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The aim of this study is to evaluate the safety and efficacy of lenvatinib in patients with metastatic or advanced GIST who have failed at least imatinib, sunitinib, and regorafenib treatment.
Full description
The discovery of KIT gene mutations and the development of the KIT tyrosine kinase inhibitor imatinib (Glivec™, Novartis) have significantly improved the survival rates of patients with advanced and metastatic gastrointestinal stromal tumors (GIST). More recently, sunitinib (Sutene™, Pfizer) and regorafenib (Stivarga®, Bayer) have been proven effective as second- and third-line therapies, respectively, for patients who have failed imatinib treatment. However, nearly all patients eventually develop resistance to first-line imatinib, second-line sunitinib, and third-line regorafenib, resulting in disease progression. Although ripretinib, a fourth-line treatment, has demonstrated an improvement in progression-free survival to 6.3 months compared to placebo in the phase III INVICTUS trial, it remains inaccessible in many regions, including Korea, limiting its clinical application. Therefore, there is an urgent need for new therapeutic alternatives after imatinib, sunitinib, and regorafenib in clinical practice.
Lenvatinib is a multi-targeted tyrosine kinase inhibitor with potent anti-angiogenic activity, primarily targeting VEGFR1-3 with IC₅₀ values of 4.7, 3.0, and 2.3 nmol/L, respectively. It also exhibits inhibitory activity against c-KIT (IC₅₀: 85 nmol/L) and PDGFR-α (IC₅₀: 29 nmol/L). Pharmacokinetically, lenvatinib is rapidly absorbed with a bioavailability of 85% and has an elimination half-life of approximately 28 hours. The LENVAGIST study, presented at ESMO 2024, was a phase II randomized, placebo-controlled trial that demonstrated the significant clinical activity of lenvatinib in patients with advanced GIST who had progressed after treatment with imatinib and sunitinib. In this study, the 4-month progression-free survival rate was 39% in the lenvatinib group versus 11% in the placebo group (HR 0.44; 95% CI 0.27-0.71; p=0.0008), and the median overall survival was 14.4 months versus 8.7 months, respectively. Treatment-related grade ≥3 adverse events were observed in 56.4% of patients in the lenvatinib group and 18.4% in the placebo group.
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Inclusion criteria
Age ≥ 20 years at the time of providing written informed consent.
Histologically confirmed metastatic and/or advanced (unresectable or recurrent) GIST with positivity for CD117(+), DOG-1(+), or harboring mutations in the KIT or PDGFRα genes.
Documented failure of prior treatment with imatinib, sunitinib, and regorafenib due to disease progression and/or intolerance.
Note: There is no limitation on the number of prior therapies. Prior use of other tyrosine kinase inhibitors (TKIs) or chemotherapy in combination with imatinib, sunitinib, or regorafenib is permitted.
Disease progression is defined as:
Intolerance to prior TKIs is defined as:
ECOG performance status of 0-2.
All toxicities from previous treatments must have recovered to Grade 0 or 1 as per NCI-CTCAE version 5.0.
At least one measurable lesion as defined by mRECIST version 1.1.
Adequate bone marrow, liver, renal, and other organ function:
Life expectancy ≥ 12 weeks
A washout period equivalent to at least 4 times the half-life of previous TKI or chemotherapeutic agents is required(Imatinib and regorafenib: ≥ 1 week; Sunitinib: ≥ 2 weeks)
Signed written informed consent
Exclusion criteria
Primary purpose
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48 participants in 1 patient group
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Central trial contact
Hyung-Don kim; Jaewon Hyung
Data sourced from clinicaltrials.gov
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