Inclusion Criteria:
* Is at least 18 years of age or the legal age of consent in the jurisdiction in which the study is taking place at the time of signing the Informed consent form (ICF).
* Has histologically or cytologically confirmed GIST that is metastatic and/or surgically unresectable.
* Has not received prior systemic therapy for their metastatic and/or surgically unresectable GIST.
* Tumor tissue must be provided to the central laboratory. Tumor tissues may be archival (preferred) or obtained from a fresh biopsy acquired for standard of care (biopsies must be collected before randomization).
* Participants must have ≥1 target lesion (TL).
* All participants must use adequate contraception according to local regulations throughout the study and for a specified period after the last dose of study medication (at least 30 days for velzatinib/imatinib, or 15 days for imatinib only, as applicable, or longer if local regulations specify).
* Male participants must either be abstinent or use a male condom (with a recommendation for their female partner to use highly effective contraception). They must also refrain from donating semen.
* Female participants must not be pregnant or breastfeeding.
1. Those of non-childbearing potential are eligible without additional contraception.
2. Those of childbearing potential must use an acceptable, highly effective contraceptive method and have a negative pregnancy test before starting the study. The investigator will assess their pregnancy risk.
* Is capable of giving signed informed consent as described in the protocol, including compliance with the requirements and restrictions listed in the ICF and in this protocol.
* Has an Eastern Cooperative Oncology Group (ECOG) performance status of ≤1.
* Has adequate organ function.
Exclusion Criteria:
* Has a malignancy (except disease under study) that has progressed or required active treatment within the past 24 months except for basal cell or squamous cell carcinomas of the skin or in-situ carcinomas \[e.g., breast, cervix, bladder\] that have been resected with no evidence of metastatic disease.
* Has any clinically significant gastrointestinal abnormalities that may alter absorption, e.g., malabsorption syndrome or major resection of the stomach and/or bowels.
* Has had any major surgery (minor surgical procedures such as central venous catheter placement and tumor needle biopsy are not considered major surgical procedures) within 14 days of the first dose of study treatment or participants who have not fully recovered from surgery.
* Has any history of prior allogenic or autologous bone marrow transplant or other solid organ transplant. Participants with a history of autologous stem cell transplant are eligible for study participation provided the following eligibility criteria are met: a) transplant was \[\>100 days\] prior to screening, and b) the participant has no active infection(s) at the time of screening.
* Has known allergy or hypersensitivity to velzatinib or imatinib, in the opinion of the investigator or medical monitor, contraindicates participation in the study.
* Has a history within 6 months prior of clinically significant or uncontrolled cardiac disease, unstable angina, acute myocardial infarction, New York Heart Association Class III or IV congestive heart failure \[New York Heart Association,1994\], or clinically significant arrhythmia not controlled by standard of care therapy, ventricular arrhythmia, cerebrovascular accident or transient ischemic attack and uncontrolled hypertension.
* Has untreated brain or Central nervous system (CNS) metastases or brain/CNS metastases that have progressed \[e.g., evidence of new or enlarging brain metastasis or new neurologic symptoms attributable to brain/CNS metastases\]. Participants with previously treated and clinically stable brain/CNS metastases and who have completed all corticosteroid therapy for ≥2 weeks before randomization are not excluded from participation
* Has ongoing adverse reaction(s) from prior therapy that has (have) not recovered to ≤Grade 1 or to the baseline status preceding prior therapy, (excluding e.g., alopecia, hearing loss, vitiligo, endocrinopathy managed with replacement therapy, and Grade 2 neuropathy) or that the investigator, with the agreement of the sponsor, considers to be not clinically relevant for the tolerability of study intervention in the current clinical study.
* Has any active renal condition (e.g., infection, requirement for dialysis, or any other significant renal condition that could affect the participant's safety).
* Has any serious and/or unstable medical or psychiatric disorder or other condition(s) (including laboratory assessment abnormalities) that could interfere with the participant's safety, obtainment of informed consent, or compliance to the study procedures.
* Has received radiotherapy within 14 days prior to first dose of study treatment.
* Has received any live vaccine within 30 days of randomization. Vaccination against Coronavirus disease 2019 (COVID-19) using vaccines that are authorized via the appropriate regulatory mechanisms (e.g., Emergency Use Authorization, Conditional Marketing Authorization, or Marketing Authorization Application) are not exclusionary.
* Has received any transfusion of blood products (including platelets or red blood cells) or administration of colony-stimulating factors (including Granulocyte colony-stimulating factor \[G-CSF\], granulocyte macrophage colony-stimulating factor, or recombinant erythropoietin) within 14 days before randomization.
* Is currently enrolled or has participated in any other clinical study involving an investigational study intervention or any other type of medical research before signing ICF.
* Has a positive drug/alcohol screening assessment.
* Has a known Human immunodeficiency virus (HIV) infection and meets at least one of the following criteria:
1. Has documented evidence of plasma HIV-1 ribonucleic acid (RNA) ≥50 c/mL within 3 months prior to or at screening. In the 3 to 12 months prior to screening, plasma HIV 1 RNA levels consistently \<50 c/mL are required for enrollment; if multiple instances of plasma HIV-1 RNA values ≥50 c/mL occurred in the 3 to 12 months prior to screening, the participant is not eligible for enrollment unless, per the investigator's assessment, the elevations were neither persistent nor associated with antiretroviral resistance; OR
2. Has not had CD4 cell counts measured in the past 12 months (i.e., at least two separate measurements taken a minimum of 28 days apart, one of which must be conducted at screening); OR
3. Has had any CD4 cell count values ≤200 cells/mm3 in the past 12 months; OR
4. Has had one or more changes in their combination antiretroviral therapy regimen (except for switches as allowed per details provided in protocol) or has received an antiretroviral therapy regimen that is inconsistent with locally recommended guidelines during the 3 months prior to screening; OR
5. Has a history of HIV-associated non-Hodgkin lymphoma within 5 years prior to screening or a history of HIV-associated invasive cervical cancer; OR
6. Has received treatment with an HIV 1 immunotherapeutic vaccine within 90 days of screening.
* Is pregnant or breastfeeding.
* Is unable to adhere to the protocol, including requirements for the Follow-up Period of the study.
* Has an alanine aminotransferase (ALT) value \>2.5x upper limit of normal (ULN) or (for participants with documented liver metastases/tumor infiltration) has an ALT value \>5x ULN
* Has a total bilirubin value \>1.5x ULN.
* Has cirrhosis or current unstable liver or biliary disease per investigator assessment defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal/gastric varices, or persistent jaundice.
* Evidence of chronic hepatitis B virus (HBV) infection with detectable viral load despite antiviral therapy with high resistance barrier.
* 12-lead electrocardiogram (ECG) demonstrating mean QT interval corrected (QTc) corrected by Fridericia's formula \>480msec at screening or history of long QT syndrome.
