Targeting <i>BRAF</i>-Mutant Non-Small Cell Lung Cancer: From Molecular Profiling to Rationally Designed Therapy

Baik, Christina S.; Myall, Nathaniel J.; Wakelee, Heather A.

doi:10.1634/theoncologist.2016-0458

Cited by 101 publications

(93 citation statements)

References 68 publications

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“…BRAF mutations, present in 2%-4% of NSCLC, are emerging therapeutic targets in NSCLC (7). In contrast to other malignancies that are predominantly driven by the BRAF V600E mutation, alternative mutations distributed throughout exons 11 and 15 collectively account for one-half of BRAF mutations in NSCLC (8).…”

Section: Introductionmentioning

confidence: 99%

Impact of BRAF Mutation Class on Disease Characteristics and Clinical Outcomes in BRAF-mutant Lung Cancer

Dagogo‐Jack

Martı́nez

Yeap

et al. 2019

Clinical Cancer Research

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mutations are divided into functional classes distinguished by signaling mechanism and kinase activity: V600-mutant kinase-activating monomers (class I), kinase-activating dimers (class II), and kinase-inactivating heterodimers (class III). The relationship between functional class and disease characteristics in BRAF-mutant non-small cell lung cancer (NSCLC) has not been fully explored. We performed a retrospective analysis of BRAF-mutant NSCLCs treated at 2 institutions from 2005 to 2017 to determine clinicopathologic characteristics, progression-free survival (PFS) on chemotherapy, and overall survival (OS). We identified 236 patients with BRAF-mutant NSCLC ( = 107 class I, = 75 class II, and = 54 class III). Patients with class II or III mutations were more likely to have brain metastases ( ≤ 0.01) and coalterations ( ≤ 0.001) than class I. Compared with class I, PFS on chemotherapy was shorter for class II ( = 0.069) and class III ( = 0.034). OS was shorter for class II and III (class I, 40.1 months; class II, 13.9 months; and class III, 15.6 months; I vs. II, < 0.001; I vs. III, = 0.023); however, this difference was driven by fewer extrathoracic metastases and higher use of targeted therapies in class I patients. When patients treated with targeted therapy and those with thoracic-only metastases were excluded, there was no difference in OS across the 3 classes. BRAF-mutant NSCLC is a heterogeneous disease that encompasses 3 distinct functional classes. Classes II and III have more aggressive clinical features leading to less favorable outcomes. The distinct biological characteristics of class II and III tumors suggest that class-specific therapies may be necessary to effectively target these molecular subsets.

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Section: Introductionmentioning

confidence: 99%

Impact of BRAF Mutation Class on Disease Characteristics and Clinical Outcomes in BRAF-mutant Lung Cancer

Dagogo‐Jack

Martı́nez

Yeap

et al. 2019

Clinical Cancer Research

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“…The prognostic significance of BRAF mutations in NSCLC largely remains unclear. The heterogeneity of the disease, the rarity of the mutation, small patient numbers, and limited number of studies contribute to this lack of understanding . In one retrospective series of patients with stage I–IV NSCLC, univariate (hazard ratio [HR], 2.97; p < .001) and multivariate (HR, 2.18; p = .014) analysis showed a significant association between BRAF V600E mutation and shorter overall survival (OS) .…”

Section: Braf Mutations In Nsclcmentioning

confidence: 99%

“…Most importantly, response to combined BRAF and MEK inhibition can be both effective and long lasting. About half of BRAF mutations in NSCLC are at V600E [2,8,10,13].…”

Section: Braf Mutations In Nsclcmentioning

confidence: 99%

“…The prognostic significance of BRAF mutations in NSCLC largely remains unclear. The heterogeneity of the disease, the rarity of the mutation, small patient numbers, and limited number of studies contribute to this lack of understanding [8]. In one retrospective series of patients with In cells that do not harbor a BRAF mutation, BRAF inhibitors can lead to paradoxical hyperactivation of BRAF, leading to enhanced MAPK signaling and increased cellular proliferation.…”

Section: Clinical Characteristics Of Patients With Braf-mutant Nsclcmentioning

confidence: 99%

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Adverse Event Management in Patients with BRAF V600E-Mutant Non-Small Cell Lung Cancer Treated with Dabrafenib plus Trametinib

2018

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Therapies for advanced non‐small cell lung cancer (NSCLC) continue to become more sophisticated. Chemotherapeutics are giving way to newer approaches such as immune checkpoint inhibitors and targeted therapies for greater efficacy and improved outcomes. Dabrafenib plus trametinib combination therapy was first approved for the treatment of metastatic melanoma harboring the BRAF V600‐mutation in 2014. In 2017, the U.S. Food and Drug Administration approved the combination for patients with NSCLC with the same mutation based on an ≈ 65% response rate and median progression‐free survival of 10–11 months. BRAF mutations are a high‐frequency event in melanoma (≈ 50%), whereas the overall incidence in lung cancer is ≈ 2%, but similar in number, because of the high incidence of the disease. As a new approach in NSCLC treatment, dabrafenib plus trametinib has a unique toxicity profile that is likely unfamiliar to care providers in thoracic and general oncology who have not used the combination to treat patients with melanoma. Common adverse events such as pyrexia, fatigue, and nausea, as well as a range of less frequent cutaneous, ocular, and hemorrhagic events, can be observed during treatment with dabrafenib plus trametinib. Previous experience in metastatic melanoma revealed that these events can be effectively managed to improve patient quality of life and reduce unnecessary drug discontinuation. The aim of this review is to summarize treatment guidelines, along with key insights obtained from previous clinical‐trial and real‐world experience in patients with metastatic melanoma, to properly manage toxicities associated with dabrafenib plus trametinib for NSCLC. Implications for Practice The combination of dabrafenib plus trametinib has demonstrated substantial clinical activity in patients with BRAF V600E‐mutant non‐small cell lung cancer, leading to U.S. Food and Drug Administration approval. Although the combination has a manageable safety profile, many toxicities associated with the regimen may not be familiar to thoracic specialists or general oncologists. Extensive clinical experience with the combination in patients with metastatic melanoma has provided a wealth of strategies to identify and manage adverse events associated with dabrafenib plus trametinib. These can be used by medical oncologists to enhance early recognition of toxicities and facilitate effective management, thereby improving quality of treatment for patients.

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“…The association of BRAF mutation with clinicopathological parameters was evaluated, and only sex (female) was statistically significant in the multivariable Editorial BRAF inhibitors in metastatic non-small cell lung cancer analysis. However, later studies have not confirmed this data (14,15), and currently there are no clinical features that can help to identify which patients with NSCLC may present a BRAF mutation (16).…”

mentioning

confidence: 95%

BRAF inhibitors in metastatic non-small cell lung cancer

Anguera¹,

Majem²

2018

J. Thorac. Dis.

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Targeting BRAF-Mutant Non-Small Cell Lung Cancer: From Molecular Profiling to Rationally Designed Therapy

Cited by 101 publications

References 68 publications

Impact of BRAF Mutation Class on Disease Characteristics and Clinical Outcomes in BRAF-mutant Lung Cancer

Impact of BRAF Mutation Class on Disease Characteristics and Clinical Outcomes in BRAF-mutant Lung Cancer

Adverse Event Management in Patients with BRAF V600E-Mutant Non-Small Cell Lung Cancer Treated with Dabrafenib plus Trametinib

BRAF inhibitors in metastatic non-small cell lung cancer

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