METEOR-1: A phase I study of GSK3326595, a first-in-class protein arginine methyltransferase 5 (PRMT5) inhibitor, in advanced solid tumours

Siu, L.L.; Rasco, Drew W.; Vinay, S. P.; Romano, P. Martin; Menis, Jessica; Opdam, Frans; Heinhuis, Kimberley M.; Egger, Jacqueline L.; Gorman, Shelby A.; Parasrampuria, Ridhi; Wang, K.; Kremer, Brandon E.; Gounder, Mrinal M.

doi:10.1093/annonc/mdz244

Cited by 73 publications

(56 citation statements)

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“…Of the selected patients, 14 (26%) had metastatic ACC. Clinical activity was observed in several tumor types, notably with partial responses observed in 3/14 ACC cases, with tolerable adverse events (79).…”

Section: Egfr Pathwaymentioning

confidence: 99%

Salivary Gland Carcinoma: Novel Targets to Overcome Treatment Resistance in Advanced Disease

et al. 2020

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Salivary gland carcinomas (SGCs) account for <5% of head and neck malignant neoplasms, further subcategorized in over 20 histological subtypes. For the most part, treatment for advanced disease is guided by morphology. SGCs in general respond poorly to a wide array of standard chemotherapy, with short durability, and significant toxicity. More recently, next-generation sequencing provided significant input on the molecular characterization of each SGC subtype, not only improving diagnostic differentiation between morphologically similar tumor types but also identifying novel driver pathways that determine tumor biology and may be amenable to targeted therapy. Among the most common histological subtype is adenoid cystic carcinoma, which often harbors a chromosome translocation resulting in an MYB-NFIB oncogene, with various degrees of Myb surface expression. In a smaller subset, NOTCH1 mutations occur, conferring a more aggressive pattern and potential sensitivity to Notch inhibitors. Salivary duct carcinomas may overexpress Her-2 and androgen receptors, with promising clinical outcomes after exposure to targeted therapies approved for other indications. Secretory carcinoma, previously known as mammary analog secretory carcinoma, is distinguished by an ETV6-NTRK3 fusion that can both help differentiate it from its morphologically similar acinar cell carcinoma and make it susceptible to Trk inhibitors. In the present article, we discuss the molecular abnormalities, their impact on tumor biology, and therapeutic opportunities for the most common SGC subtypes and review published and ongoing clinical trials and future perspectives for this rare disease.

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Section: Egfr Pathwaymentioning

confidence: 99%

Salivary Gland Carcinoma: Novel Targets to Overcome Treatment Resistance in Advanced Disease

et al. 2020

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“…Thus far, three PRMT5 inhibitors, GSK3326595 (EPZ015938), JNJ-6461978, and PF-06939999, have entered into clinical studies in patients with hematologic malignancies and solid tumors. A presentation at the European Society for Medical Oncology congress reported data from the METEOR-1 study (NCT02783300) for GSK3326595 in advanced solid tumors [123]. Patients (n = 54) received doses of 12.5 mg to 600 mg once daily, and from 50 mg to 200 mg twice daily, with a median time on treatment of 1.8 months (range 1 day to 18.7 months).…”

Section: Protein Arginine Methyltransferasesmentioning

confidence: 99%

The Promise for Histone Methyltransferase Inhibitors for Epigenetic Therapy in Clinical Oncology: A Narrative Review

et al. 2020

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Epigenetic processes are essential for normal development and the maintenance of tissuespecific gene expression in mammals. Changes in gene expression and malignant cellular transformation can result from disruption of epigenetic mechanisms, and global disruption in the epigenetic landscape is a key feature of cancer. The study of epigenetics in cancer has revealed that human cancer cells harbor both genetic alterations and epigenetic abnormalities that interplay at all stages of cancer development. Unlike genetic mutations, epigenetic aberrations are potentially reversible through epigenetic therapy, providing a therapeutically relevant treatment option. Histone methyltransferase inhibitors are emerging as an epigenetic therapy approach with great promise in the field of clinical oncology. The recent accelerated approval of the enhancer of zeste homolog 2 (EZH2; also known as histone-lysine N-methyltransferase EZH2) inhibitor tazemetostat for metastatic or locally advanced epithelioid sarcoma marks the first approval of such a compound for the treatment of cancer. Many other histone methyltransferase inhibitors are currently in development, some of which are being tested in clinical studies. This review focuses on histone methyltransferase inhibitors, highlighting their potential in the treatment of cancer. We also discuss the role for such epigenetic drugs in overcoming epigenetically driven drug resistance mechanisms, and their value in combination with other therapeutic approaches such as immunotherapy.

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“…AMG-510, an inhibitor targeting KRAS G12C, which accounts for 13% of KRAS mutant NSCLC [140], is currently under investigation in a Phase I/II clinical trial of advanced KRAS mutant solid tumors. Interim results were recently presented and showed that out of the 29 patients, 10 were diagnosed with NSCLC, of which 90% (N = 9) of patients exhibited either a partial response or stable disease [16]. Although there are currently no FDA-approved drugs targeting KRAS, small molecule inhibitors like AMG-510 and JNJ-74699157 continue to demonstrate good clinical activity.…”

Section: Krasmentioning

confidence: 99%

“…Furthermore, mature outcome data from second-generation TKIs is showing durable overall survival benefit for patients [13,14], a factor that was previously disputed with earlier TKIs [15]. of 26 Several molecular targets that were previously considered "unactionable", such as KRAS, now have several targeted therapies under consideration with promising early results [16,17]. Nevertheless, for patients without an actionable target or progression of disease, immune checkpoint inhibitors (ICIs) have resulted in durable outcomes and clinical benefit across several NSCLC trials in various lines of therapy [18][19][20][21][22][23][24].…”

Section: Introductionmentioning

confidence: 99%

Non-Small Cell Lung Cancer from Genomics to Therapeutics: A Framework for Community Practice Integration to Arrive at Personalized Therapy Strategies

Rajurkar

Mambetsariev

Pharaon

et al. 2020

JCM

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Non-small cell lung cancer (NSCLC) is a heterogeneous disease, and therapeutic management has advanced with the identification of various key oncogenic mutations that promote lung cancer tumorigenesis. Subsequent studies have developed targeted therapies against these oncogenes in the hope of personalizing therapy based on the molecular genomics of the tumor. This review presents approved treatments against actionable mutations in NSCLC as well as promising targets and therapies. We also discuss the current status of molecular testing practices in community oncology sites that would help to direct oncologists in lung cancer decision-making. We propose a collaborative framework between community practice and academic sites that can help improve the utilization of personalized strategies in the community, through incorporation of increased testing rates, virtual molecular tumor boards, vendor-based oncology clinical pathways, and an academic-type singular electronic health record system.

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METEOR-1: A phase I study of GSK3326595, a first-in-class protein arginine methyltransferase 5 (PRMT5) inhibitor, in advanced solid tumours

Cited by 73 publications

References 0 publications

Salivary Gland Carcinoma: Novel Targets to Overcome Treatment Resistance in Advanced Disease

Salivary Gland Carcinoma: Novel Targets to Overcome Treatment Resistance in Advanced Disease

The Promise for Histone Methyltransferase Inhibitors for Epigenetic Therapy in Clinical Oncology: A Narrative Review

Non-Small Cell Lung Cancer from Genomics to Therapeutics: A Framework for Community Practice Integration to Arrive at Personalized Therapy Strategies

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