Phase Ib Trial of the Combination of Imatinib and Binimetinib in Patients with Advanced Gastrointestinal Stromal Tumors (GIST)
Mené sur 23 patients atteints d'une tumeur stromale gastrointestinale, cet essai de phase IB évalue la dose maximale tolérée et l'efficacité, du point de vue du taux de réponse, de l'imatinib en combinaison avec le binimétinib
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.