For patients with gastrointestinal stromal tumor (GIST) receiving long-term TKI therapy, the arrival of a liquid imatinib formulation (Imkeldi) represents a clinically meaningful advance in the ability to individualize dosing, manage toxicity, and support adherence in a population that disproportionately faces gastrointestinal (GI) barriers to consistent oral intake, according to Jonathan Trent, MD, PhD.
In November 2024, the FDA approved imatinib oral solution, marking the first liquid formulation of a TKI approved for patients with KIT (CD117)–positive unresectable or metastatic GIST, as well as for adjuvant treatment following resection of KIT (CD117)–positive GIST.¹ Imatinib tablets (Gleevec) have been the cornerstone of GIST management since their initial FDA approval in 2002, with the standard recommended dose of 400 mg per day for patients with KIT exon 11 mutations and 800 mg per day considered for those with exon 9 mutations.2
“A liquid oncolytic therapy would be welcomed by many patients [with GIST], as it offers a different option for dosing and greater flexibility in the amount taken per day,” Trent, a professor of medicine at the University of Miami Miller School of Medicine and associate director for clinical research at the Sylvester Comprehensive Cancer Center in Florida, stated in an interview with OncLive®.“...the GIST oncology community has wanted an option like that for a very long time, as…sometimes an oral tablet or a capsule is difficult to administer.”
During the interview, Trent discussed how proactive, patient-centered conversations about adverse effects (AEs) and dose modifications are essential to achieving durable disease control with TKIs; reviewed the practical limitations of currently approved oral tablet and capsule formulations and how a liquid formulation could directly address these gaps; and identified patient populations who stand to derive the most meaningful benefit from liquid formulations.
FDA-Approved TKIs in GIST and the Arrival of the First Liquid Formulation
- In November 2024, the FDA approved imatinib oral solution for patients with KIT CD117–positive unresectable or metastatic GIST and for adjuvant treatment following resection of KIT CD117–positive GIST.
- The flavored, shelf-stable solution was designed to enable more precise dose titration and to serve as an accessible alternative to compounding for patients who have difficulty swallowing tablets or require administration via feeding tube.
- Dose individualization remains a central practical challenge in GIST management, as the inability to precisely subdivide solid tablet or capsule formulations limits clinicians' ability to implement gradual dose-escalation strategies.
OncLive: How important is treatment adherence in achieving optimal outcomes in GIST?
Trent: GIST is a very aggressive tumor that is resistant to standard chemotherapies. What has evolved over many years of research is that there are a number of kinases that are drivers of oncogenesis, sometimes as seemingly single genetic events. For instance, the most common is KIT, with mutations in exon 11 or 9. There is also platelet-derived growth factor receptor alpha, which is activated by point mutations or small deletions in the autoinhibitory domain—most commonly exon 18, occasionally exon 12. After that, there are fairly rare kinases, but we have seen patients with BRAF V600E mutations in the context of translocations, NTRK translocations, fibroblast growth factor receptor translocations, and other rare kinases. The majority—approximately 60% to 70% of patients—have mutations in KIT, and most of those are in exon 11. These mutations are very exquisitely sensitive to imatinib, with response rates in the 80% or higher range.
In fact, these agents are so effective that prior to TKIs, the median overall survival [OS] was 9 months; in the TKI era, our internal data here at Sylvester Comprehensive Cancer Center show median OS in excess of 7 years. With all the new kinase inhibitors that are performing well in clinical trials and potentially heading toward approval, we expect that number to go even higher.
What are some of the most common challenges that you encounter when patients are taking these oral therapies long term?
Patients are on these medicines for a very long time. I have patients in my practice who have been on imatinib for more than 20 years; it is really effective in some patients. Adherence is therefore very important, and the way we approach it is by assessing the patient's quality of life [QOL]. Typically, a patient might not adhere to therapy because of AEs, so we take AE management very seriously. It's not something to minimize. We always try to actively manage AEs: we manage diarrhea with loperamide, nausea with ondansetron or other agents, and if you treat proactively, you can sometimes get the patient on a regimen where they don't experience the AE at all. We try to manage [each AE] proactively so we don't have to reduce the dose, because we know that if the dose falls below a certain level, we won't be able to adequately inhibit the kinase. We do try to maintain dose intensity while preserving an acceptable QOL for the patient.
In GIST, what different oral TKIs are available, and what are their practical advantages vs limitations when it comes to dose individualization, toxicity management, and therapeutic exposure?
Patients with GIST are managed with TKIs. The agents that are FDA approved in the United States include imatinib, sunitinib [Sutent], regorafenib [Stivarga], and ripretinib [Qinlock]. There are 3 or 4 other TKIs being studied in various phases of clinical trials that may also be heading toward approval, so the future is bright with these oral agents.
At the same time, these are patients with GI cancers, so they may have had portions of their stomach or small intestine resected, or they may have tumors compressing the stomach or small intestine. Oral agents can therefore be challenging to deliver at times. Sometimes, even when the label doesn't address it, we crush tablets and administer them as a solution, a slurry, or mixed into something like applesauce. We have even administered them through feeding tubes, which I consider off-label use.
Some patients may need to alter how they take their medication to manage toxicities or fit treatment into their schedules. How can these modifications affect drug exposure, and what questions should clinicians routinely ask patients to identify these issues?
Oral agents are increasingly common in our practice. When I first started treating patients with sarcoma, we only had intravenous medicines. It has been a real learning curve for many of us in oncology as we increasingly use oral agents, which have a lot of advantages. They have longer stability, they are typically dosed daily, and you can make adjustments and fine-tune dosing for toxicity.
In my practice, the standard dose for imatinib in a patient with a KIT exon 11 mutation in either the metastatic or adjuvant setting is 400 mg per day, which is the recommended FDA-approved dose. For patients with exon 9 mutations, there is some rationale to use a higher dose of 800 mg per day, which comes with more imatinib-related AEs. Therapeutic drug monitoring by looking at imatinib plasma levels did not really pan out as a dosing panacea the way we might dose chemotherapy by body surface area. We start everyone at 400 mg, and rather than dosing based on weight, we dose based on tolerability, treating patients as close to the target dose as possible without causing unacceptable toxicity.
In my practice, I often use a crescendo approach. I might start a patient at 200 mg per day of imatinib—and the same principle applies to sunitinib, regorafenib, and ripretinib—see how they do for 2 weeks, have a clinic visit, discuss AEs, check labs for liver toxicity and anemia, and if they're doing well at 200 mg, increase to 400 mg. For sunitinib, we might start at 12.5 mg; for regorafenib, we might start at 200 or 400 mg per day, varying the approach based on how we anticipate the patient will tolerate the medicine.
It gets a little tricky when a patient is at 200 mg per day of imatinib and we think they may not be ready for 400 mg but are doing reasonably well. We might give it another week or 2, reassess, and then dose-escalate or try 300 mg for a couple of weeks. But 300 mg per day is difficult to achieve practically, because a 400 mg tablet can be split in half with a pill cutter to give 200 mg, but you can't realistically divide a tablet into precise 100 mg pieces. You could write a new prescription for 100 mg tablets, but that generates a great deal of additional work.
Still, slowly escalating the dose until reaching the target is very effective. I've had several patients who were started at 400 mg and had too much toxicity and were referred to me for imatinib intolerance. We started them at 200 mg every other day, and they did great. After two weeks, we increased to 200 mg per day, then to alternating 400 mg and 200 mg every other day, and ultimately reached the target of 400 mg over about 6 weeks with excellent tolerability.
Are there specific patient populations who you think would derive particular benefit from a liquid formulation as opposed to traditional oral tablets?
Definitely. A liquid formulation of a TKI gives us the flexibility to dose at 100 mg, 200 mg, 300 mg, 400 mg, or anywhere in between for imatinib. It would provide even more flexibility for an agent like sunitinib, which is a capsule that cannot be divided with a pill cutter, making dose adjustments very difficult to make on the fly. For all of the TKIs, a liquid formulation could also significantly help with adherence, given that many of these patients have some baseline degree of GI upset—they may have had portions of their stomach or small intestine removed—and in my experience, a pill is often more difficult to manage than a liquid in terms of GI symptoms.
Liquid dosing allows for more flexible dose amounts for a patient who appears to have a dose-response relationship with their therapy. Liquid dosing would also be ideal for patients who have undergone gastric surgery and may not be able to tolerate oral intake, but who have a G-tube, J-tube, or another type of feeding tube through which a liquid formulation could be administered. This could allow patients to receive their much-needed therapy rather than waiting months after a major GI surgery for sufficient healing to permit oral intake.
References
- Shorla Oncology announces FDA approval of Imkeldi (imatinib) oral solution, an oral liquid for the treatment of certain forms of leukemia and other cancers. News release. Shorla Oncology. November 25, 2024. Accessed June 16, 2026. https://www.businesswire.com/news/home/20241125044117/en
- Gleevec (imatinib mesylate) tablets, for oral use. Prescribing information. FDA; 2026. Accessed June 19, 2026. chrome-extension://efaidnbmnnnibpcajpcglclefindmkaj/https://www.accessdata.fda.gov/drugsatfda_docs/label/2026/021588s065lbl.pdf
