MEK162 for patients with advanced melanoma harbouring NRAS or Val600 BRAF mutations: a non-randomised, open-label phase 2 study

Ascierto, Paolo A.; Schadendorf, Dirk; Berking, Carola; Agarwala, Sanjiv S.; Herpen, Carla M.L. van; Queirolo, Paola; Blank, Christian U.; Hauschild, Axel; Beck, J. Thaddeus; St‐Pierre, Annie; Niazi, Faiz; Wandel, Simon; Peters, Malte; Zubel, Angela; Dummer, Reinhard

doi:10.1016/s1470-2045(13)70024-x

Cited by 576 publications

(437 citation statements)

References 35 publications

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“…Furthermore, in the first above-mentioned phase 2 prospective trials investigating MEK162 in NRAS-mutated melanoma patients, most of them actually harbored the NRASQ61R mutation. 7 Nevertheless, we are aware that our study has limitations. This is indeed a retrospective series; as a consequence we cannot exclude a selection bias.…”

Section: Discussionmentioning

confidence: 89%

“…6 Recently, an oral MEK inhibitor (MEK162) was tested in patients with metastatic melanoma harboring BRAF or NRAS mutations with encouraging results in NRAS-mutated patients, most of whom harbored NRASQ61R mutation. 7 The response rate was reported in 20% of patients and progression-free survival was similar in BRAF-and NRAS-mutated patients. These data backed the hypothesis that RAS may be druggable in melanoma patients and several phase II and III studies are ongoing, most of them including NRAS-mutated metastatic melanoma (https://clinicaltrials.gov/).…”

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confidence: 93%

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Immunohistochemistry is highly sensitive and specific for the detection of NRASQ61R mutation in melanoma

et al. 2015

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Testing for NRAS is now integral part in the assessment of metastatic melanoma patients because there is evidence that NRAS-mutated patients may be sensitive to MEK inhibitors, and RAS mutation is a common mechanism of acquired resistance during treatment with BRAF inhibitors. This study evaluated the sensitivity and specificity of immunohistochemical analysis using an N-Ras (Q61R) antibody to detect the presence of the NRASQ61R mutation in melanoma patients. A total of 98 primary cutaneous melanomas that have undergone examination of NRAS mutation were retrieved from a multicentric database. Formalin-fixed and paraffin-embedded melanoma tissues were analyzed for BRAF and NRAS mutations by independent, blinded observers using both conventional DNA molecular techniques and immunohistochemistry with the novel anti-human N-Ras (Q61R) monoclonal antibody (clone SP174). The antibody showed a sensitivity of 100% (14/14) and a specificity of 100% (83/83) for detecting the presence of an NRASQ61R mutation. Of the NRAS-mutated cases, none of the non-Q61R cases stained positive with the antibody (0/7). There were three cases with discordant NRAS mutational results. Additional molecular analysis confirmed the immunohistochemically obtained NRAS result in all cases, suggesting that a multiple analytical approach can be required to reach the correct sample classification. The reported immunohistochemical method is an accurate, rapid, and cost-effective method for detecting NRASQ61R mutation in melanoma patients, and represents a valuable supplement to traditional mutation testing. If validated in further studies, genetic testing would only be required for immunohistochemistry-negative patients to detect non-Q61R mutations.

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Section: Discussionmentioning

confidence: 89%

mentioning

confidence: 93%

Immunohistochemistry is highly sensitive and specific for the detection of NRASQ61R mutation in melanoma

et al. 2015

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“…As noted, MEK inhibitors have demonstrated single-agent efficacy in the BRAF-V600-mutant population, with ORRs of >20% with trametinib 53 as well as other MEK inhibitors evaluated in phase II clinical trials 71 . In addition, preclinical evidence indicates that MAPKpathway dependency and the resultant therapeutic vulnerability to MEK inhibitors exist in a substantial portion of melanomas that lack BRAF V600 mutations.…”

Section: Braf-targeted Therapiesmentioning

confidence: 91%

Targeted agents and immunotherapies: optimizing outcomes in melanoma

et al. 2017

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“…Sensitivity to MEK inhibitors has been demonstrated as monotherapy or in combination in different cancer types. Moreover, tumour control in patients has been shown in clinical studies [2][3][4][5][6][7]. The introduction of novel treatment strategies such as targeted therapy and immunomodulation have prolonged patient survival in metastatic melanoma [8][9][10][11].…”

Section: Introductionmentioning

confidence: 99%

“…The addition of selective MEK inhibitors to the BRAF inhibitor treatment improved clinical outcome and delayed the development of drug resistance in BRAF mutated melanoma patients [12,13]. Moreover, MEK inhibitors have demonstrated activity in NRAS mutated melanoma as well [2]. Common MEK inhibitor-related adverse events include acneiform skin rash, oedema, retinopathy and diarrhoea [14,15].…”

Section: Introductionmentioning

confidence: 99%

MEK inhibitor-associated retinopathy (MEKAR) in metastatic melanoma: Long-term ophthalmic effects

Urner-Bloch

Urner

Jaberg-Bentele

et al. 2016

European Journal of Cancer

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BACKGROUND: Mitogen-activated protein kinase kinase (MEK) inhibitors have aroused considerable interest in oncology. Activity has been demonstrated in various types of cancer, especially melanoma. MEK inhibitors induce a transient retinopathy, considered to be a class effect. At present, only sparse data are available on retinal effects with long-term MEK inhibition. PATIENTS AND METHODS: In this prospective, observational study, patients with advanced melanoma participating in different phase 1/2 or phase 3 clinical trials were treated with the MEK inhibitor binimetinib, with a v-Raf murine sarcoma viral oncogene homolog B (BRAF) inhibitor, or with combination therapy. They underwent regular ophthalmological examinations including determination of visual function, biomicroscopy, dilated fundoscopy and optical coherence tomography (OCT) for a period of up to 2 years. Retinopathy was diagnosed on defined OCT criteria. RESULTS: Sixty-two patients were investigated between 1st October 2011 and 31st July 2015: 13 were treated with the MEK inhibitor binimetinib alone, 10 with a selective BRAF inhibitor, and 39 with combination therapy. In 92% of patients on monotherapy and 100% of those on combination treatment, binimetinib caused dose-related lesions with serous neuroretinal detachments and oedema, strongly dependent on the time after medication. With continued treatment, retinal volume and thickness decreased to levels below baseline, without any apparent functional deficits or changes in structural integrity. CONCLUSIONS: Binimetinib induces a specific retinopathy with daily fluctuations depending on the time interval after medication. The retinopathy partially recovers, but can still be detected many months later. Retinal thinning, possible first signs of retinal atrophy have been observed after long-term treatment, but, so far, without functional relevance.

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MEK162 for patients with advanced melanoma harbouring NRAS or Val600 BRAF mutations: a non-randomised, open-label phase 2 study

Cited by 576 publications

References 35 publications

Immunohistochemistry is highly sensitive and specific for the detection of NRASQ61R mutation in melanoma

Immunohistochemistry is highly sensitive and specific for the detection of NRASQ61R mutation in melanoma

Targeted agents and immunotherapies: optimizing outcomes in melanoma

MEK inhibitor-associated retinopathy (MEKAR) in metastatic melanoma: Long-term ophthalmic effects

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