Dabrafenib in patients with melanoma, untreated brain metastases, and other solid tumours: a phase 1 dose-escalation trial

Falchook, Gerald S.; Long, Georgina V.; Kurzrock, Razelle; Kim, Kevin B.; Arkenau, Tobias; Brown, Michael P.; Hamid, Omid; Infante, Jeffrey R.; Millward, Michael; Pavlick, Anna C.; O’Day, Steven; Blackman, Samuel C.; Curtis, Craig; Lebowitz, Peter F.; Ma, Bo; Ouellet, Danièle; Kefford, Richard

doi:10.1016/s0140-6736(12)60398-5

Cited by 855 publications

(703 citation statements)

References 33 publications

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“…42 In contrast, other mutations predict resistance to therapy; for example, detection of codon 12 mutations in KRAS predicts resistance to treatment with EGFR tyrosine kinase inhibitors in lung cancer 43 and resistance to treatment with anti-EGFR monoclonal antibodies in colorectal cancer. 44 Unexpected findings, such as the discovery of BRAF V600E in an ovarian cancer, with subsequent response to treatment with a BRAF inhibitor, 45 support the utility of sequencing genes that are not strictly characteristic for the patient's tumor type. Thus, the WUCaMP assay that we have validated here provides actionable information to direct patient care in routine practice.…”

Section: Discussionmentioning

confidence: 99%

Validation of a Next-Generation Sequencing Assay for Clinical Molecular Oncology

Cottrell

Al-Kateb

Bredemeyer

et al. 2014

The Journal of Molecular Diagnostics

171

133

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Currently, oncology testing includes molecular studies and cytogenetic analysis to detect genetic aberrations of clinical significance. Next-generation sequencing (NGS) allows rapid analysis of multiple genes for clinically actionable somatic variants. The WUCaMP assay uses targeted capture for NGS analysis of 25 cancerassociated genes to detect mutations at actionable loci. We present clinical validation of the assay and a detailed framework for design and validation of similar clinical assays. Deep sequencing of 78 tumor specimens (!1000Â average unique coverage across the capture region) achieved high sensitivity for detecting somatic variants at low allele fraction (AF). Validation revealed sensitivities and specificities of 100% for detection of single-nucleotide variants (SNVs) within coding regions, compared with SNP array sequence data (95% CI Z 83.4e100.0 for sensitivity and 94.2e100.0 for specificity) or whole-genome sequencing (95% CI Z 89.1e100.0 for sensitivity and 99.9e100.0 for specificity) of HapMap samples. Sensitivity for detecting variants at an observed 10% AF was 100% (95% CI Z 93.2e100.0) in HapMap mixes. Analysis of 15 masked specimens harboring clinically reported variants yielded concordant calls for 13/13 variants at AF of !15%. The WUCaMP assay is a robust and sensitive method to detect somatic variants of clinical significance in molecular oncology laboratories, with reduced time and cost of genetic analysis allowing for strategic patient management. (J Mol Diagn 2014, 16: 89e105; http://dx.doi.org/10.1016/j.jmoldx.2013 Traditional approaches to the genetic characterization of clinical oncology specimens include cytogenetic analysis, fluorescence in situ hybridization (FISH), and molecular studies of single genes. These methodologies are complementary to each other and generate information of diagnostic and prognostic relevance. However, as new insight is gained into the complexities of cancer at the molecular level, the need emerges to obtain a more detailed cancer genetic profile for improved patient management. As illustrated by recent studies, identifying DNA mutations in cancer may aid in understanding clonal evolution, 1 risk stratification, 2 and therapeutic strategies. 3,4 With the advent of next-generation sequencing (NGS), a more complete biological characterization of a tumor can be attained at the molecular level. 5

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Section: Discussionmentioning

confidence: 99%

Validation of a Next-Generation Sequencing Assay for Clinical Molecular Oncology

Cottrell

Al-Kateb

Bredemeyer

et al. 2014

The Journal of Molecular Diagnostics

171

133

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“…Incidentally, pyrexia has been reported as a common AE with BRAF‐inhibitor monotherapy in the range of 16–26% when given as monotherapy 18, 19, 26, 27. In the current study, the first fever was observed within 8 weeks of initiation of therapy in all nine patients in whom pyrexia was observed, while the median time to onset of the first fever in a global clinical study conducted was reported to be 4.3 weeks after treatment initiation 27.…”

Section: Discussionmentioning

confidence: 99%

Phase 1/2 study assessing the safety and efficacy of dabrafenib and trametinib combination therapy in Japanese patients with BRAF V600 mutation‐positive advanced cutaneous melanoma

Yamazaki¹,

Tsutsumida²,

Takahashi³

et al. 2018

The Journal of Dermatology

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The combination of dabrafenib and trametinib demonstrated encouraging antitumor activity and tolerability, at initial analysis, in Japanese patients with BRAF V600 mutant advanced melanoma warranting further investigation. This study evaluated the safety and tolerability, pharmacokinetics (PK) and preliminary efficacy of dabrafenib 150 mg b.i.d. plus trametinib 2 mg q.d. in Japanese patients with BRAF V600E/K mutant solid tumors (phase 1) and melanoma (phase 2). Phase 1 was primarily intended to assess safety and tolerability as assessed by adverse events (AE), and the primary end‐point in phase 2 was to assess confirmed overall response rate (ORR). The secondary end‐points in phase 1 included PK, confirmed/unconfirmed ORR and duration of response (DOR). The secondary end‐points in phase 2 were PK, unconfirmed ORR, DOR, safety and tolerability. A total of 12 cutaneous melanoma patients were enrolled in the study (six in phase 1 and six in phase 2) and received the combination therapy of dabrafenib and trametinib. Common AE (≥50.0%) included pyrexia (75%), increased aspartate aminotransferase (67%), peripheral edema (50%) and nasopharyngitis (50%). The investigator‐assessed ORR was reported in five patients (83%) in phase 1 and was also reported in five patients (83%; 95% confidence interval, 35.9–99.6; P < 0.0001) in phase 2. Plasma concentrations of both dabrafenib and trametinib seemed to a reach steady state by week 3. Overall, efficacy and PK properties for the dabrafenib plus trametinib combination in Japanese patients were comparable with those seen in global studies.

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“…Emerging evidence indicates, however, that patients with brain metastases are nearly as likely to initi ally respond to BRAF-inhibitor therapy as those without brain metastases. In uncontrolled phase I-II trials of monotherapy with dabrafenib or vemurafenib in patients with melanoma brain metastasis [161][162][163] (TABLE 3), ORRs and PFS were only marginally inferior to those observed in trials that included only patients without active brain metastases. These benefits are presumed, although not yet proven, to translate into prolonged overall survival, and have led to BRAF-inhibitor therapy becoming a mainstay treatment for patients with untreated metastatic melanoma involving the brain.…”

Section: Response Criteriamentioning

confidence: 92%

Targeted agents and immunotherapies: optimizing outcomes in melanoma

et al. 2017

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Dabrafenib in patients with melanoma, untreated brain metastases, and other solid tumours: a phase 1 dose-escalation trial

Cited by 855 publications

References 33 publications

Validation of a Next-Generation Sequencing Assay for Clinical Molecular Oncology

Validation of a Next-Generation Sequencing Assay for Clinical Molecular Oncology

Phase 1/2 study assessing the safety and efficacy of dabrafenib and trametinib combination therapy in Japanese patients with BRAF V600 mutation‐positive advanced cutaneous melanoma

Targeted agents and immunotherapies: optimizing outcomes in melanoma

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