Gleevec® (imatinib mesylate), commercialized by Novartis, acts as an BCR-ABL tyrosine kinase (TK) inhibitor to treat patients with several forms of cancer, including chronic myeloid leukaemia (CML) and gastrointestinal stromal tumors (GISTs).1 It was approved by the US Food and Drug Administration (FDA) on February 1, 2001.2 Imatinib is usually the first-line therapy for advanced/metastatic GIST.
Mechanism of Action and Pharmacokinetics
In addition to inhibiting BCR-ABL, imatinib is known to inhibit other TKs such as KIT and platelet-derived growth factor receptor (PDGFR)-α/β. Gain-of-function mutations in the proto-oncogene c-kit are found in most GISTs (> 90%), and they are considered to be the main contribution to the development of these tumors. The gene c-kit encodes KIT, a cytokine receptor with TK activity that becomes active when bound to stem cell factor (SCF), also known as “c-kit ligand.” The resulting SCF-KIT pathway enhances the proliferation, differentiation, and survival of KIT-expressing cells, such as the interstitial cells of Cajal (ICC) or similar progenitors.3,4 Additionally, there were mutations identified in c-kit that resulted in the constitutive activation of KIT in the absence of SCF.3 Given that other standard chemotherapies are usually ineffective in treating GISTs,5 Gleevec is a suitable targeted therapeutic approach.
Pharmacokinetic studies in humans show that imatinib is well absorbed after oral administration, achieving the maximum serum concentration within 2-4 hours post-dose.6,7 It has a mean absolute bioavailability of 98%, independent of oral dosage method (solution, capsule, tablet) or dosage strength (100 mg, 400 mg). Following oral administration, the terminal elimination half-lives of imatinib and its major active metabolite, N-demethylated piperazine derivative (CGP 74588), are approximately 18 hours and 40 hours, respectively. At clinically relevant concentrations, imatinib is approximately 95% bound to human plasma proteins, mostly albumin and α1-acid glycoprotein.6,7 Elimination of the drug is predominantly via biliary excretion, typically in the form of metabolites, one of which (CGP 74588) with similar pharmacological activity to the original parent drug. The fecal to urinary excretion ratio is approximately 5:1, with approximately 81% of the dose being eliminated within 7 days.
Get detailed prescribing information on the Gleevec monograph page at Rare Disease Advisor.
Imatinib is metabolised primarily by cytochrome P450 (CYP) 3A4 or CYP3A5, and it can competitively repress the metabolism of drugs that are CYP3A4 or CYP3A5 substrates.6,7 Alterations in the plasma concentrations of imatinib as well as co-administered drugs can occur as a result of interactions between imatinib and inhibitors or inducers of these enzymes.
Patients with hepatic and renal dysfunction and liver metastases may experience more variable and increased exposure to the drug, although they do not typically require dosage adjustment. Instead, patients with mutations in exon 9 of c-kit should be treated with a higher dosage (800 mg daily).1
Efficacy and Safety of Imatinib
Since the first patient successfully treated in 2000, both the efficacy and safety of imatinib have been assessed in phase I, II and III clinical trials.1 The Finnish-American open-label, randomized, multicenter phase II study (B2222) found that, in a population of 147 patients with advanced GIST, the most frequent adverse events were edema or fluid retention, nausea, diarrhea, myalgia, fatigue, and dermatitis/rash.8 A partial response was seen in these patients (approximately 50%) with doses of 400 mg and 600 mg. Soon after this study, a dose-finding phase I study was initiated, including 36 patients with metastatic GIST.9 Individuals were treated with imatinib at once daily doses of 400 mg (n = 8) or 300 mg (n = 8), or twice daily with 400 mg (n = 16) or 500 mg (n = 8). Study findings established the maximum tolerated dose for future studies as 400 mg twice daily. Another phase II study was conducted, comparing 27 patients with GIST and 24 with other soft tissue sarcomas.10 All patients were given 400 mg imatinib twice daily. Results showed that imatinib was exclusively active in GIST.
Based on the promising results of these previous studies, 2 additional phase III trials were developed. In the trial, EORTC 62005, 946 patients with confirmed advanced or metastatic KIT-expressing GIST were recruited, and they randomly received either 400 mg once daily (n = 473) or 400 mg twice daily (800 mg per day, n = 473).11 Although, adverse events occurred frequently, these were mostly mild or moderate. Study findings suggested that 400 mg of imatinib was as effective as 800 mg in achieving an objective response, however, higher dosages provided significantly longer progression-free survival. The second phase III trial (S0033) included 694 North American patients with KIT-positive advanced GIST.12 In this trial, patients were also randomly assigned to receive either 400 mg imatinib once daily (n = 345) or twice daily (800 mg per day, n = 349). The main results of the study were similar to the EORTC 62005 trial, showing that 400 mg imatinib once daily was the standard dosage required to effectively treat patients with advanced or metastatic GIST.
Adjuvant and Neoadjuvant Therapies With Imatinib
The standard treatment for primary gastric GISTs without distant metastasis is surgery, aiming for complete resection margins. However, most patients with a high (> 50%) risk of relapse experience recurrence within the first 5 years.13,14 Therefore, adjuvant therapy is necessary to improve the prognosis for these patients by increasing the time to tumor recurrence and prolonging survival in both the metastatic and adjuvant phases. In these situations, adjuvant therapy with 3 years of imatinib is strongly recommended by the National Comprehensive Cancer Network (NCCN) and European Society for Medical Oncology (ESMO) guidelines.15,16
However, in circumstances when a microscopically margin-negative resection is not possible or when a reduction of tumour mass enables conservative and less invasive surgery, the standard procedure is to treat preoperatively with imatinib.1,14 This is particularly useful for GISTs located in the esophagogastric junction, duodenum, or rectum. Recommendations are that tumor removal should occur once optimal tumour regression is reached, usually after 6–12 months. However, there is still little evidence of the efficacy of neoadjuvant therapy, as several clinical trials of imatinib treatment in a neoadjuvant setting are ongoing. Nevertheless, NCCN guidelines mention that neoadjuvant chemotherapy should be considered if surgical morbidity could be reduced by downstaging the tumor.16
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2. Dagher R, Cohen M, Williams G, et al. Approval summary: imatinib mesylate in the treatment of metastatic and/or unresectable malignant gastrointestinal stromal tumors. Clin Cancer Res. 2002;8(10):3034-3038.
3. Hirota S, Isozaki K, Moriyama Y, et al. Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors. Science. 1998;279(5350):577-580. doi:10.1126/science.279.5350.577
4. Ashman LK. The biology of stem cell factor and its receptor C-kit. Int J Biochem Cell Biol. 1999;31(10):1037-1051. doi:10.1016/s1357-2725(99)00076-x
5. Plaat BE, Hollema H, Molenaar WM, et al. Soft tissue leiomyosarcomas and malignant gastrointestinal stromal tumors: differences in clinical outcome and expression of multidrug resistance proteins. J Clin Oncol. 2000;18(18):3211-3220. doi:10.1200/JCO.2000.18.18.3211
6. Peng B, Lloyd P, Schran H. Clinical pharmacokinetics of imatinib. Clin Pharmacokinet. 2005;44(9):879-894. doi:10.2165/00003088-200544090-00001
7. Gschwind HP, Pfaar U, Waldmeier F, et al. Metabolism and disposition of imatinib mesylate in healthy volunteers. Drug Metab Dispos. 2005;33(10):1503-1512. doi:10.1124/dmd.105.004283
8. 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(7):472-480. doi:10.1056/NEJMoa020461
9. van Oosterom AT, Judson I, Verweij J, et al.; European Organisation for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group. Safety and efficacy of imatinib (STI571) in metastatic gastrointestinal stromal tumours: a phase I study. Lancet. 2001;358(9291):1421-1423. doi:10.1016/s0140-6736(01)06535-7
10. Verweij J, van Oosterom A, Blay JY, et al. Imatinib mesylate (STI-571 Glivec, Gleevec) is an active agent for gastrointestinal stromal tumours, but does not yield responses in other soft-tissue sarcomas that are unselected for a molecular target. Results from an EORTC Soft Tissue and Bone Sarcoma Group phase II study. Eur J Cancer. 2003;39(14):2006-2011.
11. Verweij J, Casali PG, Zalcberg J, et al. Progression-free survival in gastrointestinal stromal tumours with high-dose imatinib: randomised trial. Lancet. 2004;364(9440):1127-1134. doi:10.1016/S0140-6736(04)17098-0
12. 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(4):626-632. doi:10.1200/JCO.2007.13.4452
13. Laurent M, Brahmi M, Dufresne A, et al. Adjuvant therapy with imatinib in gastrointestinal stromal tumors (GISTs)-review and perspectives. Transl Gastroenterol Hepatol. 2019;4:24. doi:10.21037/tgh.2019.03.07
14. Iwatsuki M, Harada K, Iwagami S, et al. Neoadjuvant and adjuvant therapy for gastrointestinal stromal tumors. Ann Gastroenterol Surg. 2018;3(1):43-49. doi:10.1002/ags3.12211
15. Casali PG, Abecassis N, Aro HT, et al.; ESMO Guidelines Committee and EURACAN. Gastrointestinal stromal tumours: ESMO-EURACAN clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2018;29(Suppl 4):iv267. doi:10.1093/annonc/mdy320
16. von Mehren M, Randall RL, Benjamin RS, et al. Soft tissue sarcoma, version 2.2018, NCCN clinical practice guidelines in oncology. J Natl Compr Canc Netw. 2018;16(5):536-563. doi:10.6004/jnccn.2018.0025
Reviewed by Debjyoti Talukdar, MD, on 8/16/2021.