Binimetinib

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Structural formula
Binimetinib structural formula
General
Non-proprietary name Binimetinib
other names
  • 5 - [(4-Bromo-2-fluorophenyl) amino] -4-fluoro- N - (2-hydroxyethoxy) -1-methyl-1 H -benzimidazole-6-carboxamide
  • ARRY-162
  • MEK162
Molecular formula C 17 H 15 BrF 2 N 4 O 3
External identifiers / databases
CAS number 606143-89-9
EC number 639-995-7
ECHA InfoCard 100.167.617
PubChem 10288191
DrugBank DB11967
Wikidata Q19903515
Drug information
ATC code

L01 XE41

Drug class

Tyrosine kinase inhibitor

properties
Molar mass 441.23 g · mol -1
safety instructions
Please note the exemption from the labeling requirement for drugs, medical devices, cosmetics, food and animal feed
GHS labeling of hazardous substances
no GHS pictograms
H and P phrases H: no H-phrases
P: no P-phrases
As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Binimetinib is a medicine that is used to treat melanoma ("black skin cancer") when there is a certain genetic change (mutation in the BRAF growth gene) and the melanoma cannot be surgically removed or has spread ( metastasized ) to other parts of the body . Binimetinib is combined with the active ingredient encorafenib .

In June 2018, the US Food and Drug Administration (FDA) approved binimetinib in combination with encorafenib. The European Medicines Agency's Committee for Medicinal Products for Human Use recommended approval in July 2018, with EU approval following in September 2018.

Binimetinib belongs to the group of protein kinase inhibitors or MEK inhibitors , which inhibit the kinase activity of mitogen-activated extracellular signal-regulated kinases 1 (MEK1) and 2 (MEK2).

Clinical information

application areas

Binimetinib, in combination with encorafenib , is indicated for the treatment of adults with unresectable (ie, inoperable) or metastatic melanoma with a BRAF V600 mutation .

Type and duration of application

Binimetinib is orally effective; the recommended total daily dose of binimetinib is 90 mg. Treatment should be continued until the patient is no longer benefiting from it or until unacceptable toxicity occurs.

Special patient groups

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

unwanted effects

The following events were observed very frequently (i.e. in more than 1 in 10 patients) under 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

Binimetinib is a non-ATP-competitive, reversible inhibitor of the kinase activity of mitogen-activated extracellular signal-regulated kinase 1 (MEK1) and MEK2. In a cell-free system, binimetinib inhibits MEK1 and MEK2 with half-maximal inhibitory concentrations (IC 50 ) of 12-46 nM. The MEK proteins are upstream regulators of the kinase signal transmission path (ERK) associated with extracellular signals, which promotes cell proliferation. In melanoma and other cancers, this signaling pathway is often activated by mutated forms of BRAF that activate MEK. Binimetinib inhibits the activation of MEK by BRAF as well as MEK kinase activity. Binimetinib inhibits the growth of melanoma cell lines with the BRAF V600 mutation and shows antitumor effects in animal models with BRAF V600 mutated melanoma.

Binimetinib can also be used for about 20 percent of melanomas with NRAS mutations.

Since binimetinib and encorafenib both inhibit the MAP kinase signaling pathway , the combined administration results in higher antitumor activity. In addition, the combination of encorafenib plus binimetinib prevented the development of resistance in vivo in human melanoma xenografts with the BRAF V600E mutation .

Binimetinib together with encorafenib increases the effectiveness compared to the BRAF inhibitor monotherapy if it is adequately tolerated.

Absorption and distribution in the body

After repeated twice-daily dosing with encorafenib, steady-state conditions for binimetinib were achieved within 15 days without major accumulation . The mean (CV%) C max, ss was 654 ng / ml (34.7%) and the mean value of the AUC ss was 2.35 μgh / ml (28.0%) in combination with encorafenib, as per population PK model estimated. The pharmacokinetics of binimetinib are approximately dose-linear.

The absorption of Binimetinib is rapid with a median T max of 1.5 hours. Binimetinib can be taken with or without food. 62.3% are excreted in the faeces and 31.4% in the urine ; the median terminal half-life is 8.66 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.

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

Early benefit assessment

In Germany, since 2011, newly approved drugs with new active ingredients must be subjected to an " early benefit assessment " by the Federal Joint Committee (G-BA) in accordance with Section 35a SGB ​​V if the pharmaceutical manufacturer wants to achieve a higher sales price than just the fixed amount . Only if there is an additional benefit can the pharmaceutical manufacturer negotiate a price with the umbrella association of statutory health insurance companies. The dossier evaluations, on the basis of which the G-BA makes its decisions, are created by the Institute for Quality and Efficiency in Health Care (IQWiG) .

The combination of binimetinib with encorafenib for the treatment of adult patients with unresectable or metastatic melanoma with a BRAF V600 mutation was evaluated in 2018 and 2019, respectively. According to the G-BA decision, an additional benefit compared to the ACT has not been proven for either previously treated or untreated patients.

Trade names

The trade name of the monopreparation from Binimetinib is Mektovi by the manufacturer Pierre Fabre .

Binimetinib is given in combination with encorafenib ( Braftovi ).

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. ↑ Template: CL Inventory / not harmonized There is not yet a harmonized classification for this substance . A labeling of 1H-Benzimidazole-6-carboxamide, 5 - [(4-bromo-2-fluorophenyl) amino] -4-fluoro-N- (2-hydroxyethoxy) -1-methyl- is shown, which is derived from a self-classification by the distributor in the Classification and Labeling Inventory of the European Chemicals Agency (ECHA), accessed on October 22, 2018.
  2. ↑ Center for Drug Evaluation and Research: Approved Drugs - FDA approves encorafenib and binimetinib in combination for unresectable or metastatic melanoma with BRAF mutations .
  3. ↑ Mektovi - binimetinib Summary of opinion (initial authorization) , PM EMA of July 26, 2018, accessed on October 21, 2018.
  4. ↑ EMA: Mektovi , EPAR of the EMA (English), accessed on October 21, 2018.
  5. ↑ a b c d e f g h EMA: Summary of the drug , accessed on October 21, 2018.
  6. ↑ Koelblinger P et al .: A review of binimetinib for the treatment of mutant cutaneous melanoma . In: Future Oncology . tape 13 , no. 20 , August 2017, p. 1755–1766 , doi : 10.2217 / fon-2017-0170 , PMID 28587477 .
  7. ↑ Community register of medicinal products for human use - Mektovi European Commission, accessed on October 21, 2018.
  8. ^ Community register of medicinal products for human use - Braftovi European Commission, accessed on October 21, 2018.
  9. ↑ Mektovi (binimetinib) - An overview of Mektovi and why it is authorized in the EU , EMA, accessed on October 21, 2018.
  10. ↑ Community register of medicinal products for human use - Mektovi European Commission, accessed on October 21, 2018.
  11. ^ Community register of medicinal products for human use - Braftovi European Commission, accessed on October 21, 2018.
  12. ↑ Mektovi (binimetinib) - An overview of Mektovi and why it is authorized in the EU , EMA, accessed on October 21, 2018.
  13. ↑ 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 .
  14. ↑ 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 .
  15. ↑ Malignant Melanoma: Breakthrough in Therapy , Deutsches Ärzteblatt 2014; 111 (45): [24], accessed October 25, 2018.
  16. ↑ technical information Mektovi , accessed on 21 October 2018th
  17. ↑ 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 .
  18. ↑ 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 .
  19. ↑ 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).
  20. ↑ Study Comparing Combination of LGX818 Plus MEK162 Versus Vemurafenib and LGX818 Monotherapy in BRAF Mutant Melanoma (COLUMBUS) , ClinicalTrials.gov, accessed October 21, 2018.
  21. ↑ A18-62 Binimetinib (melanoma) - Benefit assessment according to Section 35a SGB V; Accessed March 25, 2020.
  22. ↑ A19-18 Binimetinib (melanoma) - Addendum to commission A18-62; Accessed March 25, 2020.
  23. ↑ Benefit assessment procedure for the active ingredient binimetinib (melanoma, BRAF V600 mutation, combination with encorafenib); Accessed March 25, 2020.

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