST-E） > Dose escalation of imatinib as tolerated （if previously treated with standard-dose imatinib; may be most effective for patients with K/IT exon 9 mutation）]\n A4 --> A8[If disease is progressing despite prior therapies, consider the following options: > Clinical trial > Consider other options listed in GIST-E （based on limited data） > Consider repeat tumor biopsy to potentially identify uncommon mutations that may have a corresponding targeted therapy > Best supportive care⁵c]\n A5 --> A8\n A6 --> A8\n A7 --> A8\n](1/parseimages/figure864bc3dd8b474488b3a169d28ea665c1_0_5.png) Note: All recommendations are category 2A unless otherwise indicated.

NCCN Guidelines Version 1.2026 Gastrointestinal Stromal Tumors

NCCN Guidelines Index Table of Contents Discussion

Note: All recommendations are category 2A unless otherwise indicated.

GIST-A 1 OF 3

PRINCIPLES OF BIOPSY AND RISK STRATIFICATION FOR GIST

• An endoscopic transmural biopsy is favored over a percutaneous transperitoneal biopsy, as the risk for peritoneal seeding is lower for this

technique. However, percutaneous image-guided biopsy may be appropriate for the confirmation of locally advanced or metastatic disease.

Consideration of biopsy should be based on the suspected tumor type and extent of disease. Biopsy is necessary to confirm the diagnosis

of primary GIST prior to the initiation of preoperative therapy.

• Morphologic diagnosis based on microscopic examination of histologic sections is the standard for GIST diagnosis. Several ancillary

techniques are recommended in support of GIST diagnosis, including IHC for SDHB, CD117, and DOG1, and molecular genetic testing for KIT and PDGFRA mutations, as well as other potential drivers (eg, BRAF, NF1, NTRK, and FGFR fusions). See GIST-B.

• Diagnosis is based on the Principles of Pathologic Assessment (NCCN Guidelines for Soft Tissue Sarcoma); referral to centers with

expertise and experience in the diagnosis and management of GIST/sarcoma is recommended for those patients with complex or unusual

histopathologic features.

• Risk stratification:

Pathologic grading by mitotic rate may not be accurate in small biopsies or following neoadjuvant therapy if there is other evidence of

pathologic treatment effect (eg, necrosis, reduced cellularity). In these situations, risk stratification may need to be based on clinical

parameters, size, and anatomic location instead.

Tumor size and mitotic rate are used to predict the malignant potential of GIST, although it is notoriously difficult to predict the biologic

behavior of GIST based on pathologic features alone; thus, guidelines for risk stratification by tumor site have been developed.

Most gastric GIST behave in an indolent manner, especially when <2 cm. See Table 1 (GIST-A 2 of 3) for Guidelines for Assessing Malignant

Potential.

For non-gastric GIST, see Table 2 (GIST-A 3 of 3) for Guidelines for Assessing Malignant Potential.

◊ GIST of the small intestine tends to be more aggressive than its gastric counterpart.

◊ GIST of the colon is most commonly seen in the rectum; colorectal GIST tends to have an aggressive biological behavior, and tumors with mitotic activity can recur and metastasize despite a small size of <2 cm.

Some stratification schemes have included tumor rupture, which has been associated with a much higher risk of recurrence.

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Gastrointestinal Stromal Tumors

NCCN Guidelines Index Table of Contents Discussion

PREDICTORS OF GIST BIOLOGIC RISK

Table 1: Gastric GIST: Guidelines for Assessing Malignant Potential$^{1}$

$\bullet$ This prognostic assessment applies best to KIT- or PDGFRA-positive GIST, whereas SDH-deficient GIST are more unpredictable.

* Risk stratification is determined without prior exposure to TKI therapy.

|Tumor Size|Mitotic $Rate^{2}$|Risk|Risk Per $CAP^{2}$| |---|---|---|---| |≤2 cm|≤5 mitoses/50 HPFs|Metastasis rate: 0%|None| |≤2 cm|>5 mitoses/50 HPFs|Metastasis rate: 0%*|None| |>2 cm to ≤5 cm|≤5 mitoses/50 HPFs|Metastasis rate: 1.9%|Very low (1.9%)| |>2 cm to ≤5 cm|>5 mitoses/50 HPFs|Metastasis rate: 16%|Moderate (16%)| |>5 cm to ≤10 cm|≤5 mitoses/50 HPFs|Metastasis rate: 3.6%|Low (3.6%)| |>5 cm to ≤10 cm|>5 mitoses/50 HPFs|Metastasis rate: 55%|High (55%)| |>10 cm|≤5 mitoses/50 HPFs|Metastasis rate: 12%|Moderate (12%)| |>10 cm|>5 mitoses/50 HPFs|Metastasis rate: 86%|High (86%)|

CAP: College of American Pathologists; HPFs: High-power fields; *Predicted rate based on tumor category with very small numbers

$^{1}$ Data from Miettinen M, Lasota J. Gastrointestinal stromal tumors: pathology and prognosis at different sites. Sem Diag Path 2006;23:70-83. In the original paper, percentages referred to the percentage of patients with progressive disease, whereas low, moderate, and high referred to the risk of metastases.

$^{2}$ The mitotic rate should be measured in the most proliferative area of the tumor, and reported as the number of mitoses per 50 HPF of tissue. Per 50 HPF is a total of 5 mm$^{2}$. For most modern microscopes, 20 to 25 HPF 40 x lenses/fields encompasses 5 mm$^{2}$. Data from Laurini JA. Protocol for the Examination of Resection Specimens from Patients with Gastrointestinal Stromal Tumors (GIST). Version 4.2.0.0, June 2021. Available at: https://documents.cap.org/protocols/Stomach.GIST_4.2.0.REL_CAPCP.pdf. Prognostic contour maps are another source that provides information about risk of recurrence of GIST after surgery. Joensuu H, Vehtari A, Riihimaki J, et al. Risk of recurrence of gastrointestinal stromal tumour after surgery: an analysis of pooled population-based cohorts. Lancet Oncol 2012;13:265-274.

Note: All recommendations are category 2A unless otherwise indicated.

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PREDICTORS OF GIST BIOLOGIC RISK

Table 2: Non-Gastric GIST (includes small bowel and colorectal GIST): Guidelines for Assessing Malignant Potential$^{1}$

$\bullet$ This prognostic assessment applies best to KIT- or PDGFRA-positive GIST whereas SDH-deficient GIST are more unpredictable. For anatomic sites not listed in this table, such as esophagus, mesentery, and peritoneum, or in the case of “insufficient data,” it is best to use risk criteria for jejunum/ileum.

* Risk stratification is determined without prior exposure to TKI therapy.

|Tumor Size|Mitotic $Rate^{2}$|Risk|Risk Per $CAP^{2}$| |---|---|---|---| |≤2 cm|≤5 mitoses/50 HPFs|Metastasis rate: 0%|None| |≤2 cm|>5 mitoses/50 HPFs|Metastasis rate: 50%-54%|Insufficient data - High (54%)| |>2 cm to ≤5 cm|≤5 mitoses/50 HPFs|Metastasis rate: 1.9%-8.5%|Low (4.3%-8.5%)| |>2 cm to ≤5 cm|>5 mitoses/50 HPFs|Metastasis rate: 50%-73%|High (50%-73%)| |>5 cm to ≤10 cm|≤5 mitoses/50 HPFs|Metastasis rate: 24%|Insufficient data - Moderate (24%)| |>5 cm to ≤10 cm|>5 mitoses/50 HPFs|Metastasis rate: 85%|Insufficient data - High (85%)| |>10 cm|≤5 mitoses/50 HPFs|Metastasis rate: 34%-57%|High (34%-57%)| |>10 cm|>5 mitoses/50 HPFs|Metastasis rate: 71%-90%|High (71%-90%)|

CAP: College of American Pathologists; HPFs: High-power fields

$^{2}$ The mitotic rate should be measured in the most proliferative area of the tumor, and reported as the number of mitoses per 50 HPF of tissue. Per 50 HPF is a total of 5 mm$^{2}$. For most modern microscopes, 20 to 25 HPF 40 x lenses/fields encompasses 5 mm$^{2}$. Data from Laurini JA. Protocol for the Examination of Resection Specimens from Patients with Gastrointestinal Stromal Tumors (GIST). Version 4.2.0.0, June 2021. Available at: https://documents.cap.org/protocols/Stomach.GIST_4.2.0.0.REL_CAPCP.pdf. Prognostic contour maps are another source that provides information about risk of recurrence of GIST after surgery. Joensuu H, Vehtari A, Riihimaki J, et al. Risk of recurrence of gastrointestinal stromal tumour after surgery: an analysis of pooled population-based cohorts. Lancet Oncol 2012;13:265-274.

Note: All recommendations are category 2A unless otherwise indicated.

Abstract

Note: All recommendations are category 2A unless otherwise indicated.

NCCN Guidelines Index Table of Contents Discussion

GIST-B PRINCIPLES OF MUTATION TESTING

• Approximately 80% of GIST have a mutation in the gene encoding the KIT receptor tyrosine kinase; another 5%-10% of GIST have a mutation in the gene encoding the related PDGFRA receptor tyrosine kinase. The presence and type of KIT and PDGFRA mutations are not strongly correlated with prognosis.

• The mutations in KIT and PDGFRA in GIST result in expression of mutant proteins with constitutive tyrosine kinase activity. Testing for KIT and PDGFRA mutations should be performed if TKIs are considered as part of the treatment plan since the presence of mutations (or absence of mutations) in specific regions of the KIT and PDGFRA genes are correlated with response (or lack of a response) to specific TKIs.

• Specific mutations in KIT or PDGFRA show some correlation with tumor phenotype, but mutations are not strongly correlated with the biologic potential of individual tumors. The accumulated data show that KIT mutations are not preferentially present in high-grade tumors, and can also be found in small incidental tumors as well as tumors that have an indolent course. Similarly, mutational analysis of PDGFRA cannot be used to predict the behavior of individual tumors.

• GIST have different response rates to imatinib based upon the tumor mutation status: KIT exon 9 mutations have a lower response rate and progression-free survival (PFS) than exon 11 tumors at 400 mg, but dosing at 400 mg BID has been associated with better PFS. Most PDGFRA mutations are associated with a response to imatinib, with the exception of D842V, which responds to avapritinib and is unlikely to respond to imatinib and most other approved TKIs for GIST.

• • Germline KIT and PDGFRA testing should be considered for the following: patients with a family history of GIST and/or melanoma, patients with multifocal GIST, and/or patients with NF1 or SDH-deficient GIST.

References

NCCN Guidelines Version 1.2026 Gastrointestinal Stromal Tumors

NCCN Guidelines Index Table of Contents Discussion

Note: All recommendations are category 2A unless otherwise indicated.

GIST-C

GENERAL PRINCIPLES OF SURGERY

Primary (Resectable) GIST

The surgical procedure performed should aim to resect the tumor with histologically negative margins.

• Given the limited intramural extension, extended anatomic resections (such as total gastrectomy) are rarely indicated. Segmental or wedge resection to obtain negative margins is often appropriate.

• Lymphadenectomy is usually not required given the low incidence of nodal metastases; however, resection of pathologically enlarged nodes should be considered in

patients with known SDH-deficient GIST or known translocation-associated GIST.

• As GIST tends to be very fragile, every effort should be made not to violate the pseudocapsule of the tumor (ie, avoid tumor rupture—any tumor spillage or fracture,

laceration of the tumor capsule with or without macroscopic spillage, and piecemeal resection).

• Incisional biopsy occurring either before or at the time of the operation should be strictly avoided.

• Re-resection is generally not indicated for microscopically positive margins (R1) on final pathology.

Resection should be accomplished with minimal morbidity and, in general, complex multivisceral resection should be avoided. If the surgeon feels that a multivisceral

resection may be required, then multidisciplinary consultation is indicated regarding a course of preoperative therapy (ie, imatinib or avapritinib). Similarly, rectal GIST

should be approached via a sphincter-sparing approach. If abdominoperineal resection (APR) would be necessary to achieve a negative margin resection, then preoperative imatinib should be considered.

A minimally invasive approach may be considered for select GIST in favorable anatomic locations by surgeons with appropriate minimally invasive experience.

• All oncologic principles of GIST resection must still be followed, including preservation of the pseudocapsule and avoidance of tumor spillage.

• Resection specimens should be removed from the abdomen in a plastic bag to prevent spillage or seeding of port sites.

Unresectable GIST

Molecularly guided therapy is the primary treatment for unresectable GIST; see Principles of Systemic Therapy (GIST-E). Surgery may be indicated for:

• Previously unresectable tumors after a favorable response to systemic therapy.

• Management of symptomatic bleeding, obstruction, or perforation.

Metastatic GIST

Molecularly guided therapy is the primary therapy for metastatic GIST. Surgery (peritoneal cytoreduction and/or liver metastasectomy) may be indicated in the following

order:

• Stage IV disease after a favorable response to systemic therapy when complete cytoreduction of peritoneal and/or hepatic disease can be accomplished by an experienced surgeon

• Unifocal progression of disease that is refractory to TKI therapy when other sites of disease are having a favorable response to therapy

• Low-volume multifocal progressive disease that is safely resectable

• Management of symptomatic bleeding, obstruction, or perforation

Considerations Prior to Surgery

• Imatinib can be stopped right before surgery and restarted as soon as the patient is able to tolerate oral medications. If other TKIs such as sunitinib, regorafenib, ripretinib,or avapritinib are being used, therapy should be stopped at least 1 week prior to surgery and can be restarted based on clinical judgment or recovery from surgery.

• Patients with SDH germline mutations are at risk of paraganglioma; 24-hour urine testing is recommended prior to surgery and therefore serum/urine catecholamine/

metanephrine testing should be performed prior to surgery.

NCCN Guidelines Version 1.2026 Gastrointestinal Stromal Tumors

NCCN Guidelines Index Table of Contents Discussion

PRINCIPLES OF INTERVENTIONAL ONCOLOGY

Note: All recommendations are category 2A unless otherwise indicated.

GIST-D 1 OF 2

Catheter-Directed Therapies

• Catheter-directed therapies allow minimally invasive treatment of liver disease in select patients, including those unable to tolerate surgical resection or lesions not amenable to surgery.

• Intra-arterial therapies produce cell death by inducing ischemia and/or locally delivering cytotoxic agents or radiation to hepatic tumors.

Specific intra-arterial therapies include transarterial (bland) embolization (TAE), transarterial chemoembolization (TACE), and transarterial

radioembolization (TARE).

Transarterial Embolization (TAE)

◊ TAE involves delivery of embolic agents within hepatic arteries supplying liver tumors with the goal of vessel stasis.

◊ TAE may be considered for treatment of liver metastases refractory to targeted therapy.1,2

Transarterial Chemoembolization (TACE)

◊ TACE consists of conventional TACE and drug-eluting bead TACE (DEB-TACE). Conventional TACE involves targeted infusion of

chemotherapeutic medications in addition to embolic agents and lipiodol into tumoral blood supply while DEB-TACE drug delivery is

through embolic beads loaded with chemotherapeutic medication.

◊ TACE can be an effective and a well-tolerated treatment in patients with GIST with liver metastases not responsive to TKIs.3,4

Transarterial Radioembolization (TARE)

◊ TARE utilizes beta particle emitting microspheres by yttrium-90 decay to induce tumoricidal effects through local brachytherapy. TARE can be performed with either glass or resin microspheres.

◊ TARE can be a safe and effective treatment option for patients with hepatic metastatic GIST whose disease does not respond to TKIs.5

• Patient selection

Multidisciplinary discussion can be performed to identify candidates who may benefit from catheter-directed therapies.

Patients whose disease progresses on TKI therapies may be considered for transarterial treatments.

Unresectable liver-dominant metastases or patients with medical comorbidities prohibiting surgical resection may be considered for

catheter-directed therapies.

Contraindications to catheter-directed therapies are few, but include:

◊ Uncorrectable coagulopathy

◊ Active infection in the planned treatment area

◊ Decompensated liver failure (relative based on treatment approach)

References on GIST-D (2 of 2)

NCCN Guidelines Index Table of Contents Discussion

PRINCIPLES OF INTERVENTIONAL

Abstract

Note: All recommendations are category 2A unless otherwise indicated.

Abstract

ONCOLOGY GIST-D 2 OF 2 Ablation • Tumor ablation involves application of thermal or non-thermal therapies to a tumor to achieve cell death. Thermal ablation achieves tissue destruction by the induction of extreme hypothermia (cryoablation) or hyperthermia (radiofrequency ablation [RFA], microwave ablation, laser ablation, and highintensity focused ultrasound [HIFU] ). Non-thermal ablation such as irreversible electroporation (IRE) results in permanent cellular membrane injury. Ablation modality can be based on tumor size, location, and adjacent critical structures to optimize treatment effect while limiting potential adverse events. Ablation can include the target lesion in addition to a margin of radiologically normal tissue to ensure complete local treatment. Adjunct passive and active thermoprotective techniques, such as hydrodissection, may be used to protect adjacent critical structures during percutaneous ablation. • Specific considerations in ablation of metastatic disease Liver metastases ◊ Thermal ablation in patients previously treated with TKI is feasible and safe. 6,7,8 ◊ Intraoperative ablation may be complementary to surgical resection to obtain complete response in patients with metastatic disease that may have otherwise been inoperable. 9 • Patient selection Multidisciplinary discussion should be performed to identify candidates who may benefit from ablative therapies. Patients whose disease progresses on conventional therapy with TKIs can be considered for ablation. Unresectable metastases or patients with medical comorbidities prohibiting surgical resection can be considered for image-guided ablation. Contraindications to image-guided ablation are few, but include: ◊ Uncorrectable coagulopathy ◊ Active infection in the planned treatment area ◊ Inability to displace or protect adjacent critical structures (relative based on risk-benefit discussion)

References

NCCN Guidelines Version 1.2026 Gastrointestinal Stromal Tumors

NCCN Guidelines Index Table of Contents Discussion

SYSTEMIC THERAPY AGENTS AND REGIMENS FOR GIST

GIST-E 1 OF 4

a Although mutational analysis is recommended (other than rare circumstances, family history, etc), it is appropriate to start neoadjuvant imatinib pending confirmation

of the mutational analysis. Sharma AK, et al. Clin Cancer Res 2021;27:5334-5342.

b Data do not support routine use in GIST without mutation in KIT or with an imatinib-resistant mutation in PDGFRA. The optimal duration of adjuvant imatinib is

unknown. Available data support the use of adjuvant imatinib for high-risk disease for at least 3 years (based on overall survival benefit) or at least 6 years (based on disease-free survival benefit).

Neoadjuvant Therapy for Resectable Disease with Significant Morbidity (GIST-2)Preferred

• Imatinib for KIT or PDGFRA mutations (excluding PDGFRA exon 18 mutations that are insensitive to Imatinib, such as D842V)a

• Avapritinib for GIST with PDGFRA exon 18 mutations that are insensitive to Imatinib (including PDGFRA D842V)1,2

Useful in Certain Circumstances

• NTRK gene fusion-positive GIST

Larotrectinib

Entrectinib

Repotrectinib3 (category 2B)

• SDH-deficient GIST

Sunitinib

Regorafenib

• BRAF V600E-mutated GIST

Dabrafenib/Trametinib4

Adjuvant Therapy for Resectable Disease (GIST-3)

Preferred

• Adjuvant Imatinibb for patients with significant risk of recurrence, moderate or high risk (category 1 following complete resection with no preoperative imatinib).

References on

Note: All recommendations are category 2A unless otherwise indicated.

GIST-E (3 of 4)

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NCCN Guidelines Index Table of Contents Discussion

SYSTEMIC THERAPY AGENTS AND REGIMENS FOR UNRESECTABLE, PROGRESSIVE, OR METASTATIC DISEASE

|Imatinib-sensitive: KIT and PDGFRA mutant GIST (except PDGFRA exon 18 mutant GIST that is insensitive to Imatinib)||||| |---|---|---|---|---| |First-line Therapyc,d|Second-line Therapyc,e|Third-line Therapyc|Fourth-line Therapyc,e|Additional Options After Progression on Approved Therapiesc,e,f| |Preferred Imatinib9,5,6 (category 1)|Preferred Sunitinib9,11 (category 1).For patients intolerant of second-line Sunitinib, consider changing to Ripretinib 150 mg dailyg,12|Preferred Regorafenib9,14 (category 1)|Preferred Ripretinib 150 mg dailyg,15 (if not previously received) (category 1)|Useful in Certain CircumstancesAvapritinib9,1,2,7 Cabozantinib16Everolimus/TKIh,17Nilotinib18,19Pazopanib20Ponatinib2,21Ripretinib dose escalation to 150 mg BID (if previously treated with Ripretinib 150 mg daily)g,22,23Sorafenib24-26|

|Imatinib-insensitive: PDGFRA exon 18 mutant GIST (including PDGFRA D842V)|| |---|---| |First-line TherapyC|Second-line TherapyC| |Preferred • Avapritinibg1,2,7|Other Recommended • Dasatinib13|

|First-line TherapyC|Second-line TherapyC| |---|---| |Preferred •Avapritinibg$^{1,2,7}$|Other Recommended •Dasatinibg$^{13}$|

|Subsequent therapy irrespective of mutation status| |---| |Useful in Certain Circumstances Tumor mutational burden-high (TMB-H) ► Ipilimumab + Nivolumab27 (category 2B)|

|Other mutations|Other mutations| |---|---| |First-line $Therapy^{c,d}$|Second-line $Therapy^{c}$| |Useful in Certain Circumstances • NTRK gene fusion-positive GIST • Larotrectinib • Entrectinib • Repotrectinib3 • SDH-deficient GIST • Sunitinib • Regorafenib • Pazopanib • Binimetinib/Imatinib (category 2B) • BRAF V600E-mutated GIST • Dabrafenib/Trametinib4|Useful in Certain Circumstances • NTRK gene fusion-positive GIST • Repotrectinib3 (if not previously given)|

c Therapies based on identification of driver mutations. See GIST-B.

$^{d}$ An additional clinical benefit may be obtained with the use of imatinib 400 mg BID upon progression with imatinib.

e An additional clinical benefit may be obtained with the use of ripretinib 150 mg BID upon progression with ripretinib.

f Regimens are ordered alphabetically and not according to order of preference.

9 FDA-approved TKIs for the treatment of GIST.

h TKIs to be considered for use in combination with everolimus include imatinib, sunitinib, or regorafenib.

$^{1}$ Ponatinib demonstrated activity in advanced GIST pretreated with at least 3 prior TKIs, particularly in patients with KIT exon 11 mutant disease.

References on GIST-E (3 of 4)

Note: All recommendations are category 2A unless otherwise indicated.

Note: All recommendations are category 2A unless otherwise indicated. NCCN Guidelines Index Table of Contents Discussion 3 OF 4 SYSTEMIC THERAPY AGENTS AND REGIMENS FOR GIST

References

NCCN Guidelines Index Table of Contents Discussion

Abstract

Note: All recommendations are category 2A unless otherwise indicated.

Abstract

GIST-E 4 OF 4

References

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NCCN Guidelines Index Table of Contents Discussion

PRINCIPLES OF IMAGING

CT is performed with contrast. CT imaging of the chest can be performed with or without contrast, as clinically indicated. MRI is performed with and without contrast, unless contraindicated.

Workup

$\bullet$ For very small GIST <2 cm: CT abdomen/pelvis with contrast and/or MRI abdomen/pelvis with and without contrast

* For all other GIST:

$\bullet$ CT abdomen/pelvis with contrast and/or MRI abdomen/pelvis with and without contrast

$\bullet$ Consider baseline chest imaging (x-ray or CT) for unresectable or metastatic disease

Response Assessment

Resectable disease with significant morbidity

$\bullet$ Obtain baseline contrast-enhanced abdomen/pelvis CT and/or MRI

$\bullet$ Consider FDG-PET/CT

$\bullet$ Obtain baseline FDG-PET/CT if using FDG-PET/CT during follow-up

$\bullet$ FDG-PET/CT, with a non-diagnostic CT, is not a substitute for a diagnostic CT

* Imaging to assess response to preoperative TKI

$\bullet$ CT abdomen/pelvis with contrast and/or MRI abdomen/pelvis with and without contrast every 8-12 weeks

$\bullet$ FDG-PET/CT may give indication of TKI activity after 2-4 weeks of therapy when rapid readout of activity is necessary

* Progression may be determined by CT or MRI with clinical interpretation; FDG-PET/CT may be used to clarify if CT or MRI is ambiguous

$\bullet$ For R2 resection or discovery of metastatic disease

$\blacktriangleright$ Assess response to postoperative TKI via CT abdomen/pelvis with contrast and/or MRI abdomen/pelvis with and without contrast every 8-12 weeks

Definitively unresectable, recurrent, or metastatic disease

$\bullet$ Obtain baseline contrast-enhanced abdomen/pelvis CT and/or MRI

$\bullet$ Consider intermittent chest imaging (x-ray or CT)

* Consider FDG-PET/CT

$\bullet$ Obtain baseline FDG-PET/CT if using FDG-PET/CT during follow-up

$\bullet$ FDG-PET/CT, with a non-diagnostic CT, is not a substitute for a diagnostic CT

* Imaging to assess response to TKI

$\bullet$ CT abdomen/pelvis with contrast and/or MRI abdomen/pelvis with and without contrast every 8-12 weeks after initiating therapy

◇ In some patients, it may be appropriate to image before 2 months

* Progression may be determined by CT or MRI with clinical interpretation; FDG-PET/CT may be used to clarify if CT or MRI is ambiguous

Follow-up

$\bullet$ For completely resected primary disease, perform CT abdomen/pelvis with contrast and/or MRI abdomen/pelvis with and without contrast every 3-6 months for 5 years, then annually. After 10 years, surveillance should be individualized.

$\bullet$ Less frequent imaging surveillance may be acceptable for low-risk tumors. For low-risk tumors, see GIST-A.

$\bullet$ More frequent imaging surveillance may be required for patients with high-risk disease who discontinue TKI therapy

$\bullet$ For incompletely resected disease or discovery of metastatic disease during surgery, perform CT and/or MRI every 3-6 months

$\bullet$ Progression may be determined by CT or MRI with clinical interpretation; FDG-PET/CT may be used to clarify if CT or MRI is ambiguous

$\bullet$ After treatment for progressive disease, reassess therapeutic response with CT or MRI

$\bullet$ Consider FDG-PET/CT only if CT/MRI results are ambiguous

Note: All recommendations are category 2A unless otherwise indicated.

NCCN Guidelines Version 1.2026 Gastrointestinal Stromal Tumors

NCCN Guidelines Index Table of Contents Discussion

ST-1

Used with permission of the American College of Surgeons, Chicago, Illinois. The original source for this information is the AJCC Cancer Staging Manual, Eighth Edition

(2017) published by Springer International Publishing.

American Joint Committee on Cancer (AJCC) Staging System for Gastrointestinal Stromal Tumor (8th ed, 2017)AJCC Anatomic Stage/Prognostic Groups

Gastric GIST*

M Mitotic Rate Stage IA T1 or T2 N0 M0

Low

Stage IB

N0 M0

Low

Stage II

N0 M0

High

N0 M0

High

N0 M0

Low

Stage IIIA T3

N0 M0

High

Stage IIIB T4

N0 M0

High

Stage IV Any T

N1 M0 Any rate Any T Any N M1 Any rate

Small Intestinal GIST**

Mitotic Rate

Stage I

T1 or T2 N0 M0

Low

Stage II

N0 M0

Low

Stage IIIA

N0 M0

High

N0 M0

Low

Stage IIIB

N0 M0

High

N0 M0

High

N0 M0

High Stage IV Any T N1 M0 Any rate Any T Any N M1 Any rate

*Note: Also to be used for omentum.

**Note: Also to be used for esophagus, colorectal, mesenteric, and peritoneal.

Definitions for T, N, M

T Primary Tumor

TX Primary tumor cannot be assessed

T0 No evidence of primary tumor

T1 Tumor 2 cm or less

T2 Tumor more than 2 cm but not more than 5 cm

T3 Tumor more than 5 cm but not more than 10 cm

T4 Tumor more than 10 cm in greatest dimension

N Regional Lymph Nodes

N0 No regional lymph node metastasis or unknown lymph node status

N1 Regional lymph node metastasis

Distant Metastasis

No distant metastasis

Distant metastasis

Grading for GIST is dependent on mitotic rate

Low 5 or fewer mitoses per 5 mm2, or per 50 HPF High Over 5 mitoses per 5 mm2, or per 50 HPF

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Gastrointestinal Stromal Tumors

NCCN Guidelines Index Table of Contents Discussion

ABBREVIATIONS

APR abdominoperineal resection

IHC immunohistochemistry

IRE irreversible electroporation

CAP College of American Pathologists

NGS next-generation sequencing

ctDNA circulating tumor DNA

PFS progression-free survival

DEB-TACE drug-eluting bead transarterial chemoembolization

RFA radiofrequency ablation

EUS- endoscopic ultrasound-guided CNB core needle biopsy

SDH succinate dehydrogenase

EUS- CNB endoscopic ultrasound-guided fine-needle aspiration biopsy

SDHB succinate dehydrogenase comples subunit B

GIST gastrointestinal stromal tumor

TACE transarterial chemoembolization

TAE transarterial embolization

H&P history and physical HIFU high-intensity focused ultrasound

TARE transarterial radioembolization

TKI tyrosine kinase inhibitor

TMB tumor mutational burden-high

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Gastrointestinal Stromal Tumors

NCCN Guidelines Index Table of Contents Discussion

|NCCN Categories of Evidence and Consensus|| |---|---| |Category 1|Based upon high-level evidence (≥1 randomized phase 3 trials or high-quality, robust meta-analyses), there is uniform NCCN consensus (≥85% support of the Panel) that the intervention is appropriate.| |Category 2A|Based upon lower-level evidence, there is uniform NCCN consensus (≥85% support of the Panel) that the intervention is appropriate.| |Category 2B|Based upon lower-level evidence, there is NCCN consensus (≥50%, but <85% support of the Panel) that the intervention is appropriate.| |Category 3|Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate.|

All recommendations are category 2A unless otherwise indicated.

|NCCN Categories of Preference|| |---|---| |Preferred|Interventions that are based on superior efficacy, safety, and evidence; and, when appropriate, affordability.| |Other recommended|Other interventions that may be somewhat less efficacious, more toxic, or based on less mature data; or significantly less affordable for similar outcomes.| |Useful in certain circumstances|Other interventions that may be used for selected patient populations (defined with recommendation).|

All recommendations are considered appropriate.

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Gastrointestinal Stromal Tumors

Discussion

This discussion corresponds to the NCCN Guidelines for Gastrointestinal Stromal Tumors (GIST). The following pages were updated on September 1, 2022: MS-2 & MS-11 to MS-16. The remaining sections were updated on March 27, 2018.

Overview .................................................... MS-2

General Principles .................................................... MS-2

Biopsy and Pathologic Assessment .................................................... MS-2

Prognostic Factors .................................................... MS-3

Imaging.................................................. MS-4

Surgery .................................................... MS-4

Targeted Therapy $\ldots$ MS-5

Impact of Mutational Status on Tumor Response to First-Line Tyrosine Kinase Inhibitors in Patients with Advanced or Metastatic GIST...MS-9

Management of Resistance to Tyrosine Kinase Inhibitors ............................................ MS-12

Initial Evaluation and Workup .................................................... MS-15

Treatment Guidelines .................................................. MS-15

Resectable Disease .................................................... MS-15

Unresectable, Metastatic, or Recurrent Disease .................................................... MS-17

Progressive Disease .................................................... MS-17

Continuation of TKI Therapy .................................................... MS-18

Surveillance .................................................. MS-18

References $\ldots$ MS-19

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NCCN Guidelines Version 1.2026

Gastrointestinal Stromal Tumors

Overview

Gastrointestinal stromal tumors (GIST) are the most common STS of the GI tract, resulting primarily from KIT or PDGFRA activating mutations.$^{1}$ The annual incidence of GIST in the United States is estimated to be between 0.68 to 0.78 per 100,000.$^{2-5}$ GIST can arise anywhere along the GI tract, but stomach (60%) and small intestine (30%) are the most common primary sites.$^{6}$ Duodenum (4%–5%) and rectum (4%) are less common primary sites, and only a small number of cases have been reported in the esophagus (<1%) and colon and appendix (1%–2%).$^{6}$ In very rare occasions, GIST can occur in extraintestinal sites. Patients with a suspected GIST may present with a variety of symptoms, which may include early satiety, abdominal discomfort due to pain or swelling, intraperitoneal hemorrhage, GI bleeding, or fatigue related to anemia.

Some patients may present with an acute abdomen (as a result of tumor rupture, GI obstruction, or peritonitis-like pain), which requires immediate medical attention. Liver and/or the peritoneal surfaces are the most common sites of metastases, whereas lymph node metastases are extremely rare, except in select GIST subtypes. Metastases in the lungs, bone, and other extra-abdominal locations are observed only in advanced cases.

General Principles

Biopsy and Pathologic Assessment

GIST are soft and fragile tumors. The decision to obtain a biopsy should be based on the suspected tumor type and the extent of disease. Biopsy is necessary to confirm the diagnosis of primary GIST prior to the initiation of preoperative therapy.$^{7}$ Recent reports have suggested that definitive diagnosis of GIST requires tissue acquisition via endoscopic ultrasound (EUS)-guided FNA.$^{8}$ EUS-guided FNA (EUS-FNA) biopsy of primary site is preferred over percutaneous biopsy due to the risk of tumor hemorrhage

and intra-abdominal tumor dissemination. Percutaneous image-guided biopsy may be appropriate for confirmation of metastatic disease.

Morphologic diagnosis based on careful microscopic examination of adequate tumor tissue is essential to confirm the diagnosis of GIST. Pathology report should include anatomic location, size, and an accurate assessment of the mitotic rate measured in the most proliferative area of the tumor and reported as the number of mitoses in 50 high-power fields (HPFs) (equivalent to 5 mm$^{2}$ of tissue). The differential diagnosis of GIST should be considered for any GI sarcoma, as well as for any other intra-abdominal sarcoma. The panel recommends referral to centers with expertise in sarcomas for cases with complex or unusual histopathologic features.

Most GIST (95%) express KIT (CD117). Approximately 80% of GIST have a mutation in the gene encoding the KIT receptor tyrosine kinase; another 5% to 10% of GIST have a mutation in the gene encoding the related PDGFRA receptor tyrosine kinase.$^{9-11}$ About 10% to 15% of GIST have no detectable KIT or PDGFRA mutations (wild-type GIST). Other commonly expressed markers include CD34 antigen (70%), smooth muscle actin (25%), and desmin (less than 5%).$^{12}$

Most of the KIT mutations occur in the juxtapembrane domain encoded by KIT exon 11 and some are detected in the extracellular domain encoded by exon 9.$^{13}$ KIT mutations have also been identified in the tyrosine kinase domain (exon 13 and exon 17), although they are very rare.$^{14}$ The majority of the PDGFRA mutations affect exon 18 in the tyrosine kinase domain 2.$^{13}$ Few mutations also occur in exon 12 (juxtamembrane domain) and exon 14 (tyrosine kinase domain 1), although they are rare.$^{15}$ KIT exon 11 mutations are most common in GIST of all sites, whereas KIT exon 9 mutations are specific for intestinal GIST and PDGFRA exon 18 mutations are common in gastric GIST.$^{13}$

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Gastrointestinal Stromal Tumors

Immunohistochemical staining for CD117, DOG1, and/or CD34 and molecular genetic testing to identify KIT and/or PDGFRA mutations are useful in the diagnosis of GIST. However, KIT positivity alone may not be sufficient to confirm the diagnosis and, conversely, the absence of KIT and/or PDFGRA mutations does not exclude the diagnosis of GIST. In GIST with PDGFRA mutations, immunostaining with PDGFRA has been shown to be helpful in discriminating between KIT-negative GIST and other GI mesenchymal lesions.

Loss-of-function mutations in the SDH gene subunits or loss of SDHB protein expression by IHC have been identified in a majority of wild-type GIST lacking KIT and PDGFRA mutations; these findings have led to the use of the term SDH-deficient GIST, which is preferred over the older term, wild-type GIST, for this subset of GIST.$^{16-20}$ SDHB IHC can be useful for the diagnosis of SDH-deficient GIST. BRAF exon 15 mutation (V600E) has also been reported in a small subset of patients with intestinal high-risk GIST lacking KIT/PDGFRA mutations.$^{21,22}$ DOG1 is a calcium-dependent, receptor-activated chloride channel protein and it is expressed in GIST independent of mutation type. DOG1 expression was not different between the KIT/PDGFRA mutant or wild-type GIST, but there was a clear distinction between tumors with PDGFRA and KIT mutations. GIST with PDGFRA mutations had a low KIT expression and high DOG1 expression, which can be used in the diagnosis of KIT-negative tumors.$^{23}$ DOG1 immunostaining may be useful for cases that cannot be categorized as GIST based on CD117 immunostaining and mutation testing for KIT and PDGFRA. DOG1 and KIT could be used together in difficult cases exhibiting unexpected KIT negativity or positivity.$^{7}$

Tumors lacking KIT and PDGFRA mutations should be considered for further evaluations such as SDHB immunostaining. If the tumor is SDH-deficient, germline testing for SDH mutations would be indicated. Inactivating NF1 mutations or activating BRAF mutations are present in a

small minority of tumors that lack KIT and PDGFRA mutations but retain SDH expression.

Prognostic Factors

Tumor size and the mitotic rate are the most widely used pathologic features for the risk stratification of GIST. However, it is difficult to predict the malignant potential of GIST based on these features alone. In a long-term follow-up of 1765 patients with gastric GIST, Miettinen and colleagues reported that the metastatic rate was 86% for tumors >10 cm with a mitotic index of >5 mitoses/50 HPFs, whereas tumors of the same size with a mitotic index of <5 mitoses/50 HPFs have a relatively low metastatic rate of 11%.$^{24}$ In a subsequent report involving 906 patients with small intestinal GIST, tumors >10 cm with a mitotic index of ≤5 mitoses/50 HPF had a metastatic rate of 50%, which is a contrast to that reported for gastric GIST with similar tumor parameters.$^{25}$ Therefore, in addition to the tumor size and mitotic rate, tumor site has also been included in the guidelines developed by Miettinen and colleagues for the risk stratification of primary GIST.$^{6}$ According to these guidelines, gastric GIST have an overall indolent behavior and those that are ≤2 cm (irrespective of the mitotic index) are essentially benign, whereas small intestinal GIST tend to be more aggressive. Rectal GIST are also very aggressive, and tumors <2 cm with a mitotic index of >5 mitoses/50 HPFs have a higher risk of recurrence and malignant potential.

Mutations can be found in high-grade tumors as well as in small incidental GIST and tumors that have a benign course. Therefore, KIT mutational status is not used to determine the malignant potential of a primary GIST. Tumor genotype has been shown to be an independent prognostic factor based on review of 1056 patients with localized GIST in the ConticaGIST database. Factors associated with poorer DFS were KIT exon 9 duplication, KIT exon 11 deletions, nongastric site, larger tumor size, and high mitotic index, whereas PDGFRA exon 18 mutations were associated

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Gastrointestinal Stromal Tumors

with better prognosis.$^{26}$ Long-term follow-up (median 73 months) from the BFR14 trial by the French Sarcoma Group identified female sex as an independent prognostic factor for higher PFS and OS in patients treated with standard-dose imatinib.$^{27}$

The presence and the type of KIT or PDGFRA mutation status are predictive of response to TKI therapy in patients with advanced or metastatic GIST. GIST with SDH mutations are also less sensitive to TKIs. They typically arise in the stomach and are observed in younger individuals, frequently metastasize, may feature lymph node involvement, and tend to grow slowly. See Impact of Mutational Status on Response to Imatinib or Sunitinib in Patients with Advanced or Metastatic GIST in this Discussion.

Imaging

In patients with GIST, imaging is used for diagnosis, initial staging, restaging, monitoring response to therapy, and performing follow-up surveillance of possible recurrence. Contrast-enhanced CT is the imaging modality of choice to characterize an abdominal mass, as well as to evaluate its extent and the presence or absence of metastasis at the initial staging workup for biopsy-proven GIST. PET helps to differentiate active tumor from necrotic or inactive scar tissue, malignant from benign tissue, and recurrent tumor from nondescript benign changes. PET provides significant value to the standard CT images, because changes in the metabolic activity of tumors often precede anatomic changes on CT. However, PET is not a substitute for CT. PET/CT may be used to clarify ambiguous findings seen on CT or MRI or to assess complex metastatic disease in patients who are being considered for surgery. Even in this clinical setting there is no clear evidence that PET provides significant information that cannot be obtained using IV contrast-enhanced CT. PET may be of benefit in patients with IV contrast allergy, particularly for peritoneal disease; MRI with or without contrast usually yields excellent

anatomical definition of liver metastases.$^{7}$ If clinicians consider using PET to monitor therapy, a baseline PET should be obtained prior to the start of therapy.

Response Assessment

To assess response to TKI therapy, abdominal/pelvic CT or MRI is indicated every 8 to 12 weeks. PET may give an indication of imatinib activity after 2 to 4 weeks if rapid read-out is necessary.$^{28}$ Various CT response criteria have been investigated and compared in patients with GIST, including iterations of RECIST, Choi, and WHO criteria.$^{29-35}$

Experts have advocated that the CT response criteria proposed by Choi are much better than RECIST criteria to assess the response of GIST to TKI therapy. Choi criteria have been validated in one center in patients with GIST who had not previously received TKI therapy.$^{29}$ However, these criteria are not universally accepted, they have not been validated for patients who have received several targeted therapies, and the ease of use outside specialized centers is unknown. Some recent studies have supported the use of RECIST, WHO, or volumetric criteria for sunitinib or regorafenib response assessment following progression on imatinib.$^{32-34}$

The EORTC developed metabolic response criteria for tumors evaluated with PET that provide definitions for complete metabolic response, partial metabolic response, stable metabolic disease, or disease metabolic progression.$^{36}$ However, since there is a 95% correlation between the information from regular contrast-enhanced CT and PET/CT, CT with IV contrast is the preferred routine imaging modality for patients with GIST on TKI therapy.

Surgery

Surgery is the primary treatment of choice for patients with localized or potentially resectable GIST lesions. Preoperative imatinib can be considered to decrease surgical morbidity. If persistent metastatic or

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residual tumor remains after surgery, then imatinib should be continued as soon as the patient is able to tolerate oral intake.

GIST are fragile and should be handled with care to avoid tumor rupture. The goal is to achieve complete gross resection of the tumor with an intact pseudocapsule. After removal of any suspected GIST, postoperative pathology assessment is essential to confirm the diagnosis. Segmented or wedge resection to obtain negative margins is often appropriate.

Lymphadenectomy is usually not required given the low incidences of nodal metastases, but resection of pathologically enlarged nodes should be considered in patients with SDH-deficient GIST. Resection should be accomplished with minimal morbidity and complex multivisceral resection should be avoided. Re-resection is generally not indicated for microscopically positive margins on final pathology. If abdominoperineal resection would be necessary to achieve a negative margin, then preoperative imatinib should be considered. If the surgeon feels that a complex surgical procedure is required, then a multidisciplinary consultation regarding the use of preoperative imatinib is recommended.

Sphincter-sparing surgery and esophagus-sparing surgery should be considered for rectal and gastroesophageal junction GIST, respectively. Several case reports have demonstrated that the use of preoperative imatinib enables organ-sparing surgery and improves surgical outcomes in patients with rectal GIST.$^{7}$

The role for laparoscopy in the resection of GIST continues to expand. Although prospective studies are lacking, literature reports based on a small series of patients and retrospective analyses have demonstrated that not only are laparoscopic or laparoscopic-assisted resections possible, but they are also associated with low recurrence rates, short hospital stay duration, and low morbidity.$^{7}$ A meta-analysis of 19 studies (n = 1060 GIST cases) revealed no difference in long-term outcomes of GIST resections using laparotomy and laparoscopy, but laparoscopic

approaches were associated with less blood loss, lower complication rates, and shorter hospital stays.$^{37}$

Laparoscopic approach may be considered for selected GIST in favorable anatomic locations such as anterior wall of the stomach, jejunum, and ileum. The same surgical principles of complete macroscopic resection, including the preservation of the pseudocapsule and avoidance of tumor rupture, should be followed during laparoscopy. Resection specimen should be removed from the abdomen in a plastic bag to avoid spillage or seeding of port sites. Laparoscopic surgery could be feasible in other anatomic sites, such as smaller rectal GIST. However, data on laparoscopic resection of GIST at other sites are limited.

Targeted Therapy

GIST have previously been documented to be resistant to conventional chemotherapies. Since KIT activation occurs in the majority of cases of GIST, KIT inhibition has emerged as the primary therapeutic modality along with surgery for the treatment of GIST.

Imatinib

Imatinib, a selective inhibitor of the KIT protein tyrosine kinase, has produced durable clinical benefit and objective responses in most patients with GIST. In phase II and III studies, imatinib has resulted in high overall response rates and exceptionally good PFS in patients with unresectable and/or metastatic GIST, inducing objective responses in more than 50% of the patients.$^{38-42}$ In February 2002, the FDA approved use of imatinib for the treatment of patients with KIT-positive unresectable and/or metastatic malignant GIST. Long-term follow-up results of the B2222 study (n = 147, randomly assigned to receive 400 or 600 mg of imatinib daily) confirmed that imatinib induces durable disease control in patients with advanced GIST.$^{43}$ The estimated 9-year OS rate was 35% for all patients, 38% for

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those with CR or PR, and 49% for those with stable disease. Low tumor bulk at baseline predicted for longer TTP and improved OS.

Two separate phase III studies (EORTC 62005 study and the S0033/CALGB 150105 study) have assessed the efficacy of imatinib at two initial dose levels (400 mg daily vs. 800 mg daily, given as 400 mg twice a day) in patients with metastatic or unresectable GIST.$^{39,40,42}$ Both studies showed equivalent response rates and OS for both dose levels. Higher dose of imatinib was associated with more side effects than the lower dose in both studies. Although initial findings from the EORTC 62005 study (n = 946) suggested an earlier TTP for patients receiving 400 mg daily,$^{39}$ at a median follow-up of 10.9 years, no significant differences in survival were observed based on imatinib dose level.$^{44}$ In the 400-mg daily vs. 800-mg daily cohort, 10-year PFS rates were 9.5% versus 9.2% (HR, 0.91; 95% CI, 0.79–1.04; P = .18) and 10-year OS rates were 19.4% and 21.5%, respectively (HR, 0.93; 95% CI, 0.80–1.07; P = .31). Similarly, the S0033/CALGB 150105 study (n = 746) reported identical response rates (40% vs. 42%, respectively) at a median follow-up of 4.5 years and there were no statistical differences in PFS (18 months for low-dose arm vs. 40 months for higher-dose arm) and median OS (55 and 51 months, respectively).$^{42}$ Following progression on 400 mg daily, 33% of patients who crossed over to the higher dose achieved objective response rates and stable disease. Among the patients who crossed over to the 800-mg daily dose after progression in EORTC 62005 study (n= 196, 47%), median PFS was 2.76 months.$^{44}$

Available data confirm the safety and efficacy of imatinib at 400 mg/d as the initial standard dose to achieve response induction.$^{39,42}$ Dose escalation to 800 mg/d is a reasonable option for patients progressing on 400 mg/d.$^{40}$

Preoperative Imatinib

The RTOG 0132/ACRIN 6665 is the first prospective study that evaluated the efficacy of preoperative imatinib (600 mg/d) in patients with potentially resectable primary disease (30 patients) or potentially resectable recurrent or metastatic disease (22 patients).$^{45}$ Among patients with primary GIST, PR and stable disease were observed in 7% and 83% of patients, respectively. In patients with recurrent or metastatic GIST, PR and stable disease were observed in 4.5% and 91% of patients, respectively. The estimated 2-year OS rate was 93% and 91% for patients with primary GIST and those with recurrent or metastatic GIST, respectively. The estimated 2-year PFS rate was 83% and 77%, respectively.

In a study conducted at MD Anderson Cancer Center, 19 patients undergoing surgical resection for primary GIST (with or without metastases) or recurrent disease (local or metastatic) were randomized to receive 3, 5, or 7 days of preoperative imatinib (600 mg daily).$^{46}$ The response rate assessed by FDG-PET and dynamic CT was 69% and 71%, respectively. Median DFS of patients treated with surgery and imatinib was 46 months. Tumor size was a predictor of recurrence after postoperative imatinib. However, in this study, there was no histologic evidence of cytoreduction within 3 to 7 days of preoperative imatinib.

In another prospective study, Fiore and colleagues reported that preoperative imatinib improved resectability and reduced surgical morbidity in patients with primary GIST, unresectable or resectable through a major surgical procedure with significant surgical morbidity. Median size reduction was 34% and the estimated 3-year PFS rate was 77%.$^{47}$ Imatinib was continued postoperatively for 2 years in all patients.

In the subgroup analysis of patients with non-metastatic, locally advanced, primary GIST treated with imatinib within the prospective BFR14 phase III study, preoperative imatinib was associated with a PR rate of 60% (15 of 25 patients), and 36% (9 of 25 patients) of patients underwent surgical

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resection of primary tumor after a median of 7.3 months of imatinib treatment.$^{48}$ All patients who underwent resection were treated with postoperative imatinib. The 3-year PFS and OS rates were 67% and 89%, respectively, for patients who underwent resection. All patients who underwent resection were treated with postoperative imatinib.

While the results of these prospective studies have demonstrated the safety and efficacy of preoperative imatinib in patients undergoing surgical resection, survival benefit could not be determined since all patients included in 3 of these studies also received postoperative imatinib postoperatively for 2 years.$^{45,46,48}$ Maximal response may require treatment for ≥6 months. Preoperative imatinib may prohibit accurate assessment of recurrence risk and should be considered only if surgical morbidity could be reduced by downstaging the tumor preoperatively. At the present time, the decision to use preoperative imatinib for patients with resectable primary or locally advanced or recurrent GIST should be made on an individual basis.

Postoperative Imatinib

Surgery does not routinely cure GIST. Complete resection is possible in approximately 85% of patients with primary tumors. At least 50% of these patients will develop recurrence or metastasis following complete resection and the 5-year survival rate is about 50%.$^{49-51}$ Median time to recurrence after resection of primary high-risk GIST is about 2 years. A retrospective review of 506 patients with completely resected GIST revealed the potential for underestimating risk of recurrence, particularly in the case of intermediate size, intermediate-level mitotic count, and non-gastric tumors.$^{52}$ The data suggested that at least 3 years of adjuvant treatment was associated with higher RFS for patients with higher-risk disease. Multiple randomized studies have investigated the optimal duration of adjuvant therapy for resected GIST.

Imatinib therapy was investigated in a phase III, double-blind study (ACOSOG Z9001) that randomized patients with primary localized GIST (≥3 cm in size) to postoperative imatinib 400 mg (317 patients) or placebo (328 patients) for one year after complete resection.$^{53}$ At a median follow-up of 74 months, the RFS rate was significantly higher in the imatinib arm compared to placebo (HR, 0.6; 95% CI, 0.43–0.75; Cox model adjusted P < .001). OS was not significantly different between the imatinib and placebo arms.$^{54}$ Further analyses revealed that imatinib therapy was associated with higher RFS in patients with KIT exon 11 deletions (but not KIT exon 11 insertion or point mutation, KIT exon 9 mutation, PDGFRA mutation, or wild-type tumor). Tumor genotype was not associated with RFS in the placebo arm.

An intergroup randomized trial (EORTC-62024: NCT00103168) compared observation with 2 years of adjuvant imatinib following R0/R1 resection in 908 patients with localized, intermediate, or high-risk GIST.$^{55}$ RFS for imatinib versus observation was 84% versus 66% at 3 years and 69% versus 63% at 5 years (P < .001). However, the endpoint of 5-year imatinib failure-free survival (IFFS) did not reach significance at 87% versus 84% (HR, 0.79; 98.5% CI, 0.50–1.25; P = .21).

The results of another randomized phase III study from the Scandinavian Sarcoma Group (SSG XVIII/AIO) suggest that a longer duration of postoperative imatinib improves RFS and OS for patients with a high estimated risk of recurrence after surgery.$^{56,57}$ In this study, patients with a high risk for GIST recurrence after surgery were randomized to 12 months (n = 200) or 36 months (n = 200) of postoperative imatinib. After a median follow-up of 90 months, RFS and OS were significantly longer in the 36-month group compared to the 12-month group (5-year RFS: 71.1% vs. 52.3%, respectively; P < .001; 5-year OS: 91.9 % vs. 85.3% respectively; P = .036). The highest risk for recurrence was observed among patients with non-gastric GIST and tumors with high mitotic count.$^{58}$

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Management of Toxicities

The most common side effects of imatinib include fluid retention, diarrhea, nausea, fatigue, muscle cramps, abdominal pain, and rash. The side effect profile may improve with prolonged therapy.$^{59}$ Serious side effects (such as liver function test [LFT] abnormalities, lung toxicity, low blood counts, and GI bleeding) have rarely been reported and often improve after imatinib has been withheld. LFT abnormalities are seen in fewer than 5% of patients. Leukopenia is quite rare and imatinib has only rarely been associated with neutropenic fever. In a retrospective analysis of 219 consecutive patients treated with imatinib, grade 3 or 4 cardiotoxicity occurred in 8.2% of patients who were manageable with medical therapy, and infrequently required dose reduction or discontinuation of imatinib.$^{60}$ The side effect profile may improve with prolonged therapy and can be managed with appropriate supportive care measures. If life-threatening side effects occur with imatinib that cannot be managed by maximum supportive treatment, then sunitinib should be considered after discontinuing imatinib.

Sunitinib

Sunitinib is a multitargeted TKI that can induce objective responses and control progressive disease in patients with imatinib-resistant GIST. SDH-deficient GIST may have a higher probability of response to sunitinib.

In a randomized, phase III, placebo-controlled study, sunitinib produced significant, sustained clinical benefit in patients with imatinib-resistant or imatinib-intolerant GIST.$^{61}$ In patients with imatinib-resistant GIST, sunitinib resulted in a significant improvement in median time to progression (27.3 vs. 6.4 weeks) and significantly greater estimated OS. Sunitinib treatment induced PR in 14 patients (6.8%) and stable disease (≥22 weeks) in 36 patients (17.4%) versus no PRs and stable disease in 2 patients (1.9%) on placebo. In the imatinib-intolerant group, 4 out of 9 patients randomized to sunitinib achieved PR and one patient had

progressive disease. In contrast, 3 of the 4 patients randomized to placebo had progressive disease at the time of analysis and no PR was observed. Sunitinib was generally well tolerated. In January 2006, sunitinib received FDA approval for the treatment of GIST after disease progression on or intolerance to imatinib.

The safety and efficacy of sunitinib on a continuous daily dosing schedule at 37.5 mg was evaluated in an open-label, multicenter, randomized phase II study in patients with advanced GIST after imatinib failure.$^{62}$ Patients were randomized (1:1) to receive continuous daily sunitinib (37.5 mg/d) either in the morning or in the evening for 28 days (one cycle). The primary endpoint was the clinical benefit rate (CBR) defined as the percentage of patients with CRs, PRs, or stable disease for 24 weeks or more based on RECIST criteria. The overall CBR was 53% (13% of patients had a PR and 40% had stable disease). Median PFS and OS were 34 weeks and 107 weeks, respectively. The most commonly reported treatment-related adverse events (diarrhea, fatigue, and nausea) were consistent with those known to be associated with sunitinib intermittent dosing. Treatment-related hypertension and hypothyroidism (experienced by 28% and 12% of patients, respectively) were successfully managed with appropriate supportive care measures. Both of these adverse events have also been associated with the long-term use of sunitinib on intermittent dosing. The results of this study suggest that continuous daily dosing appears to be an effective alternative dosing strategy with acceptable safety for patients with imatinib-resistant/-intolerant GIST.

Results were recently reported from an international study of sunitinib safety and efficacy in patients with imatinib-resistant/-intolerant advanced GIST (n = 1124).$^{63}$ The median PFS was 8.3 months (95% CI, 8.0–9.4 months) and the median OS was 16.6 months (95% CI, 14.9–18.0 months); safety findings were in line with previous studies. In a follow-up

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retrospective analysis of a subset of this trial population (n = 230), PFS was significantly better for patients with a primary mutation in KIT exon 9 compared to those with a primary mutation in exon 11 (12.3 months vs. 7 months; HR, 0.59; 95% CI, 0.39–0.89; P = .011).$^{64}$

Management of Toxicities

Sunitinib-related toxicities can often be managed with dose interruptions or reductions. Fatigue, nausea, and vomiting were dose-limiting toxicities for sunitinib in clinical trials. Other common toxicities include hematologic toxicities (ie, anemia, neutropenia), diarrhea, abdominal pain, mucositis, anorexia, and skin discoloration. Sunitinib is associated with a significant risk of developing hand-foot skin reaction (HFSR).$^{65}$ Early detection and proper management of HFSR is vital during treatment with sunitinib. HFSR can be prevented with routine application of emollient lotions. If it is significant, interruption of therapy is indicated; if it is severe, dose reduction should be considered.

Hypertension is a common side effect reported in clinical trials, since sunitinib targets vascular endothelial growth factor receptor (VEGFR). However, the risk is higher in patients with renal cell carcinoma (RCC) compared to those with non-RCC.$^{66}$ Recent reports have shown that sunitinib is also associated with cardiotoxicity and hypothyroidism.$^{67,68}$ In a retrospective analysis of the data from phase I-II studies, 11% of patients had an adverse cardiovascular event including CHF in 8% of patients and absolute reduction in the left ventricular ejection fraction (LVEF) in 28% of patients.$^{67}$ In a prospective, observational cohort study, abnormal serum thyroid-stimulating hormone (TSH) concentrations were documented in 62% of patients and the risk for hypothyroidism increased with the duration of therapy.$^{68}$

Close monitoring for hypertension and LVEF is essential in patients receiving sunitinib, especially in patients with a history of heart disease or cardiac risk factors. Routine monitoring (every 3–6 months) of TSH is

indicated. If hypothyroidism is suggested, patients should receive thyroid hormone replacement therapy. Patients should monitor their blood pressure closely and those who experience an increase in blood pressure should be treated with antihypertensives.$^{7}$

Impact of Mutational Status on Tumor Response to First-Line Tyrosine Kinase Inhibitors in Patients with Advanced or Metastatic GIST

GIST are generally more resistant to traditional systemic chemotherapeutic agents and radiation therapy (RT) than other STS subtypes; therefore, treatment options for patients with advanced or metastatic GIST were historically limited.$^{69}$ The discovery that many GIST are driven by constitutively activated KIT or PDGFRA receptor tyrosine kinases was a significant breakthrough, enabling GIST to be managed with targeted therapies. TKIs have now emerged as the standard-of-care treatment for patients with advanced or metastatic GIST (GIST-4 and GIST-D 1 of 2). Imatinib, the first TKI approved for the treatment of patients with GIST, is clinically active against many GIST in the first-line setting.$^{44,70}$ However, not all GIST are responsive to imatinib, as tumor response is primarily dependent on tumor mutational status.

GIST with KIT or PDGFRA Mutations

Imatinib-Sensitive Mutations

Up to ~80% of GIST have a KIT mutation, while 5%–10% have a PDGFRA mutation.$^{15,71-73}$ The presence and type of KIT or PDGFRA mutations are not strongly correlated with prognosis. However, the presence (or absence) of mutations in specific regions of KIT and PDGFRA genes are associated with a response to specific TKIs.

In randomized trials evaluating imatinib in the advanced disease setting, the presence of a KIT exon 11 mutation was associated with better response rates, median progression-free survival (PFS), and median

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overall survival (OS) than KIT exon 9 mutations or non-mutated KIT or PDGFRA.$^{27,70,73-75}$ Long-term follow-up (median 73 months) from the randomized, phase III BFR14 trial by the French Sarcoma Group identified KIT exon 11 mutations as an independent prognostic factor for longer PFS and OS in patients treated with standard-dose imatinib when compared with KIT exon 9 mutations or non-mutated KIT.$^{27}$ In the US-Finnish B2222 phase II study, imatinib was associated with better outcomes for patients with KIT exon 11 mutations than those with KIT exon 9 mutations or who had no detectable kinase mutations.$^{70}$ The partial response (PR) rates for patients with KIT exon 11 mutations, KIT exon 9 mutations, or no detectable kinase mutations were 83.5%, 47.8%, and 0%, respectively. The presence of KIT exon 11 mutations was the strongest prognostic factor reducing the risk of death by more than 95%.

GIST with KIT exon 9 mutations treated with imatinib generally have a lower response rate and PFS than those with KIT exon 11 tumors at a dose of 400 mg daily, but imatinib 400 mg two times a day (BID) may lead to a better response and PFS. In the randomized EORTC 62005 study, the presence of KIT exon 9 mutations was the strongest adverse prognostic factor for risk of progression and death.$^{73}$ High-dose imatinib (400 mg BID) resulted in a significantly superior PFS with a reduction in the relative risk of 61% ($P = .0013$) in patients whose tumors expressed a KIT exon 9 mutation compared with the standard 400 mg/day imatinib dose.$^{73}$ Additionally, the response rate after crossover from 400 mg daily to 400 mg BID imatinib was higher in patients with KIT exon 9 mutations (57%) than patients with KIT exon 11 mutations (7%). Similarly, results from the phase III SWOG S0033/CALGB 150105 trial showed that imatinib at 400 mg BID resulted in a higher response rate in patients with a KIT exon 9 mutation than those with imatinib at 400 mg once daily (67% vs. 17%, respectively).$^{75}$ A meta-analysis of EORTC 62005 and SWOG S0033/CALGB 150105 trials that randomized 1640 patients with advanced GIST to standard-dose imatinib (400 mg daily) or high-dose

imatinib (400 mg BID) showed a benefit in PFS for patients with KIT exon 9 mutations treated with high-dose imatinib.$^{76}$

While most GIST with PDGFRA mutations are associated with a response to imatinib, those with certain mutations, such as D842V, generally do not respond.$^{11,15}$ In a survey of patients with confirmed PDGFRA mutations, none of 31 evaluable patients with a D842V mutation had a response to imatinib, and 21 of 31 (68%) experienced disease progression.$^{77}$ The median PFS was 2.8 months for patients with D842V compared with 28.5 months for patients with other PDGFRA mutations (eg, indels in exon 18). With 46 months of follow-up, the median OS was 14.7 months for patients with D842V and not reached for patients with other PDGFRA mutations.

Imatinib is included in the guidelines as a category 1 preferred first-line treatment option for patients with advanced or metastatic GIST with imatinib-sensitive mutations; however, it is not recommended for the treatment of GIST with PDGFRA exon 18 mutations that are insensitive to imatinib, especially D842V (GIST-4 and GIST-D 1 of 2).

In the adjuvant setting, a longer duration of imatinib treatment may be beneficial for patients with GIST that have certain KIT mutations. Follow-up analysis of a randomized phase III study from the Scandinavian Sarcoma Group (SSG XVIII/AIO) revealed that patients with GIST harboring a KIT exon 11 deletion appear to benefit most from longer-duration imatinib, showing higher recurrence-free survival (RFS) when allocated to the 3-year versus 1-year imatinib group.$^{78}$ A similar pattern related to duration of treatment was not observed for GIST harboring other mutations.

Imatinib-Insensitive Mutations

GIST with imatinib-insensitive mutations such as PDGFRA D842V are managed differently than most GIST. Avapritinib is a TKI approved for

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the treatment of patients with unresectable or metastatic GIST with a PDGFRA exon 18 mutation, including D842V mutations.$^{79,80}$ The approval of avapritinib for GIST was based on results from the open-label, single-arm phase I NAVIGATOR trial that evaluated the safety and antitumor activity of avapritinib in 56 patients with PDGFRA D842V-containing GIST that were unresectable and/or metastatic.$^{81,82}$ In the long-term analysis of the trial, at data cut-off (median follow-up of 27.5 months), the overall response rate (ORR) with avapritinib was 91%, with a median duration of response (DOR) of 27.6 months.$^{82}$

Given these data, the panel recommends avapritinib as the preferred first-line treatment option for patients with unresectable, progressive, or metastatic GIST with imatinib-resistant PDGFRA D842V mutations or other PDGFRA exon 18 mutations that are known to be imatinib-insensitive (GIST-4 and GIST-D 1 of 2).

GIST Without KIT or PDGFRA Mutations

Approximately 10%—15% of GIST lack a mutation in either KIT or PDGFRA.$^{16,71}$ Most of these have functional inactivation of the succinate dehydrogenase (SDH) complex (either from mutations or epigenetic silencing leading to a lack of SDH protein expression),$^{16}$ which has been shown to be a cause of tumorigenesis. GIST with SDH deficiency generally lack the gain-of-function tyrosine kinase mutations found in the majority of GIST;$^{83}$ therefore, certain TKIs (specifically imatinib) have limited efficacy in this setting.$^{84}$

However, TKIs with activity against vascular endothelial growth factor receptor (VEGFR) can be considered as potential options for SDH-deficient GIST. Data from two small retrospective studies suggested that sunitinib may be active in SDH-deficient GIST.$^{85,86}$ Although sunitinib targets KIT and PDGFRA, it is also active against other kinases, including VEGFR.$^{87}$ Regorafenib is another TKI with activity against VEGFR, and was reported to be clinically active against SDH-deficient

GIST in a small number of patients.$^{88,89}$ In a phase II study, prolonged disease control was achieved in one patient with SDH-deficient GIST treated with pazopanib, another TKI that targets VEGFR.$^{90,91}$ Based on these limited data, the guidelines recommend consideration of sunitinib, regorafenib, and pazopanib as options for unresectable SDH-deficient GIST (GIST (GIST-D 1 of 2 and GIST-D 2 of 2). There are other potential treatments on the horizon for patients with SDH-deficient GIST; for example, temozolomide has shown promise in this setting based on preclinical data,$^{92}$ and is currently undergoing clinical testing (NCT03556384).

GIST with NTRK fusions in the absence of KIT/PDGFRA mutations may occur.$^{93-95}$ NTRK fusion is an actionable alteration, as both larrotectinib and entrectinib were granted accelerated approval by the U.S. Food and Drug Administration (FDA) for the treatment of solid tumors with NTRK gene fusions.$^{96,97}$ In a combined analysis of three studies, larrotectinib resulted in an ORR of 75% (based on independent review) in children and adults with locally advanced or metastatic NTRK fusion-positive solid tumors, including GIST.$^{98}$ An integrated analysis of three trials found that entrectinib led to an objective response in 57% of adults with locally advanced or metastatic NTRK fusion-positive solid tumors.$^{99}$ The guidelines recommend larrotectinib and entrectinib as preferred first-line treatment options for patients with unresectable, progressive, or metastatic GIST that are NTRK-fusion positive (GIST-D 1 of 2).

Other genomic events, such as alterations in BRAF, NF1, and FGFR, may also occur in GIST.$^{21}$,$^{95}$,$^{100}$⁻$^{104}$ The guidelines do not recommend specific therapies for GIST with these alterations; however, the presence of these genomic events could be used to identify potential targeted therapy options. For example, combination therapy with dabrafenib and trametinib was recently approved by the FDA for the treatment of patients with advanced solid tumors with BRAF V600E mutations.$^{105}$

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Management of Resistance to Tyrosine Kinase Inhibitors

Resistance to Imatinib

While imatinib improves outcomes for patients with advanced or metastatic GIST, many will develop resistance to the drug. Primary imatinib resistance is defined as the evidence of clinical progression developing during the first 6 months of imatinib therapy; this is most commonly seen in patients with KIT exon 9 mutations treated with imatinib at 400 mg daily, PDGFRA D842V mutations, or those with tumors that lack identifiable activating mutations in KIT or PDGFRA, the majority of which are SDH-deficient GIST, thus underscoring the importance of genotyping GIST.$^{70,74,75,106}$ Secondary resistance is seen in patients who have been on imatinib for more than 6 months with an initial response or disease stabilization followed by progression, most commonly because of the outgrowth of tumor clones with secondary mutations in KIT.$^{107-110}$

For GIST with limited progression following the standard imatinib dose regimen, several options are available (GIST-5). The same dose of imatinib can be continued, while also considering resection (if feasible), ablation procedures/embolization/chemoembolization, or palliative RT (category 2B) for symptomatic lesions. The TKI can also be switched to sunitinib (category 1); alternatively, dose escalation of imatinib to 800 mg/day (400 mg BID) is another option.$^{40,61,62}$ Data have suggested that certain patients with GIST, particularly those with KIT exon 9 mutations, may derive benefit from imatinib dose escalation.$^{76,111}$ For patients with performance status (PS) 0-2 and generalized disease progression following treatment with imatinib 400 mg/day, the guidelines recommend switching to an alternate TKI or escalating the dose of imatinib, as tolerated (GIST-5 and GIST-D 1 of 2).

The approval of sunitinib for the treatment of patients with imatinib-refractory or intolerant GIST was primarily based on a phase III

randomized controlled study in 312 patients with advanced GIST that were resistant or intolerant to prior imatinib treatment.$^{61,112}$ The median time to tumor progression was 27.3 weeks in the sunitinib group versus 6.4 weeks in the placebo group (hazard ratio [HR] 0.33; P < .0001).

The clinical activity of sunitinib in imatinib-resistant GIST can vary depending on the presence of primary and secondary KIT mutations. One study found that second-line sunitinib induced higher clinical benefit (PR or stable disease for ≥6 months) in patients with imatinib-resistant/intolerant GIST with primary KIT exon 9 mutations than those with KIT exon 11 mutations (58% vs. 34%, respectively).$^{106}$ Median PFS and OS were significantly longer for patients with KIT exon 9 mutations or non-mutated KIT than those with KIT exon 11 mutations. In patients with KIT exon 11 mutations, median PFS and OS were longer for those with secondary exon 13 or 14 mutations compared to those with exon 17 or 18 mutations. Although sunitinib appears to have activity against tumors with KIT adenosine triphosphate (ATP)-binding pocket mutations (exons 13 and 14) that confer resistance to imatinib, it has little activity against tumors with imatinib-resistant mutations in the KIT activation loop (exons 17 and 18).$^{113}$-115

Based on these data, sunitinib (category 1) is recommended as a preferred second-line option for patients with unresectable, progressive, or metastatic GIST previously treated with imatinib (GIST-D 1 of 2).

For patients with a PDGFRA D842V mutation or other PDGFRA exon 18 mutations that are insensitive to imatinib, the guidelines recommend dasatinib as a second-line option. The clinical evidence supporting use of dasatinib as a second-line therapy is described in more detail in the Resistance to Avapritinib section.

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Resistance to Imatinib and Sunitinib

Regorafenib, a multikinase inhibitor with activity against KIT, PDGFR, VEGFR, and others, can be considered for patients with locally advanced, unresectable, or metastatic GIST previously treated with imatinib and sunitinib.$^{88}$ The FDA approval of regorafenib in this setting was based on results from the phase III randomized GRID trial, where regorafenib versus placebo was evaluated in 199 patients with metastatic and/or unresectable GIST that progressed on prior therapy with imatinib and sunitinib.$^{116}$ The median PFS (4.8 months vs. 0.9 months; P < .0001) and the disease control rate (DCR; 53% vs. 9%) were significantly higher for regorafenib than placebo. The PFS rates at 3 and 6 months were 60% and 38%, respectively, for regorafenib compared to 11% and 0%, respectively, for placebo. The HR for OS was 0.77 with 85% of patients in the placebo arm crossing over to regorafenib due to disease progression. Long-term follow-up (median 41 months) from a phase II study in unresectable or metastatic GIST (n = 33) suggested that patients with KIT exon 11 mutations or SDH-deficient GIST may derive a greater PFS benefit from regorafenib than KIT/PDGFRA wild-type, non-SDH-deficient tumors.$^{89}$ Given these data, regorafenib (category 1) is included in the guidelines on GIST-D 1 of 2 as a preferred third-line option following imatinib and sunitinib.

Resistance to Imatinib, Sunitinib, and Regorafenib

Ripretinib, a TKI that inhibits KIT and PDGFRA kinases, is approved by the FDA for adults with advanced GIST who have received prior treatment with 3 or more kinase inhibitors, including imatinib.$^{117}$ In the phase III INVICTUS trial, ripretinib 150 mg daily was evaluated against placebo in patients with advanced GIST who were previously treated with imatinib, sunitinib, and regorafenib.$^{118}$ The median PFS of the ripretinib group was 6.3 months, compared with 1.0 months in the placebo group ($P < .0001$). Ripretinib (category 1) is recommended in the guidelines as a preferred fourth-line option for patients with unresectable,

progressive, or metastatic GIST after treatment with imatinib, sunitinib, and regorafenib (GIST-D 1 of 2).

In a follow-up analysis of INVICTUS, dose escalation of ripretinib to 150 mg BID was evaluated in 43 patients who experienced disease progression while on ripretinib 150 mg daily.$^{119}$ The median OS was 18.4 months for patients who switched to ripretinib 150 mg BID, compared with 14.2 months for patients from INVICTUS who experienced disease progression but did not undergo dose escalation. The median PFS after receiving the first dose of 150 mg BID was 3.7 months. The guidelines include dose escalation of ripretinib to 150 mg BID as an option for patients who experience disease progression while on ripretinib 150 mg daily (GIST-D 1 of 2).

Resistance to Imatinib, Sunitinib, Regorafenib, and Ripretinib

Other TKIs are recommended in the guidelines as off-label options after disease progression on approved therapies (GIST-D 1 of 2). Much of the data on these TKIs are derived from phase II studies and retrospective analyses involving a small number of patients. Additionally, many of these studies only included patients previously treated with imatinib and sunitinib, but not regorafenib and/or ripretinib.

A few studies have evaluated sorafenib as an option for some patients with advanced or metastatic GIST.$^{120-123}$ In a prospective, multicenter, phase II study of 38 patients with unresectable, KIT-positive GIST that had progressed on imatinib and sunitinib, sorafenib resulted in a DCR of 68% (55% had stable disease and 13% had PR).$^{120}$ Median PFS and OS were 5.2 months and 11.6 months, respectively. In a retrospective analysis of 124 patients with metastatic GIST resistant to imatinib and sunitinib, the median PFS and OS of patients who received sorafenib was 6.4 months and 13.5 months, respectively.$^{122}$

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Another TKI that can be considered is nilotinib.$^{124}$⁻$^{128}$ In a retrospective analysis of 52 patients with advanced imatinib- and sunitinib-resistant GIST, nilotinib resulted in a 10% response rate and 37% DCR.$^{125}$ Median PFS and OS were 12 weeks and 34 weeks, respectively. In a randomized phase III study of nilotinib as third-line therapy in patients with GIST resistant or intolerant to imatinib and sunitinib (248 patients), the PFS on nilotinib was not superior to best supportive care (109 days vs. 111 days; P = .56).$^{127}$ In a post hoc analysis, nilotinib led to an improved OS (>4 months) compared with best supportive care (405 days vs. 280 days; P = .02) in patients whose disease progressed on both imatinib and sunitinib. This clinical benefit may be specific to patients with secondary KIT exon 17 mutations.$^{128}$ In a phase III trial that evaluated nilotinib versus imatinib in the first-line setting, none of the patients with KIT exon 9 mutations treated with nilotinib achieved an objective response. Additionally, nilotinib resulted in a shorter PFS than imatinib in those with KIT exon 9 mutations, suggesting that nilotinib is not effective for this mutation type.$^{129}$

Pazopanib also has modest activity in unselected, heavily pretreated patients with advanced GIST.$^{90,130}$ In a randomized, phase II trial comparing pazopanib to best supportive care in imatinib- and sunitinib-resistant GIST (n = 81), median PFS was 3.4 months versus 2.3 months, respectively (HR, 0.59; 95% CI, 0.37–0.96; P = .03).$^{130}$

Cabozantinib is another TKI that may be considered for patients whose disease has progressed on approved therapies.$^{131}$ Everolimus in combination with a TKI (ie, imatinib, sunitinib, regorafenib) may also be active in imatinib-resistant GIST.$^{132}$

For a complete list of additional options for GIST that have progressed on approved therapies, please see GIST-D 1 of 2.

Resistance to Avapritinib

For GIST that become avapritinib-resistant, several options are recommended (GIST-5). For limited disease progression, avapritinib treatment can be continued while also considering additional options, such as resection (if feasible), ablation procedures, embolization, chemoembolization, or palliative RT (category 2B) for symptomatic lesions. For patients with generalized disease progression following first-line avapritinib who also have PS 0–2, the guidelines recommend switching to an alternate TKI. Several studies have suggested that dasatinib can be considered as another option for GIST with PDGFRA D842V.$^{133}$⁻$^{135}$ Dasatinib has been shown to be a potent inhibitor of cells expressing the PDGFRA D842V mutation in vitro.$^{133}$ Additionally, a single arm, open-label study evaluated the antitumor activity of dasatinib in 50 patients with advanced imatinib-refractory GIST.$^{135}$ The primary endpoint (>30% 6-month PFS) was not met, as the 6-month PFS was 29%. However, the study provided evidence that dasatinib may have some clinical activity in this population, as a partial tumor response was observed in 25% of patients, including one with an imatinib-resistant PDGFRA exon 18 (D842V) mutation. Therefore, the guidelines recommend dasatinib as a preferred second-line therapy option for patients with PDGFRA exon 18 mutations (including D842V) whose disease has become resistant to either avapritinib or imatinib (GIST-D 1 of 2).

Ripretinib is another TKI that exhibits broad activity against both KIT and PDGFRA (including D842V) in the preclinical setting;$^{136}$ however, additional clinical trials are needed to confirm the efficacy of ripretinib against GIST with PDGFRA D842V mutations. The guidelines recommend ripretinib 150 mg daily as an option that may be useful in certain circumstances for GIST that progress following avapritinib and dasatinib (GIST-D 1 of 2). Dose escalation of ripretinib to 150 mg BID can also be considered.

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Other Options for Progressive Disease

In addition to the systemic therapies described above, other options are recommended for progressive disease (GIST-5). Resection (if feasible), ablation procedures, embolization, or chemoembolization are options for patients with limited disease progression; palliative RT is another alternative for those with symptomatic lesions. If the disease continues to progress despite prior therapies, a repeat tumor biopsy can be considered to potentially identify uncommon mutations that may have a corresponding targeted therapy.$^{137,138}$ Clinical trials and best supportive care are also recommended. Reintroduction of a previously tolerated and effective TKI can be considered for palliation of symptoms. Continuation of life-long TKI therapy can be considered for palliation of symptoms as part of best supportive care.

Initial Evaluation and Workup

All patients should be managed by a multidisciplinary team with expertise in sarcoma. Essential elements of the workup include the H&P, primary site and chest imaging, EUS in selected patients, endoscopy as indicated (if not previously done), and surgical assessment. Genotyping is recommended for cases in which medical therapy is anticipated. For very small GIST (<2 cm), abdominal/pelvic CT and/or MRI is sufficient. For all other GIST, workup includes baseline abdominal/pelvic CT and/or abdominal/pelvic MRI, along with chest imaging using CT or x-ray. PET/CT can be considered. Baseline PET/CT should be performed if PET/CT will be used during follow-up.

Treatment Guidelines

Resectable Disease

Primary/Preoperative Treatment

Surgery is the primary treatment for all patients with GIST (2 cm or greater) that are resectable without significant risk of morbidity.

Preoperative imatinib may be beneficial as primary treatment for patients with GIST that is resectable with negative margins but with a significant risk of morbidity.$^{45,47}$ The use of preoperative imatinib may, however, prohibit the accurate assessment of recurrence risk. Preoperative imatinib should be considered only if surgical morbidity could be reduced by downstaging the tumor prior to resection. Close monitoring is essential because some patients may rapidly become unresectable. In prospective studies, preoperative imatinib has been tested at a daily dose of either 400 mg$^{47,48}$ or 600 mg.$^{45,46}$ The guidelines recommend an initial dose of 400 mg daily. Patients with documented KIT exon 9 mutations may benefit from dose escalation up to 800 mg daily (given as 400 mg twice daily), as tolerated.

Baseline imaging is recommended prior to the start of preoperative imatinib. To assess response to TKI therapy, abdominal/pelvic CT or MRI is indicated every 8 to 12 weeks. PET may give an indication of imatinib activity after 2 to 4 weeks if rapid read-out is necessary. Since the optimal duration of preoperative therapy remains unknown, in patients with disease that is responding to therapy, imatinib should be continued until maximal response (defined as no further improvement between 2 successive CT scans, which can take as long as 6–12 months). However, it is not always necessary to wait for a maximal response to perform surgery. Surgery is recommended if bleeding and/or symptoms are present. For patients with disease that is responding to treatment, response assessment imaging can be performed less frequently. Progression may be determined by abdominal/pelvic CT or MRI with clinical interpretation, relying on PET/CT as needed to clarify ambiguous results. Assess medication adherence before determining that therapy was ineffective. If there is no progression, continuation of the same dose of imatinib is recommended and resection should be considered, if possible. If there is progression, surgery is recommended after discontinuing imatinib. In patients taking preoperative imatinib, dosing can

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be stopped right before surgery and resumed as soon as the patient is able to tolerate oral medications following surgery, regardless of surgical margins. Collaboration between the medical oncologist and the surgeon is necessary to determine the appropriateness of surgery following major response or stable disease.

However, the management of incidentally encountered small GIST less than 2 cm remains controversial.$^{7}$ At present, there are insufficient data to guide the management of very small GIST (less than 2 cm) discovered incidentally on endoscopy, and the usefulness of regular EUS surveillance has not been established. Complete surgical resection is the mainstay of treatment in symptomatic patients. For a subset of patients with very small gastric GIST (less than 2 cm) with no high-risk EUS features (ie, irregular extra-luminal border, heterogeneous echo pattern, presence of cystic spaces, echogenic foci), periodic endoscopic or radiographic surveillance may be considered.$^{8,139}$

Postoperative Treatment

Based on results of the ACOSOG Z9001 study and the randomized phase III study SSGXVIII/AIO (NCT00116935), the guidelines recommend postoperative imatinib following complete resection for primary GIST with no preoperative imatinib for patients at intermediate or high risk of recurrence (category 1).$^{53,56}$ The panel recommends that postoperative imatinib for at least 36 months should be considered for patients with high-risk GIST.$^{56,57}$

Estimation of risk of recurrence is important in selecting patients who would benefit from postoperative therapy following complete resection. In the ACOSOG Z9001 study, risk stratification was based only on tumor size and postoperative imatinib improved RFS in patients with GIST 3 cm or larger; however, it was statistically significant in patients with intermediate (6 cm or greater and less than 10 cm) and high risk (greater than 10 cm) of recurrence.$^{53,54}$ In the SSGXVIII/AIO study, risk stratification was based

on tumor size, site, mitotic count, and rupture; survival benefit was seen in patients with high risk of recurrence (mitotic index of >5 mitoses/50 HPF, size >5 cm, non-gastric location, and tumor rupture).$^{56}$ Risk stratification after surgical resection should be based on tumor mitotic rate, size, and location.$^{140}$ Gold and colleagues have developed a nomogram, taking into account tumor size, site, and mitotic index, to predict RFS after resection of localized primary GIST.$^{141}$ This nomogram accurately predicts RFS after resection of localized primary GIST and might be useful for patient care, interpretation of study results, and selection of patients for postoperative imatinib therapy.

For patients with complete resection following preoperative imatinib, the panel agreed that continuation of imatinib (at the same dose that induced objective response) is warranted. The panel acknowledged that while data from single and multicenter studies support the continuation of postoperative imatinib for 2 years following surgery, the exact duration of postoperative imatinib in this group of patients has not been studied in randomized studies.$^{45}$⁻$^{48}$ The long-term analysis of the RTOG 0132 study suggested that a high percentage of patients progressed after discontinuation of 2-year postoperative imatinib therapy.$^{142}$

For patients with completely resected disease who did not receive preoperative imatinib, postoperative imatinib is recommended for patients with intermediate or high-risk disease (category 1). Observation can be considered for completely resected, low-risk disease.

In patients with persistent gross disease following resection (R2 resection) who received preoperative imatinib, additional resection may be considered to remove residual disease. Imatinib treatment should be continued following re-resection regardless of surgical margins until progression. Postoperative imatinib should be initiated following resection if the patient did not receive prior imatinib therapy.

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Unresectable, Metastatic, or Recurrent Disease

Baseline imaging is recommended prior to initiation of treatment. Imatinib (category 1) is the primary treatment for patients with advanced, unresectable, or metastatic GIST. Imatinib has been shown to improve resectability and reduce surgical morbidity in patients with documented unresectable GIST or in patients for whom resection would carry the risk of severe postoperative functional deficit.$^{47,48}$ Several retrospective studies have demonstrated survival benefit of cytoreductive surgery following preoperative imatinib in patients with advanced or metastatic GIST responding to preoperative imatinib.$^{143-150}$ No definitive data exist to prove whether surgical resection improves clinical outcome in addition to TKI therapy for patients with resectable metastatic GIST. Prospective phase III studies are underway to assess whether or not resection changes outcome in patients with unresectable metastatic GIST responding to TKI therapy.

Providers should consider resection if complete resection can be obtained in primary metastatic disease. To assess response to TKI therapy, abdominal/pelvic CT or MRI is indicated every 8 to 12 weeks. PET may give an indication of imatinib activity after 2 to 4 weeks if rapid read-out is necessary. If there is no progression, resection can be considered following surgical consultation. Imatinib should be continued if resection is not feasible. At this time, continuous use of imatinib is recommended for metastatic GIST until progression. The patient should be maintained on the same dose, and the dose of imatinib should not be increased if patients remain stable without objective progression of the disease. Termination of imatinib in patients with GIST that is refractory to imatinib has been shown to result in a flare phenomenon, which in turn indicates that even in patients with progressive disease on imatinib therapy, there are some tumor cells for which imatinib may still be effective.$^{151}$

Recurrence following complete resection should be managed as described for unresectable or metastatic disease, because recurrent disease represents locoregional metastatic or infiltrative spread of the malignancy and carries essentially the same prognosis as distant metastases overall.

Progressive Disease

Progression is defined as the appearance of a new lesion or an increase in tumor size and may be determined by abdominal/pelvic CT or MRI with clinical interpretation, using PET/CT as needed to clarify ambiguous results. Medication adherence should be assessed prior to determining that therapy is ineffective.

Dose escalation of imatinib up to 800 mg daily (given as 400 mg twice daily) as tolerated or switching to sunitinib (category 1) are included as options for patients with progressive disease (limited disease or widespread systemic disease in patients with good performance status) on standard-dose imatinib.$^{40,61,62}$ All clinical and radiological data, including lesion density on CT and patient compliance to treatment with standard-dose imatinib, should be assessed prior to dose escalation of imatinib or switching to sunitinib.

For patients with limited progressive disease on standard-dose imatinib, second-line therapy with sunitinib should be initiated only if the majority of disease is no longer controlled by imatinib; consideration of other therapeutic interventions for progressing lesion(s) is warranted. Surgical resection should be considered in carefully selected patients with limited progressive disease that is potentially easily resectable.$^{143,148,152}$ However, incomplete resections are frequent with high complication rates. The guidelines have included, only for patients with limited progressive disease, continuation of imatinib at the same initial dose and treatment of progressing lesions with resection, RFA, chemoembolization

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� category 2B), or palliative RT (category 2B) for rare patients with bone metastases.$^{7}$

Regorafenib (category 1) is recommended for patients with disease progression on imatinib and sunitinib.$^{116}$ Based on limited data,$^{90,120-128,130,132-134}$ the guidelines have also included sorafenib, dasatinib, nilotinib, pazopanib, and everolimus plus TKI as additional options for patients who are no longer receiving clinical benefit from imatinib, sunitinib, or regorafenib, although much of the data regarding the potential benefit of these agents were collected in the pre-regorafenib era.

In patients with progressive disease no longer receiving benefit from current TKI therapy, re-introduction of previously tolerated and effective TKI therapy for palliation of symptoms can be considered.$^{153,154}$ The results of a recent randomized study demonstrated that imatinib rechallenge significantly improved PFS and DCR in patients with advanced GIST after failure of at least imatinib and sunitinib.$^{154}$ However, the duration of survival benefit was brief due to continued progression of TKI-resistant clones.

Any patient who has disease progression despite prior therapy or who has a recurrence, regardless of presentation, should be considered for enrollment in a clinical trial, if an appropriate trial is available.

Continuation of TKI Therapy

The optimal duration of TKI therapy in patients with responding or stable disease is not known. The results of a prospective, multicenter, randomized phase III study (BFR14) show that there was a significant increase in the rate of progressive disease when imatinib therapy was interrupted in patients with advanced disease that was stable or responding to imatinib therapy.$^{155,156}$ A recent report from this study confirmed that patients with rapid disease progression after interruption of imatinib had a poorer prognosis.$^{157}$ More importantly, the quality of

response upon reintroduction of imatinib did not reach the tumor status observed at randomization.

The panel strongly recommends that TKI therapy at the prescribed daily dose should be continued as long as patients are receiving clinical benefit (response or stable disease). The panel also feels that life-long continuation of TKI therapy for palliation of symptoms should be an essential component of best supportive care. However, short interruptions for one to two weeks, when medically necessary, have not been shown to negatively impact disease control or other outcomes.

Surveillance

Patients with completely resected, incompletely resected, or metastatic GIST should have a thorough H&P every 3 to 6 months; abdominal/pelvic CT scan should be performed every 3 to 6 months for 3 to 5 years, then annually. Less frequent surveillance may be acceptable for low-risk or very small tumors (<2 cm). Progression may be determined by CT or MRI with clinical interpretation; PET/CT can be considered to clarify ambiguous CT results.

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Oncol 2011;22:1828-1833. Available at: https://www.ncbi.nlm.nih.gov/pubmed/21289369.

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34. Shinagare AB, Jagannathan JP, Kurra V, et al. Comparison of performance of various tumour response criteria in assessment of regorafenib activity in advanced gastrointestinal stromal tumours after failure of imatinib and sunitinib. Eur J Cancer 2014;50:981-986. Available at: https://www.ncbi.nlm.nih.gov/pubmed/24388774.

35. Benjamin RS, Choi H, Macapinlac HA, et al. We should desist using RECIST, at least in GIST. J Clin Oncol 2007;25:1760-1764. Available at: https://www.ncbi.nlm.nih.gov/pubmed/17470866.

36. Young H, Baum R, Cremerius U, et al. Measurement of clinical and subclinical tumour response using [18F]-fluorodeoxyglucose and positron emission tomography: review and 1999 EORTC recommendations. European Organization for Research and Treatment of Cancer (EORTC) PET Study Group Eur J Cancer 1999;35:1773-1782. Available at: http://www.ncbi.nlm.nih.gov/pubmed/10673991.

37. Chen K, Zhou YC, Mou YP, et al. Systematic review and meta-analysis of safety and efficacy of laparoscopic resection for gastrointestinal stromal tumors of the stomach. Surg Endosc 2015;29:355-367. Available at: http://www.ncbi.nlm.nih.gov/pubmed/25005014.

38. Demetri GD, von Mehren M, Blanke CD, et al. Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N Engl J Med 2002;347:472-480. Available at: http://www.ncbi.nlm.nih.gov/pubmed/12181401.

39. Verweij J, Casali PG, Zalcberg J, et al. Progression-free survival in gastrointestinal stromal tumours with high-dose imatinib: randomised trial. Lancet 2004;364:1127-1134. Available at: http://www.ncbi.nlm.nih.gov/pubmed/15451219.

40. Zalcberg JR, Verweij J, Casali PG, et al. Outcome of patients with advanced gastro-intestinal stromal tumours crossing over to a daily imatinib dose of 800 mg after progression on 400 mg. Eur J Cancer 2005;41:1751-1757. Available at: http://www.ncbi.nlm.nih.gov/pubmed/16098458.

41. Blanke CD, Demetri GD, von Mehren M, et al. Long-term results from a randomized phase II trial of standard- versus higher-dose imatinib mesylate for patients with unresectable or metastatic gastrointestinal stromal tumors expressing KIT. J Clin Oncol 2008;26:620-625. Available at: http://www.ncbi.nlm.nih.gov/pubmed/18235121.

42. Blanke CD, Rankin C, Demetri GD, et al. Phase III randomized, intergroup trial assessing imatinib mesylate at two dose levels in patients with unresectable or metastatic gastrointestinal stromal tumors expressing the kit receptor tyrosine kinase: S0033. J Clin Oncol 2008;26:626-632. Available at: http://www.ncbi.nlm.nih.gov/pubmed/18235122.

43. von Mehren M, Heinrich MC, Joensuu H, et al. Follow-up results after 9 years (yrs) of the ongoing, phase II B2222 trial of imatinib mesylate (IM) in patients (pts) with metastatic or unresectable KIT+ gastrointestinal stromal tumors (GIST) [abstract]. J Clin Oncol 2011;29(15_Suppl):Abstract 10016. Available at: http://meeting.ascopubs.org/cgi/content/abstract/29/15_suppl/10016.

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44. Casali PG, Zalcberg J, Le Cesne A, et al. Ten-year progression-free and overall survival in patients with unresectable or metastatic GI stromal tumors: Long-term analysis of the European Organisation for Research and Treatment of Cancer, Italian Sarcoma Group, and Australasian Gastrointestinal Trials Group Intergroup phase III randomized trial on imatinib at two dose levels. J Clin Oncol 2017;35:1713-1720. Available at: https://www.ncbi.nlm.nih.gov/pubmed/28362562.

45. Eisenberg BL, Harris J, Blanke CD, et al. Phase II trial of neoadjuvant/adjuvant imatinib mesylate (IM) for advanced primary and metastatic/recurrent operable gastrointestinal stromal tumor (GIST): early results of RTOG 0132/ACRIN 6665. J Surg Oncol 2009;99:42-47. Available at: http://www.ncbi.nlm.nih.gov/pubmed/18942073.

46. McAuliffe JC, Hunt KK, Lazar AJF, et al. A randomized, phase II study of preoperative plus postoperative imatinib in GIST: evidence of rapid radiographic response and temporal induction of tumor cell apoptosis. Ann Surg Oncol 2009;16:910-919. Available at: http://www.ncbi.nlm.nih.gov/pubmed/18953611.

47. Fiore M, Palassini E, Fumagalli E, et al. Preoperative imatinib mesylate for unresectable or locally advanced primary gastrointestinal stromal tumors (GIST). Eur J Surg Oncol 2009;35:739-745. Available at: http://www.ncbi.nlm.nih.gov/pubmed/19110398.

48. Blesius A, Cassier PA, Bertucci F, et al. Neoadjuvant imatinib in patients with locally advanced non metastatic GIST in the prospective BFR14 trial. BMC Cancer 2011;11:72. Available at: http://www.ncbi.nlm.nih.gov/pubmed/21324142.

49. Eisenberg BL, Judson I. Surgery and imatinib in the management of GIST: emerging approaches to adjuvant and neoadjuvant therapy. Ann Surg Oncol 2004;11:465-475. Available at: http://www.ncbi.nlm.nih.gov/pubmed/15123459.

50. Gold JS, Dematteo RP. Combined surgical and molecular therapy: the gastrointestinal stromal tumor model. Ann Surg 2006;244:176-184. Available at: http://www.ncbi.nlm.nih.gov/pubmed/16858179.

51. DeMatteo RP, Lewis JJ, Leung D, et al. Two hundred gastrointestinal stromal tumors: recurrence patterns and prognostic factors for survival. Ann Surg 2000;231:51-58. Available at: http://www.ncbi.nlm.nih.gov/pubmed/10636102.

52. Guerin A, Sasane M, Keir CH, et al. Physician Underestimation of the Risk of Gastrointestinal Stromal Tumor Recurrence After Resection. JAMA Oncol 2015;1:797-805. Available at: https://www.ncbi.nlm.nih.gov/pubmed/26204106.

53. Corless CL, Ballman KV, Antonescu CR, et al. Pathologic and molecular features correlate with long-term outcome after adjuvant therapy of resected primary GI stromal tumor: the ACOSOG Z9001 trial. J Clin Oncol 2014;32:1563-1570. Available at: http://www.ncbi.nlm.nih.gov/pubmed/24638003.

54. Dematteo RP, Ballman KV, Antonescu CR, et al. Adjuvant imatinib mesylate after resection of localised, primary gastrointestinal stromal tumour: a randomised, double-blind, placebo-controlled trial. Lancet 2009;373:1097-1104. Available at: http://www.ncbi.nlm.nih.gov/pubmed/19303137.

55. Casali PG, Le Cesne A, Poveda Velasco A, et al. Time to Definitive Failure to the First Tyrosine Kinase Inhibitor in Localized GI Stromal Tumors Treated With Imatinib As an Adjuvant: A European Organisation for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group Intergroup Randomized Trial in Collaboration With the Australasian Gastro-Intestinal Trials Group, UNICANCER, French Sarcoma Group, Italian Sarcoma Group, and Spanish Group for Research on Sarcomas. J Clin Oncol 2015;33:4276-4283. Available at: https://www.ncbi.nlm.nih.gov/pubmed/26573069.

56. Joensuu H, Eriksson M, Sundby Hall K, et al. One vs three years of adjuvant imatinib for operable gastrointestinal stromal tumor: a randomized trial. JAMA 2012;307:1265-1272. Available at: http://www.ncbi.nlm.nih.gov/pubmed/22453568.

57. Joensuu H, Eriksson M, Sundby Hall K, et al. Adjuvant Imatinib for High-Risk GI Stromal Tumor: Analysis of a Randomized Trial. J Clin Oncol

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2016;34:244-250. Available at: https://www.ncbi.nlm.nih.gov/pubmed/26527782.

58. Joensuu H, Eriksson M, Hall KS, et al. Risk factors for gastrointestinal stromal tumor recurrence in patients treated with adjuvant imatinib. Cancer 2014;120:2325-2333. Available at: http://www.ncbi.nlm.nih.gov/pubmed/24737415.

59. Guilhot F. Indications for imatinib mesylate therapy and clinical management. Oncologist 2004;9:271-281. Available at: http://www.ncbi.nlm.nih.gov/pubmed/15169982.

60. Trent JC, Patel SS, Zhang J, et al. Rare incidence of congestive heart failure in gastrointestinal stromal tumor and other sarcoma patients receiving imatinib mesylate. Cancer 2010;116:184-192. Available at: http://www.ncbi.nlm.nih.gov/pubmed/19885836.

61. Demetri GD, van Oosterom AT, Garrett CR, et al. Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial. Lancet 2006;368:1329-1338. Available at: http://www.ncbi.nlm.nih.gov/pubmed/17046465.

62. George S, Blay JY, Casali PG, et al. Clinical evaluation of continuous daily dosing of sunitinib malate in patients with advanced gastrointestinal stromal tumour after imatinib failure. Eur J Cancer 2009;45:1959-1968. Available at: http://www.ncbi.nlm.nih.gov/pubmed/19282169.

63. Reichardt P, Kang YK, Rutkowski P, et al. Clinical outcomes of patients with advanced gastrointestinal stromal tumors: safety and efficacy in a worldwide treatment-use trial of sunitinib. Cancer 2015;121:1405-1413. Available at: https://www.ncbi.nlm.nih.gov/pubmed/25641662.

64. Reichardt P, Demetri GD, Gelderblom H, et al. Correlation of KIT and PDGFRA mutational status with clinical benefit in patients with gastrointestinal stromal tumor treated with sunitinib in a worldwide treatment-use trial. BMC Cancer 2016;16:22. Available at: https://www.ncbi.nlm.nih.gov/pubmed/26772734.

65. Chu D, Lacouture ME, Weiner E, Wu S. Risk of hand-foot skin reaction with the multitargeted kinase inhibitor sunitinib in patients with renal cell and non-renal cell carcinoma: a meta-analysis. Clin Genitourin Cancer 2009;7:11-19. Available at: http://www.ncbi.nlm.nih.gov/pubmed/19213662.

66. Zhu X, Stergiopoulos K, Wu S. Risk of hypertension and renal dysfunction with an angiogenesis inhibitor sunitinib: systematic review and meta-analysis. Acta Oncol 2009;48:9-17. Available at: http://www.ncbi.nlm.nih.gov/pubmed/18752081.

67. Chu TF, Rupnick MA, Kerkela R, et al. Cardiotoxicity associated with tyrosine kinase inhibitor sunitinib. Lancet 2007;370:2011-2019. Available at: http://www.ncbi.nlm.nih.gov/pubmed/18083403.

68. Torino F, Corsello SM, Longo R, et al. Hypothyroidism related to tyrosine kinase inhibitors: an emerging toxic effect of targeted therapy. Nat Rev Clin Oncol 2009;6:219-228. Available at: http://www.ncbi.nlm.nih.gov/pubmed/19333228.

69. Dematteo RP, Heinrich MC, El-Rifai WM, Demetri G. Clinical management of gastrointestinal stromal tumors: before and after STI-571. Hum Pathol 2002;33:466-477. Available at: https://www.ncbi.nlm.nih.gov/pubmed/12094371.

70. Heinrich MC, Corless CL, Demetri GD, et al. Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor. J Clin Oncol 2003;21:4342-4349. Available at: http://www.ncbi.nlm.nih.gov/pubmed/14645423.

71. Corless CL, Fletcher JA, Heinrich MC. Biology of gastrointestinal stromal tumors. J Clin Oncol 2004;22:3813-3825. Available at: https://www.ncbi.nlm.nih.gov/pubmed/15365079.

72. Martin-Broto J, Martinez-Marin V, Serrano C, et al. Gastrointestinal stromal tumors (GISTs): SEAP-SEOM consensus on pathologic and molecular diagnosis. Clin Transl Oncol 2017;19:536-545. Available at: https://www.ncbi.nlm.nih.gov/pubmed/27943096.

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73. Debiec-Rychter M, Sciot R, Le Cesne A, et al. KIT mutations and dose selection for imatinib in patients with advanced gastrointestinal stromal tumours. Eur J Cancer 2006;42:1093-1103. Available at: http://www.ncbi.nlm.nih.gov/pubmed/16624552.

74. Debiec-Rychter M, Dumez H, Judson I, et al. Use of c-KIT/PDGFRA mutational analysis to predict the clinical response to imatinib in patients with advanced gastrointestinal stromal tumours entered on phase I and II studies of the EORTC Soft Tissue and Bone Sarcoma Group. Eur J Cancer 2004;40:689-695. Available at: http://www.ncbi.nlm.nih.gov/pubmed/15010069.

75. Heinrich MC, Owzar K, Corless CL, et al. Correlation of kinase genotype and clinical outcome in the North American Intergroup Phase III Trial of imatinib mesylate for treatment of advanced gastrointestinal stromal tumor: CALGB 150105 Study by Cancer and Leukemia Group B and Southwest Oncology Group. J Clin Oncol 2008;26:5360-5367. Available at: http://www.ncbi.nlm.nih.gov/pubmed/18955451.

76. Comparison of two doses of imatinib for the treatment of unresectable or metastatic gastrointestinal stromal tumors; a meta-analysis of 1,640 patients. J Clin Oncol 2010;28:1247-1253. Available at: http://www.ncbi.nlm.nih.gov/pubmed/20124181.

77. Cassier PA, Fumagalli E, Rutkowski P, et al. Outcome of patients with platelet-derived growth factor receptor alpha-mutated gastrointestinal stromal tumors in the tyrosine kinase inhibitor era. Clin Cancer Res 2012;18:4458-4464. Available at: http://www.ncbi.nlm.nih.gov/pubmed/22718859.

78. Joensuu H, Wardelmann E, Sihto H, et al. Effect of KIT and PDGFRA mutations on survival in patients with gastrointestinal stromal tumors treated with adjuvant imatinib: An exploratory analysis of a randomized clinical trial. JAMA Oncol 2017;3:602-609. Available at: https://www.ncbi.nlm.nih.gov/pubmed/28334365.

79. Food & Drug Administration. FDA approves avapritinib for gastrointestinal stromal tumor with a rare mutation; 2020. Available at:

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80. Prescribing information for avapritinib tablets for oral use. Available at: https://www.accessdata.fda.gov/drugsatfdaocs/label/2021/2122608s007bl.pdf. Accessed June 28, 2022.

81. Heinrich MC, Jones RL, von Mehren M, et al. Avapritinib in advanced PDGFRA D842V-mutant gastrointestinal stromal tumour (NAVIGATOR): a multicentre, open-label, phase 1 trial. Lancet Oncol 2020;21:935-946. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32615108.

82. Jones RL, Serrano C, von Mehren M, et al. Avapritinib in unresectable or metastatic PDGFRA D842V-mutant gastrointestinal stromal tumours: Long-term efficacy and safety data from the NAVIGATOR phase I trial. Eur J Cancer 2021;145:132-142. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33465704.

83. Miettinen M, Wang ZF, Sarlomo-Rikala M, et al. Succinate dehydrogenase-deficient GISTs: a clinicopathologic, immunohistochemical, and molecular genetic study of 66 gastric GISTs with predilection to young age. Am J Surg Pathol 2011;35:1712-1721. Available at: https://www.ncbi.nlm.nih.gov/pubmed/21997692.

84. Heinrich MC, Rankin C, Blanke CD, et al. Correlation of long-term results of imatinib in advanced gastrointestinal stromal tumors with next-generation sequencing results: Analysis of phase 3 SWOG Intergroup Trial S0033. JAMA Oncol 2017;3:944-952. Available at: https://www.ncbi.nlm.nih.gov/pubmed/28196207.

85. Boikos SA, Pappo AS, Killian JK, et al. Molecular Subtypes of KIT/PDGFRA wild-type gastrointestinal stromal tumors: A report from the National Institutes of Health Gastrointestinal Stromal Tumor Clinic. JAMA Oncol 2016;2:922-928. Available at: https://www.ncbi.nlm.nih.gov/pubmed/27011036.

86. Liu W, Zeng X, Wu X, et al. Clinicopathologic study of succinate-dehydrogenase-deficient gastrointestinal stromal tumors: A single-

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institutional experience in China. Medicine (Baltimore) 2017;96:e7668. Available at: https://www.ncbi.nlm.nih.gov/pubmed/28796048.

87. Prescribing information for sunitinib malate capsules for oral use. 2021. Available at: https://www.accessdata.fda.gov/drugsatfdaocs/label/2021/021938s0391bledt.pdf Accessed June 28, 2022.

88. Prescribing information for regorafenib tablets, for oral use. 2020. Available at: https://tinyurl.com/2p8x5r37 Accessed June 28, 2022.

89. Ben-Ami E, Barysauskas CM, von Mehren M, et al. Long-term follow-up results of the multicenter phase II trial of regorafenib in patients with metastatic and/or unresectable GI stromal tumor after failure of standard tyrosine kinase inhibitor therapy. Ann Oncol 2016;27:1794-1799. Available at: https://www.ncbi.nlm.nih.gov/pubmed/27371698.

90. Ganjoo KN, Villalobos VM, Kamaya A, et al. A multicenter phase II study of pazopanib in patients with advanced gastrointestinal stromal tumors (GIST) following failure of at least imatinib and sunitinib. Ann Oncol 2014;25:236-240. Available at: http://www.ncbi.nlm.nih.gov/pubmed/24356634.

91. Prescribing information for pazopanib tablets for oral use. 2021. Available at: https://tinyurl.com/3yv9ueze. Accessed June 28, 2022.

92. Yebra M, Bhargava S, Kumar A, et al. Establishment of patient-derived succinate dehydrogenase-deficient gastrointestinal stromal tumor models for predicting therapeutic response. Clin Cancer Res 2022;28:187-200. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34426440.

93. Lee JH, Shin SJ, Choe EA, et al. Tropomyosin-related kinase fusions in gastrointestinal stromal tumors. Cancers (Basel) 2022;14. Available at: https://www.ncbi.nlm.nih.gov/pubmed/35681640.

94. Brenca M, Rossi S, Polano M, et al. Transcriptome sequencing identifies ETV6-NTRK3 as a gene fusion involved in GIST. J Pathol 2016;238:543-549. Available at: https://www.ncbi.nlm.nih.gov/pubmed/26606880.

95. Shi E, Chmielecki J, Tang CM, et al. FGFR1 and NTRK3 actionable alterations in "Wild-Type" gastrointestinal stromal tumors. J Transl Med 2016;14:339. Available at: https://www.ncbi.nlm.nih.gov/pubmed/27974047.

96. Prescribing information for larrotrectinib Available at: https://www.accessdata.fda.gov/drugsatfdaocs/label/2021/210861s006bl.pdf. Accessed July 5, 2022.

97. Prescribing information for entrectinib capsules for oral use. Available at: https://www.accessdata.fda.gov/drugsatfdaocs/label/2021/212725s005bl.pdf. Accessed July 5, 2022.

98. Drilon A, Laetsch TW, Kummar S, et al. Efficacy of larotrectinib in TRK fusion-positive cancers in adults and children. N Engl J Med 2018;378:731-739. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29466156.

99. Doebele RC, Drilon A, Paz-Ares L, et al. Entrectinib in patients with advanced or metastatic NTRK fusion-positive solid tumours: integrated analysis of three phase 1-2 trials. Lancet Oncol 2020;21:271-282. Available at: https://www.ncbi.nlm.nih.gov/pubmed/31838007.

100. Hostein I, Faur N, Primois C, et al. BRAF mutation status in gastrointestinal stromal tumors. Am J Clin Pathol 2010;133:141-148. Available at: https://www.ncbi.nlm.nih.gov/pubmed/20023270.

101. Maertens O, Prenen H, Debiec-Rychter M, et al. Molecular pathogenesis of multiple gastrointestinal stromal tumors in NF1 patients. Hum Mol Genet 2006;15:1015-1023. Available at: https://www.ncbi.nlm.nih.gov/pubmed/16461335.

102. Belinsky MG, Rink L, Cai KQ, et al. Somatic loss of function mutations in neurofibromin 1 and MYC associated factor X genes identified by exome-wide sequencing in a wild-type GIST case. BMC Cancer 2015;15:887. Available at: https://www.ncbi.nlm.nih.gov/pubmed/26555092.

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103. Burgoyne AM, De Siena M, Alkhuziem M, et al. Duodenal-jejal flexure GI stromal tumor frequently heralds somatic NF1 and notch pathway mutations. JCO Precis Oncol 2017;2017. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29938249.

104. Charo LM, Burgoyne AM, Fanta PT, et al. A novel PRKAR1B-BRAF fusion in gastrointestinal stromal tumor guides adjuvant treatment decision-making during pregnancy. J Natl Compr Canc Netw 2018;16:238-242. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29523662.

105. Dabrafenib-trametinib combination approved for solid tumors with BRAF mutations. 2022. Available at: https://www.cancer.gov/news-events/cancer-currents-blog/2022/fda-dabrafenib-trametinib-braf-solid-tumors. Accessed August 16, 2022.

106. Heinrich MC, Maki RG, Corless CL, et al. Primary and secondary kinase genotypes correlate with the biological and clinical activity of sunitinib in imatinib-resistant gastrointestinal stromal tumor. J Clin Oncol 2008;26:5352-5359. Available at: http://www.ncbi.nlm.nih.gov/pubmed/18955458.

107. Antonescu CR, Besmer P, Guo T, et al. Acquired resistance to imatinib in gastrointestinal stromal tumor occurs through secondary gene mutation. Clin Cancer Res 2005;11:4182-4190. Available at: http://www.ncbi.nlm.nih.gov/pubmed/159308355.

108. Heinrich MC, Corless CL, Blanke CD, et al. Molecular correlates of imatinib resistance in gastrointestinal stromal tumors. J Clin Oncol 2006;24:4764-4774. Available at: http://www.ncbi.nlm.nih.gov/pubmed/16954519.

109. Wardelmann E, Merkelbach-Bruse S, Pauls K, et al. Polyclonal evolution of multiple secondary KIT mutations in gastrointestinal stromal tumors under treatment with imatinib mesylate. Clin Cancer Res 2006;12:1743-1749. Available at: http://www.ncbi.nlm.nih.gov/pubmed/16551858.

110. Desai J, Shankar S, Heinrich MC, et al. Clonal evolution of resistance to imatinib in patients with metastatic gastrointestinal stromal tumors. Clin

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111. Patel S, Zalcberg JR. Optimizing the dose of imatinib for treatment of gastrointestinal stromal tumours: lessons from the phase 3 trials. Eur J Cancer 2008;44:501-509. Available at: https://www.ncbi.nlm.nih.gov/pubmed/18234488.

112. Goodman VL, Rock EP, Dagher R, et al. Approval summary: sunitinib for the treatment of imatinib refractory or intolerant gastrointestinal stromal tumors and advanced renal cell carcinoma. Clin Cancer Res 2007;13:1367-1373. Available at: https://www.ncbi.nlm.nih.gov/pubmed/17332278.

113. Gajiwala KS, Wu JC, Christensen J, et al. KIT kinase mutants show unique mechanisms of drug resistance to imatinib and sunitinib in gastrointestinal stromal tumor patients. Proc Natl Acad Sci U S A 2009;106:1542-1547. Available at: http://www.ncbi.nlm.nih.gov/pubmed/19164557.

114. Guo T, Hajdu M, Agaram NP, et al. Mechanisms of sunitinib resistance in gastrointestinal stromal tumors harboring KITAY502-3ins mutation: an in vitro mutagenesis screen for drug resistance. Clin Cancer Res 2009;15:6862-6870. Available at: http://www.ncbi.nlm.nih.gov/pubmed/19861442.

115. Nishida T, Takahashi T, Nishitani A, et al. Sunitinib-resistant gastrointestinal stromal tumors harbor cis-mutations in the activation loop of the KIT gene. Int J Clin Oncol 2009;14:143-149. Available at: http://www.ncbi.nlm.nih.gov/pubmed/19390946.

116. Demetri GD, Reichardt P, Kang YK, et al. Efficacy and safety of regorafenib for advanced gastrointestinal stromal tumours after failure of imatinib and sunitinib (GRID): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet 2013;381:295-302. Available at: http://www.ncbi.nlm.nih.gov/pubmed/23177515.

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117. Prescribing information for ripretinib tablets for oral use. Available at: https://www.accessdata.fda.gov/drugsatfadocs/label/2021/213973s0011bl.pdf. Accessed July 5, 2022.

118. 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 trial. Lancet Oncol 2020;21:923-934. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32511981.

119. Zalcberg JR, Heinrich MC, George S, et al. Clinical benefit of ripretinib dose escalation after disease progression in advanced gastrointestinal stromal tumor: An analysis of the INVICTUS study. Oncologist 2021;26:e2053-e2060. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34313371.

120. Kindler HL, Campbell NP, Wroblewski K, et al. Sorafenib (SOR) in patients (pts) with imatinib (IM) and sunitinib (SU)-resistant (RES) gastrointestinal stromal tumors (GIST): Final results of a University of Chicago Phase II Consortium trial [abstract]. J Clin Oncol 2011;29(15_Suppl):Abstract 10009. Available at: http://meeting.ascopubs.org/cgi/content/abstract/29/15_suppl/10009.

121. Park SH, Ryu MH, Ryo BY, et al. Sorafenib in patients with metastatic gastrointestinal stromal tumors who failed two or more prior tyrosine kinase inhibitors: a phase II study of Korean gastrointestinal stromal tumors study group. Invest New Drugs 2012;30:2377-2383. Available at: http://www.ncbi.nlm.nih.gov/pubmed/22270258.

122. Montemurro M, Gelderblom H, Bitz U, et al. Sorafenib as third- or fourth-line treatment of advanced gastrointestinal stromal tumour and pretreatment including both imatinib and sunitinib, and nilotinib: A retrospective analysis. Eur J Cancer 2013;49:1027-1031. Available at: http://www.ncbi.nlm.nih.gov/pubmed/23140824.

123. Kefeli U, Benekli M, Sevinc A, et al. Efficacy of sorafenib in patients with gastrointestinal stromal tumors in the third- or fourth-line treatment: A retrospective multicenter experience. Oncol Lett 2013;6:605-611. Available at: http://www.ncbi.nlm.nih.gov/pubmed/24137379.

124. Demetri GD, Casali PG, Blay JY, et al. A phase I study of single-agent nilotinib or in combination with imatinib in patients with imatinib-resistant gastrointestinal strom tumors. Clin Cancer Res 2009;15:5910-5916. Available at: http://www.ncbi.nlm.nih.gov/pubmed/19723647.

125. Montemurro M, Schoffski P, Reichardt P, et al. Nilotinib in the treatment of advanced gastrointestinal stromal tumours resistant to both imatinib and sunitinib. Eur J Cancer 2009;45:2293-2297. Available at: http://www.ncbi.nlm.nih.gov/pubmed/19467857.

126. Sawaki A, Nishida T, Doi T, et al. Phase 2 study of nilotinib as third-line therapy for patients with gastrointestinal stromal tumor. Cancer 2011;117:4633-4641. Available at: http://www.ncbi.nlm.nih.gov/pubmed/21456006.

127. Reichardt P, Blay JY, Gelderblom H, et al. Phase III study of nilotinib versus best supportive care with or without a TKI in patients with gastrointestinal stromal tumors resistant to or intolerant of imatinib and sunitinib. Ann Oncol 2012;23:1680-1687. Available at: http://www.ncbi.nlm.nih.gov/pubmed/22357255.

128. Cauchi C, Somaiah N, Engstrom PF, et al. Evaluation of nilotinib in advanced GIST previously treated with imatinib and sunitinib. Cancer Chemother Pharmacol 2012;69:977-982. Available at: http://www.ncbi.nlm.nih.gov/pubmed/22119758.

129. Blay JY, Shen L, Kang YK, et al. Nilotinib versus imatinib as first-line therapy for patients with unresectable or metastatic gastrointestinal stromal tumours (ENESTg1): a randomised phase 3 trial. Lancet Oncol 2015;16:550-560. Available at: https://www.ncbi.nlm.nih.gov/pubmed/25882987.

130. Mir O, Cropet C, Toumonde M, et al. Pazopanib plus best supportive care versus best supportive care alone in advanced gastrointestinal stromal tumours resistant to imatinib and sunitinib (PAZOGIST): a randomised, multicentre, open-label phase 2 trial. Lancet Oncol 2016;17:632-641. Available at: https://www.ncbi.nlm.nih.gov/pubmed/27068858.

NCCN NCCN NCCN

National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026

Gastrointestinal Stromal Tumors

131. Schoffski P, Mir O, Kasper B, et al. Activity and safety of the multi-target tyrosine kinase inhibitor cabozantinib in patients with metastatic gastrointestinal stromal tumour after treatment with imatinib and sunitinib: European Organisation for Research and Treatment of Cancer phase II trial 1317 "CaboGIST". Eur J Cancer 2020;134:62-74. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32470848.

132. Schoffski P, Reichardt P, Blay JY, et al. A phase I-II study of everolimus (RAD001) in combination with imatinib in patients with imatinib-resistant gastrointestinal strom tumors. Ann Oncol 2010;21:1990-1998. Available at: https://www.ncbi.nlm.nih.gov/pubmed/20507881.

133. Dewaele B, Wasag B, Cools J, et al. Activity of dasatinib, a dual SRC/ABL kinase inhibitor, and IPI-504, a heat shock protein 90 inhibitor, against gastrointestinal stromal tumor-associated PDGFRAD842V mutation. Clin Cancer Res 2008;14:5749-5758. Available at: http://www.ncbi.nlm.nih.gov/pubmed/18794084.

134. Trent JC, Wathen K, von Mehren M, et al. A phase II study of dasatinib for patients with imatinib-resistant gastrointestinal stromal tumor (GIST) [abstract]. J Clin Oncol 2011;29(15_Suppl):Abstract 10006. Available at: http://meeting.ascopubs.org/cgi/content/abstract/29/15_suppl/10006.

135. Schuetze SM, Bolejack V, Thomas DG, et al. Association of dasatinib with progression-free survival among patients with advanced gastrointestinal stromal tumors resistant to imatinib. JAMA Oncol 2018;4:814-820. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29710216.

136. Smith BD, Kaufman MD, Lu WP, et al. Ripretinib (DCC-2618) is a switch control kinase inhibitor of a broad spectrum of oncogenic and drug-resistant KIT and PDGFRA variants. Cancer Cell 2019;35:738-751 e739. Available at: https://www.ncbi.nlm.nih.gov/pubmed/31085175.

137. Alkhuziem M, Burgoyne AM, Fanta PT, et al. The call of "the wild"-type GIST: It's time for domestication. J Natl Compr Canc Netw 2017;15:551-554. Available at: https://www.ncbi.nlm.nih.gov/pubmed/28476734.

138. Kato S, Adashek JJ, Shaya J, et al. Concomitant MEK and cyclin gene alterations: Implications for response to targeted therapeutics. Clin Cancer Res 2021;27:2792-2797. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33472910.

139. Committee ASoP, Evans JA, Chandrasekhara V, et al. The role of endoscopy in the management of premalignant and malignant conditions of the stomach. Gastrointest Endosc 2015;82:1-8. Available at: http://www.ncbi.nlm.nih.gov/pubmed/25935705.

140. Dematteo RP, Gold JS, Saran L, et al. Tumor mitotic rate, size, and location independently predict recurrence after resection of primary gastrointestinal stromal tumor (GIST). Cancer 2008;112:608-615. Available at: http://www.ncbi.nlm.nih.gov/pubmed/18076015.

141. Gold JS, Gonen M, Gutierrez A, et al. Development and validation of a prognostic nomogram for recurrence-free survival after complete surgical resection of localised primary gastrointestinal stromal tumour: a retrospective analysis. Lancet Oncol 2009;10:1045-1052. Available at: http://www.ncbi.nlm.nih.gov/pubmed/19793678.

142. Wang D, Zhang Q, Blanke CD, et al. Phase II trial of neoadjuvant/adjuvant imatinib mesylate for advanced primary and metastatic/recurrent operable gastrointestinal stromal tumors: long-term follow-up results of Radiation Therapy Oncology Group 0132. Ann Surg Oncol 2011. Available at: http://www.ncbi.nlm.nih.gov/pubmed/22203182.

143. Raut CP, Posner M, Desai J, et al. Surgical management of advanced gastrointestinal stromal tumors after treatment with targeted systemic therapy using kinase inhibitors. J Clin Oncol 2006;24:2325-2331. Available at: http://www.ncbi.nlm.nih.gov/pubmed/16710031.

144. Rutkowski P, Nowecki Z, Nyckowski P, et al. Surgical treatment of patients with initially inoperable and/or metastatic gastrointestinal stromal tumors (GIST) during therapy with imatinib mesylate. J Surg Oncol 2006;93:304-311. Available at: http://www.ncbi.nlm.nih.gov/pubmed/16496358.

![NCCN\n](1/parseimages/figure50ba4a34020b41e0808c7baa3b1432d1_0_1.png) National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026

Gastrointestinal Stromal Tumors

145. Andtbacka RH, Ng CS, Scaife CL, et al. Surgical resection of gastrointestinal stromal tumors after treatment with imatinib. Ann Surg Oncol 2007;14:14-24. Available at: http://www.ncbi.nlm.nih.gov/pubmed/17072676.

146. DeMatteo RP, Maki RG, Singer S, et al. Results of tyrosine kinase inhibitor therapy followed by surgical resection for metastatic gastrointestinal stromal tumor. Ann Surg 2007;245:347-352. Available at: http://www.ncbi.nlm.nih.gov/pubmed/17435539.

147. Gronchi A, Fiore M, Miselli F, et al. Surgery of residual disease following molecular-targeted therapy with imatinib mesylate in advanced/metastatic GIST. Ann Surg 2007;245:341-346. Available at: http://www.ncbi.nlm.nih.gov/pubmed/17435538.

148. Sym SJ, Ryu M-H, Lee J-L, et al. Surgical intervention following imatinib treatment in patients with advanced gastrointestinal stromal tumors (GISTs). J Surg Oncol 2008;98:27-33. Available at: http://www.ncbi.nlm.nih.gov/pubmed/18452195.

149. Mussi C, Ronellenfitsch U, Jakob J, et al. Post-imatinib surgery in advanced/metastatic GIST: is it worthwhile in all patients? Ann Oncol 2010;21:403-408. Available at: http://www.ncbi.nlm.nih.gov/pubmed/19628568.

150. Yeh C-N, Chen T-W, Tseng J-H, et al. Surgical management in metastatic gastrointestinal stromal tumor (GIST) patients after imatinib mesylate treatment. J Surg Oncol 2010;102:599-603. Available at: http://www.ncbi.nlm.nih.gov/pubmed/20976730.

151. Van Den Abbeele AD, Badawi RD, Manola J, et al. Effects of cessation of imatinib mesylate (IM) therapy in patients (pts) with IM-refractory gastrointestinal stromal tumors (GIST) as visualized by FDG-PET scanning [abstract]. J Clin Oncol 2004;22(14_Suppl):Abstract 3012. Available at: http://meeting.jco.org/cgi/content/abstract/22/14_suppl/3012.

152. Raut CP, Wang Q, Manola J, et al. Cytoreductive surgery in patients with metastatic gastrointestinal stromal tumor treated with sunitinib malate.

Ann Surg Oncol 2010;17:407-415. Available at: http://www.ncbi.nlm.nih.gov/pubmed/19898902.

153. Fumagalli E, Coco P, Morosi C, et al. Rechallenge with Imatinib in GIST patients resistant to second or third line therapy [abstract]. Connective Tissue Oncology Society (CTOS) 15th Annual Meeting; 2009:Abstract 39404. Available at: http://www.ctos.org/meeting/2009/program.asp.

154. Kang YK, Ryu MH, Yoo C, et al. Resumption of imatinib to control metastatic or unresectable gastrointestinal stromal tumours after failure of imatinib and sunitinib (RIGHT): a randomised, placebo-controlled, phase 3 trial. Lancet Oncol 2013;14:1175-1182. Available at: http://www.ncbi.nlm.nih.gov/pubmed/24140183.

155. Blay JY, Le Cesne A, Ray-Coquard I, et al. Prospective multicentric randomized phase III study of imatinib in patients with advanced gastrointestinal stromal tumors comparing interruption versus continuation of treatment beyond 1 year: the French Sarcoma Group. J Clin Oncol 2007;25:1107-1113. Available at: http://www.ncbi.nlm.nih.gov/pubmed/17369574.

156. Le Cesne A, Ray-Coquard I, Bui BN, et al. Discontinuation of imatinib in patients with advanced gastrointestinal stromal tumours after 3 years of treatment: an open-label multicentre randomised phase 3 trial. Lancet Oncol 2010;11:942-949. Available at: http://www.ncbi.nlm.nih.gov/pubmed/20864406.

157. Patrikidou A, Chabaud S, Ray-Coquard I, et al. Influence of imatinib interruption and rechallenge on the residual disease in patients with advanced GIST: results of the BFR14 prospective French Sarcoma Group randomised, phase III trial. Annals of Oncology 2013;24:1087-1093. Available at: http://www.ncbi.nlm.nih.gov/pubmed/23175622.

表 1
φ Diagnostic/Interventional radiology	≠ Pathology radiology	≠ Pathology ¥ Patient advocacy € Pediatric oncology § Radiotherapy/Radiation oncology
φ Hematology/Hematologic oncology	€ Pediatric oncology § Radiotherapy/Radiation oncology	€ Pediatric oncology § Radiotherapy/Radiation oncology
β Internal medicine	β Internal medicine ↑ Medical oncology	κ Surgery/Surgical oncology * Discussion writing committee member
τ Orthopedics/Orthopedic oncology	τ Orthopedics/Orthopedic oncology	★ Discussion writing committee member

表 2
Tumor Size	Mitotic $Rate^{2}$	Risk	Risk Per $CAP^{2}$
≤2 cm	≤5 mitoses/50 HPFs	Metastasis rate: 0%	None
≤2 cm	>5 mitoses/50 HPFs	Metastasis rate: 0%*	None
>2 cm to ≤5 cm	≤5 mitoses/50 HPFs	Metastasis rate: 1.9%	Very low (1.9%)
>2 cm to ≤5 cm	>5 mitoses/50 HPFs	Metastasis rate: 16%	Moderate (16%)
>5 cm to ≤10 cm	≤5 mitoses/50 HPFs	Metastasis rate: 3.6%	Low (3.6%)
>5 cm to ≤10 cm	>5 mitoses/50 HPFs	Metastasis rate: 55%	High (55%)
>10 cm	≤5 mitoses/50 HPFs	Metastasis rate: 12%	Moderate (12%)
>10 cm	>5 mitoses/50 HPFs	Metastasis rate: 86%	High (86%)
≤2 cm	≤5 mitoses/50 HPFs	Metastasis rate: 0%	None
≤2 cm	>5 mitoses/50 HPFs	Metastasis rate: 50%-54%	Insufficient data - High (54%)
>2 cm to ≤5 cm	≤5 mitoses/50 HPFs	Metastasis rate: 1.9%-8.5%	Low (4.3%-8.5%)
>2 cm to ≤5 cm	>5 mitoses/50 HPFs	Metastasis rate: 50%-73%	High (50%-73%)
>5 cm to ≤10 cm	≤5 mitoses/50 HPFs	Metastasis rate: 24%	Insufficient data - Moderate (24%)
>5 cm to ≤10 cm	>5 mitoses/50 HPFs	Metastasis rate: 85%	Insufficient data - High (85%)
>10 cm	≤5 mitoses/50 HPFs	Metastasis rate: 34%-57%	High (34%-57%)
>10 cm	>5 mitoses/50 HPFs	Metastasis rate: 71%-90%	High (71%-90%)

表 4
Imatinib-sensitive: KIT and PDGFRA mutant GIST (except PDGFRA exon 18 mutant GIST that is insensitive to Imatinib)
First-line Therapyc,d	Second-line Therapyc,e	Third-line Therapyc	Fourth-line Therapyc,e	Additional Options After Progression on Approved Therapiesc,e,f
Preferred Imatinib9,5,6 (category 1)	Preferred Sunitinib9,11 (category 1).For patients intolerant of second-line Sunitinib, consider changing to Ripretinib 150 mg dailyg,12	Preferred Regorafenib9,14 (category 1)	Preferred Ripretinib 150 mg dailyg,15 (if not previously received) (category 1)	Useful in Certain CircumstancesAvapritinib9,1,2,7 Cabozantinib16Everolimus/TKIh,17Nilotinib18,19Pazopanib20Ponatinib2,21Ripretinib dose escalation to 150 mg BID (if previously treated with Ripretinib 150 mg daily)g,22,23Sorafenib24-26

表 5
Imatinib-insensitive: PDGFRA exon 18 mutant GIST (including PDGFRA D842V)
First-line TherapyC	Second-line TherapyC
Preferred • Avapritinibg1,2,7	Other Recommended • Dasatinib13

表 6
First-line TherapyC	Second-line TherapyC
Preferred •Avapritinibg$^{1,2,7}$	Other Recommended •Dasatinibg$^{13}$

表 7
Subsequent therapy irrespective of mutation status
Useful in Certain Circumstances Tumor mutational burden-high (TMB-H) ► Ipilimumab + Nivolumab27 (category 2B)

表 8
Other mutations	Other mutations
First-line $Therapy^{c,d}$	Second-line $Therapy^{c}$
Useful in Certain Circumstances • NTRK gene fusion-positive GIST • Larotrectinib • Entrectinib • Repotrectinib3 • SDH-deficient GIST • Sunitinib • Regorafenib • Pazopanib • Binimetinib/Imatinib (category 2B) • BRAF V600E-mutated GIST • Dabrafenib/Trametinib4	Useful in Certain Circumstances • NTRK gene fusion-positive GIST • Repotrectinib3 (if not previously given)

表 9
NCCN Categories of Evidence and Consensus
Category 1	Based upon high-level evidence (≥1 randomized phase 3 trials or high-quality, robust meta-analyses), there is uniform NCCN consensus (≥85% support of the Panel) that the intervention is appropriate.
Category 2A	Based upon lower-level evidence, there is uniform NCCN consensus (≥85% support of the Panel) that the intervention is appropriate.
Category 2B	Based upon lower-level evidence, there is NCCN consensus (≥50%, but <85% support of the Panel) that the intervention is appropriate.
Category 3	Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate.

表 10
NCCN Categories of Preference
Preferred	Interventions that are based on superior efficacy, safety, and evidence; and, when appropriate, affordability.
Other recommended	Other interventions that may be somewhat less efficacious, more toxic, or based on less mature data; or significantly less affordable for similar outcomes.
Useful in certain circumstances	Other interventions that may be used for selected patient populations (defined with recommendation).

图示：NCCN

引用 / 出处

（2026.V1）NCCN临床实践指南：胃肠道间质瘤. 2026.