Combined Vemurafenib and Cobimetinib in <i>BRAF</i>-Mutated Melanoma

Larkin, James; Ascierto, Paolo A.; Dréno, Brigitte; Atkinson, Victoria; Liszkay, Gabriella; Maio, Michele; Mandalà, Mario; Демидов, Лев В.; Stroyakovskiy, Daniil; Thomas, Luc; Cruz‐Merino, Luis de la; Dutriaux, Caroline; Garbe, Claus; Sovak, Mika A.; Chang, Ilsung; Choong, Nicholas W.; Hack, Stephen P.; McArthur, Grant A.; Ribas, Antoni

doi:10.1056/nejmoa1408868

Cited by 1,864 publications

(1,548 citation statements)

References 26 publications

(35 reference statements)

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“…The MAPK signaling pathway is a key regulator of cell growth and survival, and it is overactivated in nearly 30% of human cancers. 58 Two MEK inhibitors, trametinib and cobimetinib, 59,60 are currently approved for the treatment of melanoma and more than 10 other MEK1/2 inhibitors are in various stages of clinical testing across a spectrum of cancer types including breast cancer. 61 In addition to its cell-intrinsic protumorigenic effects, MAPK signaling has also been implicated in the upregulation of checkpoint ligands such as PD-L1.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of RON kinase potentiates anti-CTLA-4 immunotherapy to shrink breast tumors and prevent metastatic outgrowth

et al. 2018

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The advent of immune checkpoint blockade as a new strategy for immunotherapy has changed the outlook for many aggressive cancers. Although complete tumor eradication is attainable in some cases, durable clinical responses are observed only in a small fraction of patients, underlining urgent need for improvement. We previously showed that RON, a receptor tyrosine kinase expressed in macrophages, suppresses antitumor immune responses, and facilitates progression and metastasis of breast cancer. Here, we investigated the molecular changes that occur downstream of RON activation in macrophages, and whether inhibition of RON can cooperate with checkpoint immunotherapy to eradicate tumors. Activation of RON by its ligand, MSP, altered the gene expression profile of macrophages drastically and upregulated surface levels of CD80 and PD-L1, ligands for T-cell checkpoint receptors CTLA-4 and PD-1. Genetic deletion or pharmacological inhibition of RON in combination with anti-CTLA-4, but not with anti-PD-1, resulted in improved clinical responses against orthotopically transplanted tumors compared to single-agent treatment groups, resulting in complete tumor eradication in 46% of the animals. Positive responses to therapy were associated with higher levels of T-cell activation markers and tumor-infiltrating lymphocytes. Importantly, co-inhibition of RON and anti-CTLA-4 was also effective in clearing metastatic breast cancer cells in lungs, resulting in clinical responses in nearly 60% of the mice. These findings suggest that RON inhibition can be a novel approach to potentiate responses to checkpoint immunotherapy in breast cancer.

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Section: Discussionmentioning

confidence: 99%

Inhibition of RON kinase potentiates anti-CTLA-4 immunotherapy to shrink breast tumors and prevent metastatic outgrowth

et al. 2018

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“…The most common toxicities included diarrhoea, rash, liver-enzyme abnormalities, fatigue, and nausea 65 . These data led to initiation of the phase III coBRIM trial [66][67][68] , in which 495 patients received vemurafenib plus cobimetinib, or vemurafenib plus placebo, with ORRs of 70% versus 50%, a median PFS of 12.3 months versus 7.2 months, and a median overall survival of 22.3 months versus 17.4 months (HR 0.70; P = 0.005). The toxicities observed were similar to those seen in the phase I study [65][66][67][68] .…”

Section: Braf-targeted Therapiesmentioning

confidence: 99%

Targeted agents and immunotherapies: optimizing outcomes in melanoma

et al. 2017

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“…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]. 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].…”

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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Combined Vemurafenib and Cobimetinib in BRAF-Mutated Melanoma

Cited by 1,864 publications

References 26 publications

Inhibition of RON kinase potentiates anti-CTLA-4 immunotherapy to shrink breast tumors and prevent metastatic outgrowth

Inhibition of RON kinase potentiates anti-CTLA-4 immunotherapy to shrink breast tumors and prevent metastatic outgrowth

Targeted agents and immunotherapies: optimizing outcomes in melanoma

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

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