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

Chi, Ping; Qin, Li‐Xuan; Nguyen, Bastien; Kelly, Ciara M.; D’Angelo, Sandra P.; Dickson, Mark A.; Gounder, Mrinal M.; Keohan, Mary Lou; Movva, Sujana; Nacev, Benjamin A.; Rosenbaum, Evan; Thornton, Katherine A.; Crago, Aimeé M.; Yoon, Sam S.; Ulaner, Gary A.; Yeh, Randy; Martindale, Moriah; Phelan, Haley T.; Biniakewitz, Matthew; Warda, Sarah; Lee, Cindy J.; Berger, Michael F.; Singer, Samuel; Hwang, Sinchun; Chen, Yu; Antonescu, Cristina R.; Tap, William D.

doi:10.1200/jco.21.02029

Cited by 14 publications

(11 citation statements)

References 49 publications

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“… 764 For example, the combination of ABL1 inhibitor imatinib and MEK inhibitor binimetinib for treatment‐naive adult patients with confirmed advanced GISTs received 69.0% of ORR, which was 20% improvement in the ORR over imatinib alone. 776 Addition of BCL‐2 inhibitor navitoclax to ongoing ruxolitinib therapy could reverse the resistance for patients with myelofibrosis, whose disease had been progressed or suboptimal response to ruxolitinib monotherapy. 777 In addition, the combination of antibody drugs and small molecule inhibitors is also an effective way to jointly inhibit multiple signaling pathways.…”

Section: Discussionmentioning

confidence: 99%

“…Although the combination of different selective small molecule inhibitors that inhibit different signaling pathways have not been approved, many similar efforts have been made 764 . For example, the combination of ABL1 inhibitor imatinib and MEK inhibitor binimetinib for treatment‐naive adult patients with confirmed advanced GISTs received 69.0% of ORR, which was 20% improvement in the ORR over imatinib alone 776 . Addition of BCL‐2 inhibitor navitoclax to ongoing ruxolitinib therapy could reverse the resistance for patients with myelofibrosis, whose disease had been progressed or suboptimal response to ruxolitinib monotherapy 777 .…”

Section: Discussionmentioning

confidence: 99%

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Small molecule inhibitors targeting the cancers

Liu

Chen

Zhang

et al. 2022

MedComm

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Compared with traditional therapies, targeted therapy has merits in selectivity, efficacy, and tolerability. Small molecule inhibitors are one of the primary targeted therapies for cancer. Due to their advantages in a wide range of targets, convenient medication, and the ability to penetrate into the central nervous system, many efforts have been devoted to developing more small molecule inhibitors. To date, 88 small molecule inhibitors have been approved by the United States Food and Drug Administration to treat cancers. Despite remarkable progress, small molecule inhibitors in cancer treatment still face many obstacles, such as low response rate, short duration of response, toxicity, biomarkers, and resistance. To better promote the development of small molecule inhibitors targeting cancers, we comprehensively reviewed small molecule inhibitors involved in all the approved agents and pivotal drug candidates in clinical trials arranged by the signaling pathways and the classification of small molecule inhibitors. We discussed lessons learned from the development of these agents, the proper strategies to overcome resistance arising from different mechanisms, and combination therapies concerned with small molecule inhibitors. Through our review, we hoped to provide insights and perspectives for the research and development of small molecule inhibitors in cancer treatment.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Small molecule inhibitors targeting the cancers

Liu

Chen

Zhang

et al. 2022

MedComm

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“…Binimetinib is currently being investigated in a phase 1 study in patients with advanced GISTs in combination with pexidartinib (NCT03158103) ( 106 ). Another phase II trial (NCT0199379) was designed to test the efficacy and safety of binimetinib plus imatinib as a first-line treatment for GIST, which met the primary endpoint and showed good efficacy and manageable toxicity ( 107 ). Dual targeting of the GIST lineage-specific master regulators, ETV1 and KIT, by MEK and KIT inhibitors, respectively, may enhance clinical efficacy of these agents, and more studies should be conducted to explore this combination.…”

Section: Agent Combination Based On Different Strategiesmentioning

confidence: 99%

An overview of agents and treatments for PDGFRA-mutated gastrointestinal stromal tumors

Sun

Yue

2022

Front. Oncol.

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Platelet-derived growth factor receptor A (PDGFRA) mutations occur in approximately 10–15% of gastrointestinal stromal tumors (GISTs). These tumors with PDGFRA mutations have a different pathogenesis, clinical characteristics, and treatment response compared to tumors with receptor tyrosine kinase protein (KIT) mutations (60–70%). Many clinical studies have investigated the use of tyrosine kinase inhibitors mainly in patients with KIT mutations; however, there is a lack of attention to the PDGFRA-mutated molecular subtype. The main effective inhibitors of PDGFRA are ripretinib, avapritinib, and crenolanib, and their mechanisms and efficacy in GIST (as confirmed in clinical trials) are described in this review. Some multi-targeted tyrosine kinase inhibitors with inhibitory effects on this molecular subtype are also introduced and summarized in this paper. This review focuses on PDGFRA-mutated GISTs, introduces their clinical characteristics, downstream molecular signaling pathways, and existing resistance mechanisms. We focus on the most recent literature that describes the development of PDGFRA inhibitors and their use in clinical trials, as well as the potential benefits from different combination therapy strategies.

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“…In addition, we found that approximately 5-15% of adult GIST patients and most children with GIST did not have any mutations in KIT or PDGFRA (initially designated as 'wild type'), and the KIT small molecule TKI imatinib was ineffective in these patients. Therefore, most studies have focused on identifying new inhibitors to improve the outcome of imatinib-resistant GIST patients [17][18][19].…”

Section: Introductionmentioning

confidence: 99%

Clinicopathologic features and prognosis of gastrointestinal stromal tumors: A retrospective study

shen

Zhang²,

Jia³

et al. 2022

Preprint

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ObjectiveGastrointestinal stromal tumors (GISTs) are rare but are the most common mesenchymal tumors of the digestive tract. GISTs represent a spectrum of tumors characterized by variable behaviors and activating mutations in KIT proto-oncogene, receptor tyrosine kinase (KIT) or platelet derived growth factor receptor α (PDGFRA) genes. This study aimed to analyze the histological and molecular characteristics of GISTs and the clinicopathologic features associated with its prognosis.MethodsWe retrospectively analyzed clinical, pathological and prognostic data for 941 patients who underwent GIST surgery at our hospital from 2010 to 2020. Influencing factors associated with GIST gene mutations and clinicopathological features related to patient prognosis were evaluated. The Kaplan-Meier method was used for survival analysis.ResultsGISTs were found to be more common in women than in men, to occur at an older age, and were located mainly in the stomach. GISTs were generally small in size, had a low mitotic index and were more often rated as very low risk/low risk. Immunohistochemistry showed that 96.7% and 98.4% of tumors were positive for CD117 and DOG-1. KIT and PDGFRA mutations were identified in 113 (76.4%) and 4 (4.0%) cases, respectively. Survival analysis showed GIST patient prognosis to be related to sex, age, tumor site, tumor size, mitotic count and the combined with other tumors. Patients with exon 11 mutation in KIT had a better prognosis than those with exon 9 mutation in KIT. Relapse or metastasis occurred in 39 patients during the follow-up period. Most relapsed or metastatic GISTs had concordant pathological and mutational characteristics with the primary tumor; they carried an identical KIT/PDGFRA mutation, and the mitotic index was usually high. But 4 metastatic GISTs carried a different KIT mutation compared to the promary tumor. Furthermore, coexistence of double mutations in KIT was observed in five tumors, with worse prognostic features.ConclusionsClinicopathological features( sex, age, site, tumor size, mitotic count, and the coexisting with other types of tumors) of GISTs, and mutation sites of KIT and PDGFRA were associated with the risk of GIST progression, which may contribute to optimization of individualized adjuvant therapy.

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

Cited by 14 publications

References 49 publications

Small molecule inhibitors targeting the cancers

Small molecule inhibitors targeting the cancers

An overview of agents and treatments for PDGFRA-mutated gastrointestinal stromal tumors

Clinicopathologic features and prognosis of gastrointestinal stromal tumors: A retrospective study

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