Phase Ib Trial of the Combination of Imatinib and Binimetinib in Patients with Advanced Gastrointestinal Stromal Tumors

Chi, Ping; Qin, Li‐Xuan; Camacho, Niedzica; 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.; Francis, Jasmine H.; Martindale, Moriah; Phelan, Haley T.; Biniakewitz, Matthew; Lee, Cindy J.; Singer, Samuel; Hwang, Sinchun; Berger, Michael F.; Chen, Yu; Antonescu, Cristina R.; Tap, William D.

doi:10.1158/1078-0432.ccr-21-3909

Cited by 8 publications

(5 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Binimetinib is an allosteric inhibitor of MAP kinase 1 and 2 (MEK1/2), which has been investigated in combination with imatinib for patients with advanced GIST. A phase 1b study showed only limited activity in the general cohort of patients with imatinib-resistant advanced GIST, with only one of 22 patients showing a PR and a best ORR of 4.5% [ 77 ]. A phase 2 study of the binimetinib-imatinib combination in patients with treatment-naïve advanced GIST found a confirmed PR in 29 of 42 evaluable patients, with a best ORR of 69% and a median PFS of 29.9 months [ 78 ].…”

Section: Upcoming Treatments For Advanced Gistmentioning

confidence: 99%

Current status of and future prospects for the treatment of unresectable or metastatic gastrointestinal stromal tumours

2023

View full text Add to dashboard Cite

Gastrointestinal stromal tumours (GISTs) are soft-tissue sarcomas of the gastrointestinal tract. Surgery is the standard treatment for localised disease, but the risk of relapse and progression to more advanced disease is substantial. Following the discovery of the molecular mechanisms underlying GISTs, targeted therapies for advanced GIST were developed, with the first being the tyrosine kinase inhibitor (TKI) imatinib. Imatinib is recommended in international guidelines as first-line therapy to reduce the risk of GIST relapse in high-risk patients, and for locally advanced, inoperable and metastatic disease. Unfortunately, imatinib resistance frequently occurs and, therefore, second-line (sunitinib) and third-line (regorafenib) TKIs have been developed. Treatment options are limited for patients with GIST that has progressed despite these therapies. A number of other TKIs for advanced/metastatic GIST have been approved in some countries. Ripretinib is approved as fourth-line treatment of GIST and avapritinib is approved for GIST harbouring specific genetic mutations, while larotrectinib and entrectinib are approved for solid tumours (including GIST) with specific genetic mutations. In Japan, pimitespib, a heat shock protein 90 (HSP90) inhibitor, is now available as a fourth-line therapy for GIST. Clinical studies of pimitespib have indicated that it has good efficacy and tolerability, importantly not displaying the ocular toxicity of previously developed HSP90 inhibitors. Additional approaches for advanced GIST have been investigated, including alternative uses of currently available TKIs (such as combination therapy), novel TKIs, antibody–drug conjugates, and immunotherapies. Given the poor prognosis of advanced GIST, the development of new therapies remains an important goal.

show abstract

Section: Upcoming Treatments For Advanced Gistmentioning

confidence: 99%

Current status of and future prospects for the treatment of unresectable or metastatic gastrointestinal stromal tumours

2023

View full text Add to dashboard Cite

show abstract

“… 103 Phase I and II (NCT01991379) testing found this combination to be safe and well-tolerated in treatment-naïve patients. 104 , 105 The ORR was 69%, and median PFS was 30 months. 105 …”

Section: Future Directionmentioning

confidence: 96%

Molecular Advances in the Treatment of Advanced Gastrointestinal Stromal Tumor

2023

View full text Add to dashboard Cite

Most gastrointestinal stromal tumors (GIST) are driven by activating mutations in Proto-oncogene c-KIT (KIT) or PDGFRA receptor tyrosine kinases (RTK). The emergence of effective therapies targeting these mutations has revolutionized the management of advanced GIST. However, following initiation of first-line imatinib, a tyrosine kinase inhibitor (TKI), nearly all patients will develop resistance within 2 years through the emergence of secondary resistance mutations in KIT, typically in the Adenosine Triphosphate (ATP)-binding site or activation loop of the kinase domain. Moreover, some patients have de novo resistance to imatinib, such as those with mutations in PDGFRA exon 18 or those without KIT or PDGFRA mutation. To target resistance, research efforts are primarily focused on developing next-generation inhibitors of KIT and/or PDGFRA, which can inhibit alternate receptor conformations or unique mutations, and compounds that impact complimentary pathogenic processes or epigenetic events. Here, we review the literature on the medical management of high-risk localized and advanced GIST and provide an update on clinical trial approaches to this disease.

show abstract

“…Surgical resection is not appropriate for advanced GIST with multiple metastases. Approximately 10–15% of GIST exhibit specific gene mutations and exhibit resistance to targeted therapy ( 4 ). Radiotherapy provides analgesic effects for bone metastases, with a relief rate of 60% ( 5 ).…”

Section: Introductionmentioning

confidence: 99%

Microwave ablation for painful chest wall metastases from gastrointestinal stromal tumor: a case report

Wang,

et al. 2024

Front. Oncol.

View full text Add to dashboard Cite

BackgroundGastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the digestive tract, with the potential to metastasize. Metastases to bone and soft tissue are more frequent in advanced cases, where targeted therapy is the standard treatment. However, around 10–15% of patients develop disease progression despite treatment. Studies have shown the efficacy of ablation in managing bone and soft tissue metastases (1, 2), but there are no reports of ablation for treating GIST bone or soft tissue metastases.Case presentationIn 2022, a 58-year-old man complaining of left back pain was admitted to Sichuan Cancer Hospital. He had undergone radical resection of the primary gastric GIST and vertebral metastases in 2014 and 2018, respectively. In 2019, rib metastases still occurred despite the use of targeted therapy. During the course of radiotherapy, targeted therapy, and immunotherapy, he experienced persistent chest wall pain. In addition, new lesions occurred in the lungs and chest wall in 2022. After a thorough assessment, microwave ablation (MWA) was recommended in response to his demand for immediate pain relief. The large rib metastasis constricted the spleen, so we completed the ablation in two sessions to reduce the risk of complications. He had 17 months of follow-up until September 2023, during which time his discomfort was considerably reduced.ConclusionFor GIST patients with soft tissue and bone metastases, MWA may offer substantial immediate pain alleviation. When other treatment procedures fail to achieve adequate efficacy, it provides an option.

show abstract

Phase Ib Trial of the Combination of Imatinib and Binimetinib in Patients with Advanced Gastrointestinal Stromal Tumors

Abstract: SKI2016-021-03 pending to MSKCC/SKI. W.D.T. is on the SAB of Certis Oncology Solutions with stock ownership, on the SAB of Innova Therapeutics, and is the co-founder of Atropos Therapeutics with stock ownership.Research.

Cited by 8 publications

References 33 publications

Current status of and future prospects for the treatment of unresectable or metastatic gastrointestinal stromal tumours

Current status of and future prospects for the treatment of unresectable or metastatic gastrointestinal stromal tumours

Molecular Advances in the Treatment of Advanced Gastrointestinal Stromal Tumor

Microwave ablation for painful chest wall metastases from gastrointestinal stromal tumor: a case report

Contact Info

Product

Resources

About