Synapse - Phase Ib trial of the combination of imatinib and binimetinib in patients with advanced gastrointestinal stromal tumors

Phase Ib trial of the combination of imatinib and binimetinib in patients with advanced gastrointestinal stromal tumors Journal Article

Authors:	Chi, P.; Qin, L.; Camacho, N.; Kelly, C. M.; D'Angelo, S. P.; Dickson, M. A.; Gounder, M. M.; Keohan, M. L.; Movva, S.; Nacev, B. A.; Rosenbaum, E.; Thornton, K. A.; Crago, A. M.; Francis, J. H.; Martindale, M.; Phelan, H. T.; Biniakewitz, M. D.; Lee, C. J.; Singer, S.; Hwang, S.; Berger, M. F.; Chen, Y.; Antonescu, C. R.; Tap, W. D.
Article Title:	Phase Ib trial of the combination of imatinib and binimetinib in patients with advanced gastrointestinal stromal tumors
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 gastrointestinal stromal tumors (GISTs). Patients and Methods: This trial 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 succinate dehydrogenase (SDH)-deficient GISTs to explore potential efficacy. Results: The trial enrolled nine patients in the dose-escalation cohort and 14 in the dose-expansion cohort including six with SDH-deficient GISTs. Imatinib 400 mg daily with binimetinib 45 mg twice daily was established as the RP2D. Dose-limiting toxicity (DLT) was asymptomatic grade 4 creatinine phosphokinase (CPK) elevation. The most common non-DLT grade 3/4 toxicity was asymptomatic CPK elevation (69.6%). Other common >= grade 2 toxicities included peripheral edema (17.4%), acneiform rash (21.7%), anemia (30.4%), hypophosphatemia (39.1%), and aspartate aminotransferase (AST) increase (17.4%). Two serious adverse events occurred (grade 2 dropped head syndrome and grade 3 central retinal vein occlusion). No unexpected toxicities were observed. Limited clinical activity was observed in KIT-mutant GIST. For SDH-deficient GISTs, one of five had confirmed RECIST1.1 partial response (PR). The median progression-free survival (mPFS) in patients with SDH-deficient GIST was 45.1 months [95% confidence interval (CI), 15.8-not estimable (NE)]; the median overall survival (mOS) was not reached (95% CI, 31.6 months-NE). One patient with a refractory metastatic SDH-deficient GIST had an exceptional pathologic 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 GISTs. The observed clinical benefits provide a motivation for a larger trial of the combination strategy in SDH-deficient GISTs.
Keywords:	adult; kit; resistance; mutations; failure; cells; kinase; sensitivity; etv1; wild-type
Journal Title:	Clinical Cancer Research
Volume:	28
Issue:	8
ISSN:	1078-0432
Publisher:	American Association for Cancer Research
Date Published:	2022-04-15
Start Page:	1507
End Page:	1517
Language:	English
ACCESSION:	WOS:000789062100001
DOI:	10.1158/1078-0432.Ccr-21-3909
PROVIDER:	wos
PMCID:	PMC9012681
PUBMED:	35110417
Notes:	Article -- Source: Wos