Dabrafenib in patients with BRAFV600E-positive advanced non-small-cell lung cancer: a single-arm, multicentre, open-label, phase 2 trial

Planchard, David; Kim, Tae Min; Mazières, Julien; Quoix, Élisabeth; Riely, Gregory J.; Barlési, Fabrice; Souquet, Pierre Jean; Smit, Egbert F.; Groen, Harry J.M.; Kelly, Ronan J.; Cho, B. C.; Socinski, Mark A.; Pandite, Lini; Nase, Christine; Ma, Bo; D’Amelio, Anthony M.; Mookerjee, Bijoyesh; Curtis, Craig; Johnson, Bruce E.

doi:10.1016/s1470-2045(16)00077-2

Cited by 387 publications

(292 citation statements)

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“…Recently, a phase II clinical trial (no. NCT01336634) has made its results public (16). Dabrafenib exhibited clinical activity in BRAF V600E-positive metastatic NSCLC; these results indicated that dabrafenib could represent a treatment option for a population of patients with limited therapeutic options (16).…”

Section: Discussionmentioning

confidence: 99%

“…NCT01336634) has made its results public (16). Dabrafenib exhibited clinical activity in BRAF V600E-positive metastatic NSCLC; these results indicated that dabrafenib could represent a treatment option for a population of patients with limited therapeutic options (16). Certain studies (57-62) have evaluated BRAF mutations in NSCLC samples; however, the use of CastPCR in assessing these mutations has not, to the best of our knowledge, been reported.…”

Section: Discussionmentioning

confidence: 99%

“…Therefore it is recommended that patients should be tested for EGFR mutations in order to personalize the treatment regime. Since BRAF inhibitors have already demonstrated promise in patients with advanced stage non-small-cell lung cancer and who are BRAF-positive (16), it is necessary to obtain the information concerning the type of population that typically exhibits BRAF mutations. However, no consensus exists for this and further studies are required.…”

Section: Discussionmentioning

confidence: 99%

“…clinical activity of dabrafenib in metastatic NSCLC patients (of which 96% were adenocarcinomas) with BRAF V600E mutations (16). However, the incidence of BRAF mutations in NSCLC has not been conclusively determined.…”

Section: Detection Of Egfr and Braf Mutations By Competitive Allele-smentioning

confidence: 99%

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Detection of EGFR and BRAF mutations by competitive allele-specific TaqMan polymerase chain reaction in lung adenocarcinoma

et al. 2017

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Abstract. Epithelial growth factor receptor (EGFR)-tyrosine kinase inhibitors are the standard first-line treatment for patients with metastatic non-small cell lung cancer (NSCLC) expressing sensitive EGFR-mutants. Other drugs target different driver mutants, including the serine/threonine-protein kinase B-raf (BRAF) inhibitor dabrafenib, which has exhibited promising efficacy for treating patients with metastatic BRAF-mutated NSCLC. Therefore, identifying patients carrying mutations that may be treated using targeted therapies is important. However, the methods of molecular detection presently applied in clinical practice, particularly detection of BRAF in NSCLC patients, require further investigation. Therefore, more sensitive and economic methods are required. The present study applied the competitive allele-specific TaqMan polymerase chain reaction (CastPCR) technology to the molecular detection of EGFR (del2235-2249, del2236-2250, T790M, L858R) and BRAF (V600E, G469A, D594G) mutations in 144 treatment-naive patients with lung adenocarcinoma, and analyzed the association between the mutation rates and patients' clinicopathological features. 51.4% (74/144) cases were identified harboring EGFR mutations. A total of 40.3% (58/144) patients carried sensitizing mutations (exon 19 deletion or L858R) and 14.6% (21/144) carried T790M mutations. 6.9% (10/144) mutation-positive patients were double-mutated. Total EGFR mutation rate was significantly increased in female compared with that of males (60.9 vs. 43.8%, P<0.05), in non-smokers compared with that of smokers (62.8 vs. 34.5%, P<0.05). In total, 8.3% (12/144) patients were identified with BRAF mutations. 16.7% were V600E (2/12) and 83.3% (10/12) were non-V600E mutants. Among the 10 non-V600E mutations, D594G accounted for 90.0% (9/10) and G469A accounted for 10.0% (1/10). Statistical analysis demonstrated that the BRAF mutation rate was not associated with any of the following clinicopathological features: Sex, age, smoking history, clinical stages, distant metastasis, differentiation degree, tumor size and regional lymph node metastasis (P≥0.05). CastPCR technology is a robust method with high sensitivity for the molecular detection of EGFR and BRAF mutations in clinical formalin-fixed paraffin-embedded samples.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Detection Of Egfr and Braf Mutations By Competitive Allele-smentioning

confidence: 99%

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Detection of EGFR and BRAF mutations by competitive allele-specific TaqMan polymerase chain reaction in lung adenocarcinoma

et al. 2017

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“…Mutant BRAF promotes tumor growth by hyperactivating the RAF-MEK-ERK signaling cascade (2)(3)(4)(5). BRAF V600E is the most common oncogenic form of BRAF in most tumor types, and selective RAF inhibitors such as vemurafenib and dabrafenib have demonstrated clinical efficacy in melanoma and LA harboring BRAF V600E (6)(7)(8)(9). Despite these findings, ∼15% of BRAF mutant cancers do not respond to BRAF inhibitors, and the majority of patients who achieve a response will inevitably acquire resistance to these targeted agents, predominantly through reactivation of MAPK pathway signaling (4,(10)(11)(12)(13)(14)(15)(16).…”

Section: G466vmentioning

confidence: 99%

Preclinical efficacy of a RAF inhibitor that evades paradoxical MAPK pathway activation in protein kinase BRAF -mutant lung cancer

Okimoto

Olivas

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Oncogenic activation of protein kinase BRAF drives tumor growth by promoting mitogen-activated protein kinase (MAPK) pathway signaling. Because oncogenic mutations in BRAF occur in ∼2-7% of lung adenocarcinoma (LA), BRAF-mutant LA is the most frequent cause of BRAF-mutant cancer mortality worldwide. Whereas most tumor types harbor predominantly the BRAF V600E -mutant allele, the spectrum of BRAF mutations in LA includes BRAF V600E (∼60% of cases) and non-V600E mutant alleles (∼40% of cases) such as BRAF G469A and BRAF G466V. The presence of BRAF V600E in LA has prompted clinical trials testing selective BRAF inhibitors such as vemurafenib in BRAF V600E -mutant patients. Despite promising clinical efficacy, both innate and acquired resistance often result from reactivation of MAPK pathway signaling, thus limiting durable responses to the current BRAF inhibitors. Further, the optimal therapeutic strategy to block non-V600E BRAF-mutant LA remains unclear. Here, we report the efficacy of the Raf proto-oncogene serine/ threonine protein kinase (RAF) inhibitor, PLX8394, that evades MAPK pathway reactivation in BRAF-mutant LA models. We show that PLX8394 treatment is effective in both BRAF V600E and certain non-V600 LA models, in vitro and in vivo. PLX8394 was effective against treatment-naive BRAF-mutant LAs and those with acquired vemurafenib resistance caused by an alternatively spliced, truncated BRAF V600E that promotes vemurafenib-insensitive MAPK pathway signaling. We further show that acquired PLX8394 resistance occurs via EGFR-mediated RAS-mTOR signaling and is prevented by upfront combination therapy with PLX8394 and either an EGFR or mTOR inhibitor. Our study provides a biological rationale and potential polytherapy strategy to aid the deployment of PLX8394 in lung cancer patients.ncogenic mutations in the BRAF serine/threonine protein kinase occur in a wide spectrum of solid tumor malignancies, most notably melanoma, colorectal cancer, and lung adenocarcinoma (1). Mutant BRAF promotes tumor growth by hyperactivating the RAF-MEK-ERK signaling cascade (2-5). BRAF V600E is the most common oncogenic form of BRAF in most tumor types, and selective RAF inhibitors such as vemurafenib and dabrafenib have demonstrated clinical efficacy in melanoma and LA harboring BRAF V600E (6-9). Despite these findings, ∼15% of BRAF mutant cancers do not respond to BRAF inhibitors, and the majority of patients who achieve a response will inevitably acquire resistance to these targeted agents, predominantly through reactivation of MAPK pathway signaling (4, 10-16).The clinical efficacy of RAF inhibitors depends on the degree of suppression of MAPK pathway output (8). Vemurafenib and dabrafenib paradoxically activate the MAPK pathway in cells with oncogenic RAS or increased upstream receptor signaling, thereby enhancing cellular proliferation that can promote cutaneous squamous cell carcinomas and keratoacanthomas that often harbor RAS mutations, and potentially other RAS-driven malignancies (17-25). Combination therapy with a MEK i...

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Systemic Therapy for Locally Advanced and Metastatic Non–Small Cell Lung Cancer

Arbour

Riely

2019

JAMA

868

697

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IMPORTANCE Non-small cell lung cancer remains the leading cause of cancer death in the United States. Until the last decade, the 5-year overall survival rate for patients with metastatic non-small cell lung cancer was less than 5%. Improved understanding of the biology of lung cancer has resulted in the development of new biomarker-targeted therapies and led to improvements in overall survival for patients with advanced or metastatic disease.OBSERVATIONS Systemic therapy for metastatic non-small cell lung cancer is selected according to the presence of specific biomarkers. Therefore, all patients with metastatic non-small cell lung cancer should undergo molecular testing for relevant mutations and expression of the protein PD-L1 (programmed death ligand 1). Molecular alterations that predict response to treatment (eg, EGFR mutations, ALK rearrangements, ROS1 rearrangements, and BRAF V600E mutations) are present in approximately 30% of patients with non-small cell lung cancer. Targeted therapy for these alterations improves progression-free survival compared with cytotoxic chemotherapy. For example, somatic activating mutations in the EGFR gene are present in approximately 20% of patients with advanced non-small cell lung cancer. Tyrosine kinase inhibitors such as gefitinib, erlotinib, and afatinib improve progression-free survival in patients with susceptible EGFR mutations. In patients with overexpression of ALK protein, the response rate was significantly better with crizotinib (a tyrosine kinase inhibitor) than with the combination of pemetrexed and either cisplatin or carboplatin (platinum-based chemotherapy) (74% vs 45%, respectively; P < .001) and progression-free survival (median, 10.9 months vs 7.0 months; P < .001). Subsequent generations of tyrosine kinase inhibitors have improved these agents. For patients without biomarkers indicating susceptibility to specific targeted treatments, immune checkpoint inhibitor-containing regimens either as monotherapy or in combination with chemotherapy are superior vs chemotherapy alone. These advances in biomarker-directed therapy have led to improvements in overall survival. For example, the 5-year overall survival rate currently exceeds 25% among patients whose tumors have high PD-L1 expression (tumor proportion score of Ն50%) and 40% among patients with ALK-positive tumors.CONCLUSIONS AND RELEVANCE Improved understanding of the biology and molecular subtypes of non-small cell lung cancer have led to more biomarker-directed therapies for patients with metastatic disease. These biomarker-directed therapies and newer empirical treatment regimens have improved overall survival for patients with metastatic non-small cell lung cancer.

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Dabrafenib in patients with BRAFV600E-positive advanced non-small-cell lung cancer: a single-arm, multicentre, open-label, phase 2 trial

Cited by 387 publications

References 36 publications

Detection of EGFR and BRAF mutations by competitive allele-specific TaqMan polymerase chain reaction in lung adenocarcinoma

Detection of EGFR and BRAF mutations by competitive allele-specific TaqMan polymerase chain reaction in lung adenocarcinoma

Preclinical efficacy of a RAF inhibitor that evades paradoxical MAPK pathway activation in protein kinase BRAF -mutant lung cancer

Systemic Therapy for Locally Advanced and Metastatic Non–Small Cell Lung Cancer

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