Phase Ib Trial of the Combination of Imatinib and Binimetinib in Patients with Advanced Gastrointestinal Stromal Tumors (GIST).
Academic Article
Overview
abstract
PURPOSE: This phase Ib trial was designed to evaluate the safety and early efficacy signal of the combination of imatinib and binimetinib in patients with imatinib-resistant advanced GIST. EXPERIMENTAL DESIGN: This used a standard 3+3 design to determine the recommended phase II dose (RP2D). Additional patients were enrolled on an expansion cohort at the RP2D enriching for SDH-deficient GIST to explore potential efficacy. RESULTS: The trial enrolled 9 patients in dose-escalation and 14 in dose-expansion cohorts including 6 with SDH-deficient GIST. Imatinib 400mg daily with binimetinib 45mg twice daily was established as the RP2D. Dose limiting toxicity (DLT) was asymptomatic grade 4 (Gr4) Creatinine Phosphokinase (CPK) elevation. The most common non-DLT Gr3/4 toxicity was asymptomatic CPK elevation (69.6%). Other common {greater than or equal to}Gr2 toxicities included peripheral edema (17.4%), acneiform rash (21.7%), anemia (30.4%), hypophosphatemia (39.1%) and AST increase (17.4%). Two serious adverse events occurred (Gr2 dropped head syndrome and Gr3 central retinal vein occlusion). No unexpected toxicities were observed. Limited clinical activity was observed in KIT-mutant GIST. For SDH-deficient GIST, 1/5 had confirmed RECIST1.1 PR. The mPFS in SDH-deficient GIST patients was 45.1 months (95%CI, 15.8-NE); the mOS was not reached (95%CI, 31.6 months-NE). One patient with refractory metastatic SDH-deficient GIST had an exceptional pathological response and durable clinical benefit. CONCLUSIONS: The combination of imatinib and binimetinib is safe with manageable toxicity and has encouraging activity in SDH-deficient but not imatinib-refractory KIT/PDGFRA-mutant GIST. The observed clinical benefits provide a motivation for a larger trial of the combination strategy in SDH-deficient GIST.
