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Dabrafenib response

MedGen UID:
893731
Concept ID:
CN239586
Sign or Symptom
Synonym: Tafinlar response
Drug:
Dabrafenib
MedGen UID:
483194
Concept ID:
C3467876
Organic Chemical
An orally bioavailable inhibitor of B-raf (BRAF) protein with potential antineoplastic activity. Dabrafenib selectively binds to and inhibits the activity of B-raf, which may inhibit the proliferation of tumor cells which contain a mutated BRAF gene. B-raf belongs to the raf/mil family of serine/threonine protein kinases and plays a role in regulating the MAP kinase/ERKs signaling pathway, which may be constitutively activated due to BRAF gene mutations. [from NCI]
 
Gene (location): BRAF (7q34)

Definition

Dabrafenib is a kinase inhibitor used in the treatment of individuals with unresectable or metastatic melanoma, metastatic non-small cell lung cancer (NSCLC), locally advanced or metastatic anaplastic thyroid cancer (ATC), pediatric low-grade glioma (LGG), and other unresectable or metastatic solid tumors with specific BRAF variants. Dabrafenib can be used as a single agent to treat melanoma with the BRAF valine 600 to glutamic acid (V600E) variant or in combination with the MEK inhibitor trametinib to treat multiple tumor types with BRAF V600E or V600K variants.The BRAF protein is an intracellular kinase in the mitogen-activated protein kinases (MAPK) pathway. Functionally, BRAF regulates essential cell processes such as cell growth, division, differentiation, and apoptosis. The gene BRAF is also a proto-oncogene—when mutated, it transforms normal cells into cancerous cells. Variation in the kinase domain of BRAF is associated with various cancers. The most common BRAF variant, V600E, constitutively activates the kinase and causes cell proliferation in the absence of growth factors that would usually be needed. The V600E variant is detected in approximately 50% of melanomas, 25% of ATC, 2% of NSCLC, and 20% of pediatric LGGs. The FDA-approved label for dabrafenib states that the presence of BRAF mutation in tumor specimens (V600E for dabrafenib monotherapy; V600E or V600K for dabrafenib plus trametinib) should be confirmed using an FDA-approved test before starting treatment with dabrafenib. Dabrafenib is not indicated for the treatment of individuals with wild-type BRAF tumors, or the treatment of colorectal cancer due to intrinsic resistance to BRAF inhibitor monotherapy. The label also states that individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency should be monitored for signs of hemolytic anemia while taking dabrafenib (1). However, it is important to note that an independent literature review by the Clinical Pharmacogenetics Implementation Consortium found no publications to support or refute this risk and thus issued no guidance for G6PD deficiency and dabrafenib therapy. [from Medical Genetics Summaries]

Professional guidelines

PubMed

Gorry C, McCullagh L, O'Donnell H, Barrett S, Schmitz S, Barry M, Curtin K, Beausang E, Barry R, Coyne I
Cochrane Database Syst Rev 2023 Jan 17;1(1):CD012974. doi: 10.1002/14651858.CD012974.pub2. PMID: 36648215Free PMC Article
Chihara D, Kreitman RJ
Expert Rev Hematol 2020 Oct;13(10):1107-1117. Epub 2020 Sep 24 doi: 10.1080/17474086.2020.1819231. PMID: 32893700
Boespflug A, Thomas L
Expert Opin Pharmacother 2016;17(7):1005-11. doi: 10.1517/14656566.2016.1168806. PMID: 26999478

Curated

DailyMed Drug Label, TAFINLAR, 2023

Gammal et al, Expanded Clinical Pharmacogenetics Implementation Consortium Guideline for Medication Use in the Context of G6PD Genotype. 2 Sept 2022. Clin Pharmacol Ther.

Therapeutic recommendations

From Medical Genetics Summaries

This section contains excerpted1 information on gene-based dosing recommendations. Neither this section nor other parts of this review contain the complete recommendations from the sources.

2023 Statement from the US Food and Drug Administration (FDA):

BRAF V600E Mutation-Positive Unresectable or Metastatic Melanoma: Dabrafenib is indicated as a single agent for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E mutation as detected by an FDA-approved test.

BRAF V600E or V600K Mutation-Positive Unresectable or Metastatic Melanoma: Dabrafenib is indicated, in combination with trametinib, for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations, as detected by an FDA-approved test.

Adjuvant Treatment of BRAF V600E or V600K Mutation-Positive Melanoma

Dabrafenib is indicated, in combination with trametinib, for the adjuvant treatment of patients with melanoma with BRAF V600E or V600K mutations, as detected by an FDA-approved test, and involvement of lymph node(s), following complete resection.

BRAF V600E Mutation-Positive Metastatic NSCLC

Dabrafenib is indicated, in combination with trametinib, for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) with BRAF V600E mutation as detected by an FDA-approved test

BRAF V600E Mutation-Positive Locally Advanced or Metastatic Anaplastic Thyroid Cancer

Dabrafenib is indicated, in combination with trametinib, for the treatment of patients with locally advanced or metastatic anaplastic thyroid cancer (ATC) with BRAF V600E mutation and with no satisfactory locoregional treatment options

BRAF V600E Mutation-Positive Unresectable or Metastatic Solid Tumors

Dabrafenib is indicated, in combination with trametinib, for the treatment of adult and pediatric patients 6 years of age and older with unresectable or metastatic solid tumors with BRAF V600E mutation who have progressed following prior treatment and have no satisfactory alternative treatment options ... This indication is approved under accelerated approval based on overall response rate (ORR) and duration of response (DoR) … Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).

BRAF V600E Mutation-Positive Low-Grade Glioma

Dabrafenib is indicated, in combination with trametinib, for the treatment of pediatric patients 1 year of age and older with low-grade glioma (LGG) with a BRAF V600E mutation who require systemic therapy.

Limitation of Use: Dabrafenib is not indicated for treatment of patients with colorectal cancer because of known intrinsic resistance to BRAF inhibition … Dabrafenib is not indicated for treatment of patients with wild-type BRAF solid tumors.

Patient Selection: Confirm the presence of BRAF V600E mutation in tumor specimens prior to initiation of treatment with dabrafenib as a single agent. Confirm the presence of BRAF V600E or V600K mutation in tumor specimens prior to initiation of treatment with dabrafenib and trametinib. Information on FDA-approved tests for the detection of BRAF V600 mutations in melanoma is available at: http://www.fda.gov/CompanionDiagnostics.

[…]

Glucose-6-phosphate Dehydrogenase (G6PD) Deficiency

Advise patients that dabrafenib may cause hemolytic anemia in patients with G6PD deficiency. Advise patients with known G6PD deficiency to contact their healthcare provider to report signs or symptoms of anemia or hemolysis.

Please review the complete therapeutic recommendations that are located here: (1).

Supplemental Content

Table of contents

    Clinical resources

    Practice guidelines

    • PubMed
      See practice and clinical guidelines in PubMed. The search results may include broader topics and may not capture all published guidelines. See the FAQ for details.
    • Bookshelf
      See practice and clinical guidelines in NCBI Bookshelf. The search results may include broader topics and may not capture all published guidelines. See the FAQ for details.

    Curated

    • DailyMed Drug Label, 2023
      DailyMed Drug Label, TAFINLAR, 2023
    • CPIC, 2022
      Gammal et al, Expanded Clinical Pharmacogenetics Implementation Consortium Guideline for Medication Use in the Context of G6PD Genotype. 2 Sept 2022. Clin Pharmacol Ther.

    Consumer resources

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