Encorafenib

Structural formula
General
Non-proprietary name	Encorafenib
other names	N - [(2 S ) -1 - {[4- (3- {5-chloro-2-fluoro-3- (methanesulfonamindo) phenyl} -1-propan-2-ylpyrazol-4-yl) -pyrimidin-2 -yl] amino} -propan-2-yl] - O -methyl carbamate
Molecular formula	C 22 H 27 Cl 1 F 1 N 7 O 4 S 1
External identifiers / databases
CAS number 1269440-17-6 PubChem 50922675 DrugBank DB11718 Wikidata Q15409405
Drug information
ATC code	L01 XE
Drug class	Serine / Threonine Kinase Inhibitor
properties
Molar mass	540.01 g · mol -1
safety instructions
Please note the exemption from the labeling requirement for drugs, medical devices, cosmetics, food and animal feed GHS hazard labeling no classification available
As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Encorafenib (formerly LGX818) is a drug from the group of protein kinase inhibitors , respectively. the MAP kinase inhibitor , which inhibits the function of the BRAF protein . Encorafenib - in combination with binimetinib - is used to treat adults with unresectable (that is, inoperable) or metastatic melanoma with a BRAF V600 mutation.

In biochemical studies, encorafenib has a long retention time ( dissociation half-life) of more than 30 hours on the mutated BRAFV600E protein - in contrast to 2 hours for dabrafenib and 0.5 hours for vemurafenib .

In June 2018, the US Food and Drug Administration (FDA) approved encorafenib in combination with binimetinib. The Committee for Medicinal Products for Human Use (CHMP) recommended approval for the member states of the EU in July 2018. The European Commission followed this positive recommendation and granted EU approval in September 2018.

Clinical information

application areas

Encorafenib in combination with binimetinib is indicated for the treatment of adult patients with unresectable or metastatic melanoma with a BRAF V600 mutation.

Type and duration of application

Braftovi is for oral use and the recommended dose is 450 mg encorafenib in combination with binimetinib per day. Meals do not affect the effect. Treatment should be continued until the patient is no longer benefiting from it or until unacceptable toxicity occurs.

Special patient groups

Before taking encorafenib in combination with binimetinib, the patient must have a BRAF V600 mutation using a valid test. The efficacy and safety of encorafenib has only been established in patients with tumors expressing a BRAF V600E and V600K mutation. Encorafenib must not be used in patients with wild-type BRAF malignant melanoma.

BRAF mutation test

The BRAF mutation test (BRAF assay) can identify tumors with the BRAF mutation and should determine their possible response to BRAF inhibitors such as B. Encorafenib help to assess. Testing can be done using DNA-based methods or immunohistochemistry for the most common mutation (BRAF-V600E).

The role of the BRAF gene

The BRAF gene belongs to a class of genes called oncogenes . It provides instructions for the production of a protein that helps transmit chemical signals from outside the cell into the cell nucleus. This protein is part of a signaling pathway known as the RAS / MAPK signaling pathway that controls several important cell functions. Specifically, the RAS / MAPK path regulates the growth and division ( proliferation ) of cells, the process of cell maturation for the exercise of certain functions (differentiation), cell movement (migration) and the self-destruction of cells ( apoptosis ). Chemical signals via this pathway are essential for normal development before birth and postnatal cell division and differentiation. Once mutated , oncogenes have the potential to turn normal cells into cancerous ones. During cancer treatment, targeted therapies can prevent the mutation from occurring and thus slow the growth of the tumor.

unwanted effects

The following events were observed very frequently (> = 1/10) during combination therapy with encorafenib and binimetinib in the standard dose: anemia , peripheral neuropathy , dizziness , headache , visual disturbances , detachment of the retinal pigment epithelium , bleeding , hypertension , abdominal pain , diarrhea , vomiting , Nausea , constipation , hyperkeratosis , rash , dry skin, pruritus , alopecia , arthralgia , muscle disorders / myalgia, back pain, pain in the extremities, pyrexia , peripheral edema , fatigue , increase in blood creatine kinase , increase in transaminases , increase in gamma-glutamyl transferase .

Pharmacological properties

Mechanism of action

Encorafenib is a highly selective, ATP-competitive, low molecular weight inhibitor of RAF kinase. The half-maximal inhibitory concentration (IC ₅₀ ) of encorafenib against BRAF ^V600E , BRAF and CRAF enzymes was determined to be 0.35 nM, 0.47 nM and 0.30 nM, respectively. The dissociation half-life of encorafenib was> 30 hours and resulted in prolonged pERK inhibition. Encorafenib suppresses the RAF / MEK / ERK signaling pathway in tumor cells that express various mutation forms of the BRAF kinase (V600E, D and K). Encorafenib specifically inhibits the growth of melanoma cells with BRAF ^{V600E, D and K} mutations in vitro and in vivo . Encorafenib does not suppress the RAF / MEK / ERK signaling pathway in cells expressing the wild-type BRAF.

Encorafenib and the MEK inhibitor binimetinib both block the MAP kinase signaling pathway , which leads to higher antitumor activity. In addition, the combination of encorafenib plus binimetinib prevents the development of resistance in vivo in human melanoma xenografts with a BRAF ^V600E mutation . Binimetinib together with encorafenib increases the effectiveness compared to the BRAF inhibitor monotherapy if it is adequately tolerated. In the COLUMBUS registration study, Braftovi in combination with Mektovi proved to be adequately tolerated and, compared to BRAF inhibitor monotherapy, showed a more favorable side effect profile in some aspects with a comparable rate of higher-grade adverse events - despite the higher dosage and longer therapy duration compared to monotherapy.

Absorption and distribution in the body

In biochemical studies, encorafenib has a long retention time ( dissociation half-life) of more than 30 hours on the mutated BRAFV600E protein - in contrast to 2 hours for dabrafenib and 0.5 hours for vemurafenib , both also MAP kinase inhibitors.

The absorption of Encorafenib is rapid with a median T _max of 1.5-2 hours. Encorafenib can be taken with or without food. It is excreted in equal parts in the faeces and urine ; the terminal half-life is 6.32 hours.

Studies

COLUMBUS (pivotal study): The safety and efficacy of encorafenib in combination with binimetinib was established in a phase III, 2-part, randomized , drug-controlled, open - label , multi-center study (CMEK162B2301) in patients with unresectable or metastatic melanoma examined with BRAF V600E or -K mutation detected by the BRAF assay. The patients had a histologically confirmed cutaneous melanoma or a histologically confirmed melanoma with an unknown primary tumor ; Patients with choroidal or mucosal melanoma were excluded from participating in the study. A previous adjuvant therapy , as well as a prior immunotherapy line for treatment of the unresectable, locally advanced or metastatic disease were permitted. Previous treatment with BRAF / MEK inhibitors was not permitted.

Part 1 of the COLUMBUS study was particularly relevant for approval. In this part of the study, 577 patients were randomized in a 1: 1: 1 ratio into the following 3 treatment arms: encorafenib 450 mg once daily plus binimetinib 45 mg twice daily; Encorafenib 300 mg once daily; Vemurafenib 960 mg twice a day. According to an independent central review, the phase III study showed that the combination of encorafenib 450 mg once daily and binimetinib 45 mg twice daily significantly improved progression-free survival (PFS) compared to vemurafenib monotherapy 960 mg twice daily (median 14, 9 versus 7.3 months; hazard ratio [HR] = 0.54; 95% confidence interval [CI]: 0.41–0.71; p <0.0001). The PFS was the primary endpoint of the study.

Part 2 data published in The Lancet Oncology in September 2018 show that treatment with encorafenib + binimetinib - as the secondary endpoint of the study - achieved a median overall survival (OS) of 33.6 months, compared to 16.9 months for patients who were treated with vemurafenib as monotherapy (HR = 0.61; 95% CI: 0.47-0.79; nominal p <0.0001).

Trade names

The trade name of the monopreparation of encorafenib is Braftovi by the manufacturer Pierre Fabre .

literature

• Ernst Mutschler et al .: Mutschler - drug effects textbook of pharmacology and toxicology . 10th edition. Scientific Verlagsgesellschaft, Stuttgart 2012, ISBN 978-3-8047-2898-1 .

Individual evidence

1. ↑ This substance has either not yet been classified with regard to its hazardousness or a reliable and citable source has not yet been found.
2. ↑ ^{a b} Koelblinger P et al .: Development of encorafenib for BRAF-mutated advanced melanoma . In: Current Opinion in Oncology . tape 30 , no. 2 , March 2018, p. 125-133 , doi : 10.1097 / CCO.0000000000000426 , PMID 29356698 , PMC 5815646 (free full text).
3. ^ Community register of medicinal products for human use - Braftovi European Commission, accessed on October 21, 2018.
4. ↑ Community register of medicinal products for human use - Mektovi European Commission, accessed on October 21, 2018.
5. ↑ Braftovi (encorafenib) - An overview of Braftovi and why it is authorized in the EU , EPAR of the EMA, accessed on October 21, 2018.
6. ↑ ^{a b c} Technical information Braftovi , accessed on October 21, 2018.
7. ↑ ^{a b} Delord JP et al .: Phase I Dose-Escalation and -Expansion Study of the BRAF Inhibitor Encorafenib (LGX818) in Metastatic BRAF-Mutant Melanoma . In: Clinical Cancer Research . tape 23 , no. 19 , September 2017, p. 5339-5348 , doi : 10.1158 / 1078-0432.CCR-16-2923 , PMID 28611198 .
8. ↑ Center for Drug Evaluation and Research: Approved Drugs - FDA approves encorafenib and binimetinib in combination for unresectable or metastatic melanoma with BRAF mutations .
9. ↑ Braftovi - encorafenib Summary of opinion (initial authorization) , PM EMA of July 26, 2018, accessed on October 21, 2018.
10. ↑ EMA: Braftovi , EPAR of the EMA (English), accessed on October 21, 2018
11. ↑ ^{a b c d e} EMA: Summary of the drug , accessed on October 21, 2018.
12. ↑ D. Capper, AS Berghoff, M. Magerle, A. Ilhan, A. Wöhrer, M. Hackl, J. Pichler, S. Pusch, J. Meyer, A. Habel, P. Petzelbauer, P. Birner, A. von Deimling, M. Preusser : Immunohistochemical testing of BRAF V600E status in 1,120 tumor tissue samples of patients with brain metastases. In: Acta Neuropathol. 123 (2), Feb 2012, pp. 223-233. doi: 10.1007 / s00401-011-0887-y .
13. ↑ D. Capper, M. Preusser, A. Habel, F. Sahm, U. Ackermann, G. Schindler, S. Pusch, G. Mechtersheimer, H. Zentgraf, A. von Deimling: Assessment of BRAF V600E mutation status by immunohistochemistry with a mutation-specific monoclonal antibody. In: Acta Neuropathol. 122 (1), Jul 2011, pp. 11-19. doi: 10.1007 / s00401-011-0841-z .
14. ↑ Braftovi® + Mektovi® Germany , brief information on oncosite.de, accessed on October 21, 2018.
15. ↑ technical information Mektovi , accessed on 21 October 2018th
16. ↑ ^{a b} Dummer R et al .: Encorafenib plus binimetinib versus vemurafenib or encorafenib in patients with BRAF-mutant melanoma (COLUMBUS): a multicentre, open-label, randomized phase 3 trial . In: The Lancet Oncology . tape 19 , no. 5 , May 2018, p. 603-615 , doi : 10.1016 / S1470-2045 (18) 30142-6 , PMID 29573941 .
17. ↑ ^{a b} Dummer R et al .: Overall survival in patients with BRAF-mutant melanoma receiving encorafenib plus binimetinib versus vemurafenib or encorafenib (COLUMBUS): a multicentre, open-label, randomized, phase 3 trial. In: The Lancet Oncology . tape 19 , no. 10 , October 2018, p. 1315-27 , doi : 10.1016 / S1470-2045 (18) 30497-2 , PMID 30219628 .
18. ↑ Study Comparing Combination of LGX818 Plus MEK162 Versus Vemurafenib and LGX818 Monotherapy in BRAF Mutant Melanoma (COLUMBUS) , ClinicalTrials.gov, accessed October 21, 2018.

Web links

• Cancer Information Service (KID). Skin cancer: basal cell carcinoma, squamous cell carcinoma, malignant melanoma. February 2013.

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