Management of Side Effects Associated With GIST Therapies

Initial Treatment and Toxicities

A 48-year-old man diagnosed with metastatic gastrointestinal stromal tumor (GIST) was found to have a KIT exon 9 mutation. He was started on first-line imatinib 400 mg twice daily, which was complicated by significant nausea and vomiting (N&V) and fatigue, as well as peripheral and periorbital edema. He was prescribed ondansetron 30 minutes prior to each imatinib dose in additional to prochlorperazine as needed, which significantly improved his symptoms.

Multiple strategies were attempted to help address his peripheral and periorbital edema, including compression stockings and twice daily ice packs for his eyes. These were insufficient, so the patient was given a diuretic trial with furosemide. The dose was increased several times, which ultimately led to resolution of his peripheral edema; however, it only had a minimal impact on his periorbital edema. This was monitored closely for another 2 months before it became significantly bothersome and imatinib was held.

Over the next 3 weeks, the patient's periorbital edema had resolved, and he was started on a reduced dose of imatinib 600 mg. He was able to remain on this dose for 3 years before restaging scans demonstrated multiple new liver lesions. He was then started on second-line sunitinib 50 mg daily for 4 weeks on and 2 weeks off, which was complicated by significant hypertension, hand-foot skin reaction, mucositis, and diarrhea. Given the severity and multisystem involvement, the sunitinib was held and restarted at a reduced dose of 37.5mg after symptoms had resolved.

Upon resumption, the patient’s symptoms recurred but were less significant and better tolerated. Several supportive care medications were prescribed, including an anti-hypertensive, urea cream, and loperamide, which led to marked improvement of his symptoms.

Discussion

Management of side effects associated with GIST therapies is critical. Given the high sensitivity to targeted therapies and prolonged duration of response, patients are often on active treatment for many years. Additionally, each specific agent may have different side-effect profiles given the various on-target and off-target kinase activities of each medication.

Imatinib is the most frequently used treatment for GIST given the high prevalence of activating cKIT mutations and robust data for use as neoadjuvant, adjuvant, and first-line therapy for metastatic disease. The most common side effect is N&V, with rash, edema (both peripheral and periorbital), diarrhea, fatigue, myalgias, and myelosuppression also occurring.

Specific recommendations for these side effects are listed below:¹

• N&V: Daily doses greater than 400 mg are best administered twice daily to minimize risk. Additionally, administering each dose with food as well as use of prophylactic anti-emetics prior to each dose may help further reduce this risk.
• Rash: Topical moisturizing lotions or corticosteroids with antihistamines can be used if the rash is pruritic. More severe rashes may necessitate oral steroids and imatinib dose interruptions/reductions.
• Edema: Management is similar to non–drug-induced peripheral edema, which can include strategies such as compression, elevation, and decreased dietary salt intake. If insufficient, diuretics are often effective for peripheral edema. Periorbital edema may be more challenging to manage, with trial doses of diuretics appropriate for moderate to severe cases. However, dose reductions may often be needed to address this issue.
• Diarrhea: Changes in diet (e.g., avoiding excessively fatty foods) as well as antidiarrheal agents such as loperamide or diphenoxylate and atropine can help.
• Fatigue and myalgia: No specific recommendations are available, but effective strategies including ensuring sufficient fluid intake and repleting any electrolyte abnormalities that may be present. NSAIDs or acetaminophen may be helpful for pain. If fatigue is secondary to anemia, red blood cell transfusions, iron supplementation, and the use of an erythropoiesis-stimulating agent may be effective in addressing the underlying cause. In the most severe cases, however, dose reductions may be needed for imatinib.
• Myelosuppression: This generally presents early into treatment and is asymptomatic. Close monitoring is recommended, particularly the first 2 months of treatment (e.g., weekly for the first month and every 2 weeks for the second month).² If significant myelosuppression occurs, imatinib should be held until counts normalize and then restarted at a lower dose.

Imatinib Toxicities¹

Subsequent-line therapies upon disease progression include sunitinib, regorafenib, and ripretinib. These agents have a different spectrum of activity compared to imatinib, and therefore cause different side effects. Most common toxicities include hypertension, hand–foot–skin reaction (HFSR), stomatitis/mucositis, N&V, diarrhea, fatigue, and transaminitis.

Additional guidance for management of toxicities:^{1, 3}

• Hypertension: This presents early in treatment so it’s important to obtain baseline reading and manage any preexisting HTN prior to starting GIST treatment. Monitor closely while on treatment (e.g., weekly for the first 6 weeks of regorafenib)⁴ and manage with appropriate anti-hypertensives if blood pressure is >140/90 mm Hg. The drug should be temporarily held if blood pressure is >160/100 mm Hg. With close monitoring and anti-hypertensive adjustments, dose reductions are generally not needed.
• HFSR: Prevention strategies are often more effective than treatment, so it is recommended to use a topical keratinolytic agent such as urea cream (10-40%) twice daily as prophylaxis when starting treatment. Patients should be closely monitored while on treatment (e.g., every 1-2 weeks for first 2 months then monthly thereafter with regorafenib).⁴ If symptoms develop, the patient can be treated with highly potent topical steroids such as clobetasol as well as systemic analgesics for pain control. For severe symptoms, the drug should be held until resolution and restarted at a lower dose.
• Stomatitis/Mucositis: Prevention strategies include practicing good oral hygiene, avoidance of alcohol-containing mouth rinses, and use of saline rinses, which can prevent the development of symptoms. If mild to moderate symptoms develop, topical protective mouthwashes including antihistamine, lidocaine, and antacids may be effective. Oral dexamethasone mouth rinses can be effective for recurrent or severe symptoms; however, dose interruptions/reductions may be warranted depending on symptom severity.
• Transaminitis: This often presents asymptomatically, so routine monitoring is recommended (e.g., every 2 weeks for the first 2 months then monthly with regorafenib).⁴ If liver function test elevation occurs, minimize additional offending agents such as alcohol, acetaminophen, and statins. If grade 3 toxicities occur, hold treatment until resolution and restart at a lower dose. The drug may need to be permanently discontinued if the patient experiences concurrent LFT and bilirubin elevations.⁴

Sunitinib and Regorafenib Toxicities⁵

Avapritinib is a new TKI that has activity in patients with PDGFRA D842V mutations, which is resistant to other TKIs used for GIST. In addition to significant risk of N&V, peripheral/periorbital edema, and myelosuppression, it can also cause significant central nervous system toxicities, including encephalopathy and memory impairments.⁶ These can been seen as early as days after starting treatment or present after years on therapy. If these are observed, therapy should be held until symptom resolution and then restarted at a lower dose.

Lastly, it is vital to assess for the presence of any potential drug-drug interactions with a patient’s home medications, as these can often lead to supratherapeutic levels of GIST therapies, leading to excessive toxicities. Equally important is to assess for any non-prescription supplements as many available agents may also interact with the various GIST treatments discussed above.

References

1. Joensuu H, Trent JC, Reichardt P. Practical management of tyrosine kinase inhibitor-associated side effects in GIST. Cancer Treat Rev. 2011;37(1):75-88. doi:10.1016/j.ctrv.2010.04.008
2. Imatinib [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 3/2024.
3. De Wit M, Boers-Doets CB, Saettini A, et al. Prevention and management of adverse events related to regorafenib. Support Care Cancer. 2014;22(3):837-846. doi:10.1007/s00520-013-2085-z
4. Regorafenib [package insert]. Whippany, NJ: Bayer HealthCare Pharmaceuticals Inc.; 12/2020.
5. Deutsch A, Leboeuf NR, Lacouture ME, McLellan BN. Dermatologic Adverse Events of Systemic Anticancer Therapies: Cytotoxic Chemotherapy, Targeted Therapy, and Immunotherapy. Am Soc Clin Oncol Educ Book. 2020;40:485-500. doi:10.1200/EDBK_289911
6. Avapritinib [package insert]. Cambridge MA: Blueprint Medicines Corporation; 11/2024.