Dual MAPK Inhibition Is an Effective Therapeutic Strategy for a Subset of Class II BRAF Mutant Melanomas

Dankner, Matthew; Lajoie, Mathieu; Moldoveanu, Dan; Nguyen, Tan-Trieu; Savage, Paul; Rajkumar, Shivshankari; Huang, Xiaofeng; Lvova, Maria; Protopopov, Alexei; Vuzman, Dana; Hogg, David; Park, Morag; Guiot, Marie‐Christine; Petrecca, Kevin; Mihalcioiu, Catalin; Watson, Ian R.; Siegel, Peter M.; Rose, April A.N.

doi:10.1158/1078-0432.ccr-17-3384

Cited by 64 publications

(64 citation statements)

References 48 publications

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“…In concordance with these data, we found that patients with advanced melanoma with class 2 or 3 BRAF mutations (and/or NRAS mutations) also have shorter survival compared with those with class 1 BRAF mutations (3). We have reported that subsets of class 2 BRAF-mutant melanomas are sensitive to MAPK inhibition (3). As such, we expect that class 2 BRAF-mutant NSCLC may also be sensitive to a similar therapeutic approach.…”

supporting

confidence: 85%

“…Dagogo-Jack and colleagues found that patients with class 2 or 3 BRAF mutations have shorter survival times than patients with class 1 BRAF mutations. In concordance with these data, we found that patients with advanced melanoma with class 2 or 3 BRAF mutations (and/or NRAS mutations) also have shorter survival compared with those with class 1 BRAF mutations (3). We have reported that subsets of class 2 BRAF-mutant melanomas are sensitive to MAPK inhibition (3).…”

supporting

confidence: 84%

“…There is now a growing body of evidence demonstrating that class 2/3 BRAF mutations are associated with an aggressive clinical course in NSCLC and melanoma (1)(2)(3). These are actionable mutations and effective targeted therapies are thus warranted.…”

mentioning

confidence: 99%

See 2 more Smart Citations

BRAF Mutation Class and Clinical Outcomes—Letter

Dankner¹,

Rose²

2019

Clinical Cancer Research

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supporting

confidence: 85%

supporting

confidence: 84%

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BRAF Mutation Class and Clinical Outcomes—Letter

Dankner¹,

Rose²

2019

Clinical Cancer Research

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“…However, precision medicine efforts to date have largely focused on the V600 subset where repurposing melanoma drugs has led to significant and durable responses (19,20). Preclinical studies suggest that classifying BRAF mutants by underlying kinase activity and RAF signaling mechanism may be more informative than grouping tumors according to V600 status (14,16,21). These preclinical observations are supported by case reports and small series demonstrating distinct activity of available BRAF inhibitors in lung cancers with class I, II, or III mutations (19,22,23).…”

Section: Discussionmentioning

confidence: 96%

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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“…Specifically, BRAF inhibitors facilitate dimerization of wild type RAF proteins, and actually paradoxically activate the MAPK signaling pathway; this was particularly demonstrated in the promotion of cutaneous squamous cell carcinomas in patients receiving BRAF inhibitors. However, the addition of a MEK inhibitor mitigates these concerns, and even some patients without BRAF V600 mutations may derive benefits from BRAF/MEK inhibition .…”

Section: Discussionmentioning

confidence: 99%

Empiric Therapy with BRAF and MEK Inhibitors in Metastatic Melanoma

et al. 2019

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BRAF and MEK inhibitors are highly active in the setting of BRAFV600 mutant melanoma. Rarely, patients without previous testing present with fulminant progression necessitating emergent treatment prior to BRAF testing results. The safety and efficacy of empiric treatment in this setting is unclear. Herein, we present two patients treated with empiric BRAF and MEK inhibitors, resulting in dramatic clinical improvement in one patient later found to have a BRAF mutation, and lack of improvement (but no accelerated progression) in a patient lacking this mutation. Empiric BRAF and MEK inhibitor treatment should not be routinely pursued but may be given safely in rare, emergent situations.

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Dual MAPK Inhibition Is an Effective Therapeutic Strategy for a Subset of Class II BRAF Mutant Melanomas

Cited by 64 publications

References 48 publications

BRAF Mutation Class and Clinical Outcomes—Letter

BRAF Mutation Class and Clinical Outcomes—Letter

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

Empiric Therapy with BRAF and MEK Inhibitors in Metastatic Melanoma

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