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Ref Type

Journal Article

PMID

(35041493)

Authors

Chi P, Qin LX, Nguyen B, Kelly CM, D'Angelo SP, Dickson MA, Gounder MM, Keohan ML, Movva S, Nacev BA, Rosenbaum E, Thornton KA, Crago AM, Yoon S, Ulaner G, Yeh R, Martindale M, Phelan HT, Biniakewitz MD, Warda S, Lee CJ, Berger MF, Schultz ND, Singer S, Hwang S, Chen Y, Antonescu CR, Tap WD

Title

Phase II Trial of Imatinib Plus Binimetinib in Patients With Treatment-Naive Advanced Gastrointestinal Stromal Tumor.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Journal of clinical oncology : official journal of the American Society of Clinical Oncology			2022 Jan 18	997-1008	J Clin Oncol

URL

Abstract Text

Dual targeting of the gastrointestinal stromal tumor (GIST) lineage-specific master regulators, ETV1 and KIT, by MEK and KIT inhibitors were synergistic preclinically and may enhance clinical efficacy. This trial was designed to test the efficacy and safety of imatinib plus binimetinib in first-line treatment of GIST.In this trial (NCT01991379), treatment-naive adult patients with confirmed advanced GISTs received imatinib (400 mg once daily) plus binimetinib (30 mg twice daily), 28-day cycles. The primary end point was RECIST1.1 best objective response rate (ORR; complete response plus partial response [PR]). The study was designed to detect a 20% improvement in the ORR over imatinib alone (unacceptable rate of 45%; acceptable rate of 65%), using an exact binomial test, one-sided type I error of 0.08 and type II error of 0.1, and a planned sample size of 44 patients. Confirmed PR or complete response in > 24 patients are considered positive. Secondary end points included Choi and European Organisation for Research and Treatment of Cancer Response Rate, progression-free survival (PFS), overall survival (OS), pathologic responses, and toxicity.Between September 15, 2014, and November 15, 2020, 29 of 42 evaluable patients with advanced GIST had confirmed RECIST1.1 PR. The best ORR was 69.0% (two-sided 95% CI, 52.9 to 82.4). Thirty-nine of 41 (95.1%) had Choi PR approximately 8 weeks. Median PFS was 29.9 months (95% CI, 24.2 to not estimable); median OS was not reached (95% CI, 50.4 to not estimable). Five of eight patients with locally advanced disease underwent surgery after treatment and achieved significant pathologic response (≥ 90% treatment effect). There were no unexpected toxicities. Grade 3 and 4 toxicity included asymptomatic creatinine phosphokinase elevation (79.1%), hypophosphatemia (14.0%), neutrophil decrease (9.3%), maculopapular rash (7.0%), and anemia (7.0%).The study met the primary end point. The combination of imatinib and binimetinib is effective with manageable toxicity and warrants further evaluation in direct comparison with imatinib in frontline treatment of GIST.

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Molecular Profile	Treatment Approach
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Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role
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Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
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Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
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Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance
KIT	Y870*	nonsense	unknown	KIT Y870* results in a premature truncation of the Kit protein at amino acid 870 of 976 (UniProt.org). Y870* has been identified in sequencing studies (PMID: 35041493), but has not been biochemically characterized and therefore, its effect on Kit protein function is unknown (PubMed, Nov 2024).

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Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
KIT A502_Y503dup	gastrointestinal stromal tumor	predicted - sensitive	Binimetinib + Imatinib	Case Reports/Case Series	Actionable	In a Phase II trial, Gleevec (imatinib) and Mektovi (binimetinib) combination treatment resulted in a 90% pathological response and 27% RECIST response in the primary tumor and 100% pathological response in metastatic lesions of a patient with an esophageal gastrointestinal stromal tumor harboring KIT A502_Y503dup (PMID: 35041493; NCT01991379).	35041493
KIT E554_K558del	gastrointestinal stromal tumor	predicted - sensitive	Binimetinib + Imatinib	Case Reports/Case Series	Actionable	In a Phase II trial, Gleevec (imatinib) and Mektovi (binimetinib) combination treatment had manageable toxicity and resulted in a 99% pathological response and 29% RECIST response in a patient with a rectal gastrointestinal stromal tumor harboring KIT E554_K558del (PMID: 35041493; NCT01991379).	35041493
KIT E554_K558del KIT V654A	gastrointestinal stromal tumor	predicted - resistant	Binimetinib + Imatinib	Case Reports/Case Series	Actionable	In a Phase II trial, KIT V654A was identified as a secondary resistance mutation in a patient with a gastrointestinal stromal tumor harboring a primary KIT E554_K558del mutation who developed resistance to Gleevec (imatinib) and Mektovi (binimetinib) treatment (PMID: 35041493; NCT01991379).	35041493
KIT E562_L576del	gastrointestinal stromal tumor	predicted - sensitive	Binimetinib + Imatinib	Case Reports/Case Series	Actionable	In a Phase II trial, Gleevec (imatinib) and Mektovi (binimetinib) combination treatment resulted in an 80% pathological response and 23% RECIST response in a patient with a small bowel gastrointestinal stromal tumor harboring KIT E562_L576del (PMID: 35041493; NCT01991379).	35041493
KIT E562_L576del KIT N822Y	gastrointestinal stromal tumor	predicted - resistant	Binimetinib + Imatinib	Case Reports/Case Series	Actionable	In a Phase II trial, KIT N822Y was identified as a secondary mutation in a patient with a gastrointestinal stromal tumor harboring a primary KIT E562_L576del mutation who developed resistance to Gleevec (imatinib) and Mektovi (binimetinib) (PMID: 35041493; NCT01991379).	35041493
KIT K558_V559del	gastrointestinal stromal tumor	predicted - sensitive	Binimetinib + Imatinib	Case Reports/Case Series	Actionable	In a Phase II trial, Gleevec (imatinib) and Mektovi (binimetinib) combination treatment resulted in a 70% pathological response and 46% RECIST response in a patient with a rectal gastrointestinal stromal tumor harboring KIT K558_V559del (PMID: 35041493; NCT01991379).	35041493
KIT Q556_I571del KIT V654A	gastrointestinal stromal tumor	predicted - resistant	Binimetinib + Imatinib	Case Reports/Case Series	Actionable	In a Phase II trial, KIT V654A was identified as a secondary mutation in a patient with a gastrointestinal stromal tumor harboring a primary KIT Q556_I571del mutation who developed resistance to Gleevec (imatinib) and Mektovi (binimetinib) (PMID: 35041493; NCT01991379).	35041493
KIT Q556_V559delinsHT KIT V654A	gastrointestinal stromal tumor	predicted - resistant	Binimetinib + Imatinib	Case Reports/Case Series	Actionable	In a Phase II trial, KIT V654A was identified as a secondary resistance mutation in a patient with a gastrointestinal stromal tumor harboring a primary KIT Q556_V559delinsHT mutation who developed resistance to Gleevec (imatinib) and Mektovi (binimetinib) (PMID: 35041493; NCT01991379).	35041493
KIT V560D	gastrointestinal stromal tumor	predicted - sensitive	Binimetinib + Imatinib	Case Reports/Case Series	Actionable	In a Phase II trial, Gleevec (imatinib) and Mektovi (binimetinib) combination treatment had manageable toxicity and resulted in a 95% pathological response and 6% RECIST response in a patient with gastrointestinal stromal tumor of the stomach harboring KIT V560D (PMID: 35041493; NCT01991379).	35041493
KIT V560D KIT D820G KIT N822K KIT Y870*	gastrointestinal stromal tumor	predicted - resistant	Binimetinib + Imatinib	Case Reports/Case Series	Actionable	In a Phase II trial, KIT N822K and KIT D820G were identified as secondary resistance mutations in a patient with a gastrointestinal stromal tumor harboring primary KIT Y870* and V560D mutations who developed resistance to Gleevec (imatinib) and Mektovi (binimetinib) treatment (PMID: 35041493; NCT01991379).	35041493
KIT W557_K558del KIT N822K	gastrointestinal stromal tumor	predicted - resistant	Binimetinib + Imatinib	Case Reports/Case Series	Actionable	In a Phase II trial, KIT N822K was identified as a secondary resistance mutation in a patient with a gastrointestinal stromal tumor harboring a primary KIT W557_K558del mutation who developed resistance to Gleevec (imatinib) and Mektovi (binimetinib) (PMID: 35041493; NCT01991379).	35041493

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