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Association of Combination of Conformation-Specific KIT Inhibitors With Clinical Benefit in Patients With Refractory
Andrew J Wagner1, Paul L Severson2, Anthony F Shields3
1Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
Importance:
Many cancer subtypes, including KIT-mutant gastrointestinal stromal tumors (GISTs), are driven by activating mutations in tyrosine kinases and may initially respond to kinase inhibitors but frequently relapse owing to outgrowth of heterogeneous subclones with resistance mutations. KIT inhibitors commonly used to treat GIST (eg, imatinib and sunitinib) are inactive-state (type II) inhibitors.
Objective:
To assess whether combining a type II KIT inhibitor with a conformation-complementary, active-state (type I) KIT inhibitor is associated with broad mutation coverage and global disease control.
Design, Setting, And Participants:
A highly selective type I inhibitor of KIT, PLX9486, was tested in a 2-part phase 1b/2a trial. Part 1 (dose escalation) evaluated PLX9486 monotherapy in patients with solid tumors. Part 2e (extension) evaluated PLX9486-sunitinib combination in patients with GIST. Patients were enrolled from March 2015 through February 2019; data analysis was performed from May 2020 through July 2020.
Interventions:
Participants received 250, 350, 500, and 1000 mg of PLX9486 alone (part 1) or 500 and 1000 mg of PLX9486 together with 25 or 37.5 mg of sunitinib (part 2e) continuously in 28-day dosing cycles until disease progression, treatment discontinuation, or withdrawal.
Main Outcomes And Measures:
Pharmacokinetics, safety, and tumor responses were assessed. Clinical efficacy end points (progression-free survival and clinical benefit rate) were supplemented with longitudinal monitoring of KIT mutations in circulating tumor DNA.
Results:
A total of 39 PLX9486-naive patients (median age, 57 years [range, 39-79 years]; 22 men [56.4%]; 35 [89.7%] with refractory GIST) were enrolled in the dose escalation and extension parts. The recommended phase 2 dose of PLX9486 was 1000 mg daily. At this dose, PLX9486 could be safely combined with 25 or 37.5 mg daily of sunitinib continuously. Patients with GIST who received PLX9486 at a dose of 500 mg or less, at the recommended phase 2 dose, and with sunitinib had median (95% CI) progression-free survivals of 1.74 (1.54-1.84), 5.75 (0.99-11.0), and 12.1 (1.34-NA) months and clinical benefit rates (95% CI) of 14% (0%-58%), 50% (21%-79%), and 80% (52%-96%), respectively.
Conclusions And Relevance:
In this phase 1b/2a nonrandomized clinical trial, type I and type II KIT inhibitors PLX9486 and sunitinib were safely coadministered at the recommended dose of both single agents in patients with refractory GIST. Results suggest that cotargeting 2 complementary conformational states of the same kinase was associated with clinical benefit with an acceptable safety profile.
Trial Registration:
ClinicalTrials.gov Identifier: NCT02401815.
Insights
Combining KIT inhibitors PLX9486 and sunitinib showed promising results for gastrointestinal stromal tumors (GIST). This combination therapy demonstrated improved progression-free survival and clinical benefit rates in patients with refractory GIST.
Area of Science:
- Oncology
- Pharmacology
- Clinical Trials
Background:
- Gastrointestinal stromal tumors (GISTs) often develop resistance to kinase inhibitors due to heterogeneous subclones.
- KIT inhibitors, such as imatinib and sunitinib, are standard treatments but have limitations in overcoming resistance mutations.
Purpose of the Study:
- To evaluate the safety and efficacy of combining a type I KIT inhibitor (PLX9486) with a type II KIT inhibitor (sunitinib) in patients with GIST.
- To assess if this combination therapy broadens mutation coverage and improves overall disease control in refractory GIST.
Main Methods:
- A phase 1b/2a clinical trial involving dose escalation of PLX9486 and a combination arm with sunitinib.
- Patients received continuous daily dosing of PLX9486 alone or in combination with sunitinib until disease progression.
- Pharmacokinetics, safety, tumor responses, progression-free survival, and clinical benefit rate were assessed, alongside monitoring of KIT mutations in circulating tumor DNA.
Main Results:
- The recommended phase 2 dose for PLX9486 was determined to be 1000 mg daily, safely combined with sunitinib (25 or 37.5 mg daily).
- Patients with refractory GIST receiving the combination therapy showed improved median progression-free survival (up to 12.1 months) and clinical benefit rates (up to 80%).
Conclusions:
- Coadministration of type I (PLX9486) and type II (sunitinib) KIT inhibitors is safe and feasible in patients with refractory GIST.
- Cotargeting complementary conformational states of KIT kinase offers clinical benefit with an acceptable safety profile, suggesting a potential new therapeutic strategy for GIST.
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