A randomized phase II study of the MEK1/MEK2 inhibitor trametinib (GSK1120212) compared with docetaxel in KRAS-mutant advanced non-small-cell lung cancer (NSCLC)

Blumenschein, George R.; Smit, Egbert F.; Planchard, David; Kim, D. W.; Cadranel, Jacques; Pas, Tommaso De; Dunphy, Frank; Udud, Katalin; Ahn, Myung Ju; Hanna, Nasser H.; Kim, Joo Hang; Mazières, Julien; Kim, S. W.; Baas, Paul; Rappold, Erica; Redhu, Suman; Puski, A.; Wu, Frank; Jänne, Pasi A.

doi:10.1093/annonc/mdv072

Cited by 305 publications

(229 citation statements)

References 28 publications

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“…The primary endpoint was PFS. Although there was no statistically significant difference in PFS between the treatment groups, patients treated with trametinib had a response rate of 12% (39).…”

Section: Clinical-translational Advancesmentioning

confidence: 76%

Molecular Pathways: The Basis for Rational Combination Using MEK Inhibitors in KRAS-Mutant Cancers

Okumura¹

2014

Clinical Cancer Research

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Mutations in RAS oncogenes are frequently observed in human cancers, and the mutations result in activation of the RAS-RAF-MEK-ERK pathway, leading to cell proliferation and survival. The pathway is, therefore, a potent therapeutic target in the RAS-mutant cancers. MEK inhibitors can specifically block the pathway and are one of the key types of drugs for the treatment of the RAS-mutant cancers. As RAS proteins activate other downstream signaling proteins in addition to the RAS-RAF-MEK-ERK pathway, combination therapeutic approaches with MEK inhibitors are also being evaluated. Moreover, MEK inhibitors can arrest cancer cells in G 1 phase and repress prosurvival Bcl2 family proteins such as MCL1 and BCL2/BCLXL, and increase expression of Bim, a proapoptotic BH3-only family protein. This mechanism may explain the efficacy of the combination of MEK inhibitors with cytotoxic agents or other targeted inhibitors. A better understanding of the pathway will help us with development of rational combinations for the treatment of the RAS-mutant cancers.

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Section: Clinical-translational Advancesmentioning

confidence: 76%

Molecular Pathways: The Basis for Rational Combination Using MEK Inhibitors in KRAS-Mutant Cancers

Okumura¹

2014

Clinical Cancer Research

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“…Trametinib belongs to the same molecular class as selumetinib and has been developed in BRAF-mutated metastatic melanoma. A second-line phase II trial comparing trametinib to docetaxel revealed similar survival outcomes, while grade 4 toxicity occurred only in the experimental arm [31]. Two phase I/Ib trials evaluating trametinib combinations with docetaxel and pemetrexed, respectively, as a second line showed a disease control rate of ∼60% [32,33].…”

Section: If Direct Blocking Of Rasmentioning

confidence: 99%

KRASoncogene in lung cancer: focus on molecularly driven clinical trials

et al. 2016

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KRAS mutations are the most frequent molecular abnormalities found in one out of four nonsmall cell lung cancers (NSCLC). Their incidence increases in cases of adenocarcinoma, smokers and Caucasian patients. Their negative value in terms of prognosis and responsiveness to both standard chemotherapy and targeted therapies remains under debate. Many drugs have been developed specifically for KRAS-mutated NSCLC patients. Direct inhibition of RAS activation failed to show any clinical efficacy. Inhibition of downstream targets of the mitogen-activated protein kinase (MEK) pathway is a promising strategy: phase II combinations of MEK 1/2 kinase inhibitors with chemotherapy doubled patients' clinical outcomes. One phase III trial in such a setting is ongoing. Double inhibition of MEK and epidermal growth factor receptor proteins is currently being assessed in early-phase trials. The association with mammalian target of rapamycin pathway inhibition leads to non-manageable toxicity. Other strategies, such as inhibition of molecular heat-shock proteins 90 or focal adhesion kinase are currently assessed. Abemaciclib, a cyclindependent kinase 4/6 inhibitor, showed promising results in a phase I trial, with a 54% disease control rate. Results of an ongoing phase III trial are warranted. Immunotherapy might be the next relevant step in KRAS-mutated NSCLC management due to the high burden of associated mutations and neo-antigens. @ERSpublications MEK inhibition and immunotherapy are very promising therapeutic advances in KRAS-mutated nonsmall cell lung cancer http://ow.ly/U2ohp KRAS mutations in lung cancer: epidemiology and clinical outcomesSince the beginning of the 21st century, the paradigm of precision medicine has shaken up the landscape of lung cancer classification and treatment. The discovery of cancer-related driver molecular abnormalities led to the development of efficient targeted therapies. RAS proteins are GTP kinases, discovered in the 1960s, whose GTP-RAS active isoform stimulates several pathways involved in cellular growth. V-Ki-ras2 Kirsten rat sarcoma viral oncogene homologue (KRAS) mutations are found in ∼25-35% of newly diagnosed nonsmall cell lung cancer (NSCLC), with a higher proportion in the adenocarcinoma subtype [1,2]. Figure 1 summarises the main amino acid substitutions and genomic features that are associated with KRAS mutations in NSCLC [3,4]. Other molecular abnormalities related to RAS pathway activation are diagnosed in 25% of NSCLC cases, such as epidermal growth factor receptor (EGFR) (10-23%), BRAF mutations (2%), MET amplifications (2%), human epidermal growth factor (HER)2 (1%) and NRAS (0.2%) mutations. Loss of the negative regulator neurofibromin is found in ∼11% of other cases.

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“…The target region of genes selected ranged from 311 to 572 bp. The genes chosen for validation are functionally important in cell-cell interaction/cell migration [ADAM22 (Bolger and Young, 2013); WNT5A (Endo et al, 2015;Lu et al, 2015)], tumor suppression [ATF2 (Rudraraju et al, 2014); RBM38 (Xue et al, 2014)], transcription [BCR (Marega et al, 2010); CREBBP (Crisafulli et al, 2012;Lee et al, 2015)], immune regulation [CD83 (Fujimoto and Tedder, 2006); IL12B (Glas et al, 2012;; IL17RA (Jiang et al, 2015)] and protein binding [MAP2K2 (Blumenschein et al, 2015); TGFBR2 (Lei et al, 2015;Busch et al, 2015); TGFBR3 (Jurisic et al, 2015;Zheng et al, 2013)]. These genes are already reported as possible marker of prognostic and therapeutic significance in various types of cancer, inflammatory diseases and bipolar disorder.…”

Section: Targeted Next Generation Bisulfite Sequencing (Tnbs)mentioning

confidence: 99%

DNA methylation detection at single base resolution using targeted next generation bisulfite sequencing and cross validation using capillary sequencing

Bhat

Mallya

Varghese

et al. 2016

Gene

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A randomized phase II study of the MEK1/MEK2 inhibitor trametinib (GSK1120212) compared with docetaxel in KRAS-mutant advanced non-small-cell lung cancer (NSCLC)

Cited by 305 publications

References 28 publications

Molecular Pathways: The Basis for Rational Combination Using MEK Inhibitors in KRAS-Mutant Cancers

Molecular Pathways: The Basis for Rational Combination Using MEK Inhibitors in KRAS-Mutant Cancers

KRASoncogene in lung cancer: focus on molecularly driven clinical trials

DNA methylation detection at single base resolution using targeted next generation bisulfite sequencing and cross validation using capillary sequencing

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