Alectinib

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Structural formula
Alectinib structural formula
General
Non-proprietary name Alectinib
other names

9-ethyl-6,6-dimethyl-8- (4-morpholin-4-ylpiperidin-1-yl) -11-oxo-5 H -benzo [ b ] carbazole-3-carbonitrile ( IUPAC )

Molecular formula C 30 H 34 N 4 O 2
External identifiers / databases
CAS number 1256580-46-7
EC number 821-541-6
ECHA InfoCard 100.256.083
PubChem 49806720
DrugBank DB11363
Wikidata Q21099132
Drug information
ATC code

L01 L01XE36

Drug class

Cytostatic

Mechanism of action

Tyrosine kinase inhibitor

properties
Molar mass 482.628 g mol −1
Physical state

firmly

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 .

Alectinib (trade name Alecensa ) is a drug active substance, which for the treatment of patients with non-small cell lung cancer (NSCLC, non-small cell lung cancer ) that a mutation in the ALK gene ( ALK = anaplastic lymphoma kinase have), is used. It is a tyrosine kinase inhibitor (TKI) that can be used orally .

background

About 5 percent of patients with NSCLC have mutations in the ALK gene. Often these patients are lifelong non-smokers. In 2011, with crizotinib (trade name Xalkori , Pfizer ), a specific TKI that acts against mutated ALK protein was approved for the treatment of these patients for the first time. However, it has been shown that the effects of crizotinib usually do not last very long. Usually within the first year of therapy there is a loss of effectiveness of the drug. Various molecular resistance mechanisms have been described as the cause of this: amplification of the mutated ALK gene, the formation of other ALK mutations that cannot be inhibited by crizotinib, and the activation of alternative signal transduction pathways ( EGFR , KIT etc.).

The development of gene mutations that impart resistance to the respective inhibitor is a phenomenon that can often be observed in TKI therapy. In the case of crizotinib, a whole series of ALK mutations are known that confer crizotinib resistance: G1269A, L1152R, G1202R, F1174C, I1171T, S1206Y, T1156Tins and others (G1269A means: mutation that replaces the amino acid glycine (G. ) against alanine (A) at position 1269 of the ALK protein). About a third of crizotinib resistance appears to be mediated by such mutations. In response to this, so-called second generation ALK inhibitors were developed by various pharmaceutical companies. One of them was alectinib.

Study situation, admission

Alectinib has shown significant efficacy in various smaller studies and was first approved in Japan in 2013 as an orphan drug for the treatment of ALK- mutated NSCLC patients in whom administration of crizotinib was not useful or possible. It was fully approved in Japan in September 2014. On December 11, 2015, the US Food and Drug Administration (FDA) granted an analogous approval in the United States for second-line therapy or for crizotinib intolerance. The European Medicines Agency (EMA) granted similar approval on February 21, 2017.

In August 2017, the results of the so-called ALEX therapy study, which was sponsored by the Hoffmann-La Roche company , and in which ALK mutated NSCLC patients were treated in first-line therapy , were published in the New England Journal of Medicine . The therapeutic study had two arms and the patients received either 250 mg crizotinib once daily or 600 mg alectinib twice daily (the standard dose in each case). Approximately 150 patients were enrolled in each study arm. The progression-free survival at one year was in the former group significantly better than in the latter (68.4% versus 48.7%, p <0.001 ). In the alectinib group, 18 percent showed evidence of disease progression in the CNS (new or widening CNS metastases), while this was 45 percent in the crizotinib group. One point of criticism of the study was that the study evaluation was carried out very early so that the median progression-free survival in the alectinib group had not been achieved. The investigators concluded that alectinib was more effective (and also less toxic) than crizotinib.

Side effects

The standard daily dose is 1200 mg. No dose reduction is necessary in the case of mild or moderate impairment of kidney or liver function. Overall, the substance is considered to be relatively well tolerated and - like all TKIs - does not cause the typical side effects of conventional cytostatics . The following were described most frequently: anemia , muscle pain, elevated liver values ​​( bilirubin , transaminases ), edema , nausea, etc. a.

Early benefit assessment according to § 35a SGB V

The IQWiG has investigated in several reviews and Dossier Addenda whether Alectinib in the treatment of adults with ALK-positive advanced NSCLC compared with the the Federal Joint Committee (G-BA) has an additional benefit set appropriate comparator therapies. Accordingly, there is a hint of a non-quantifiable added benefit in the first-line treatment of adults with ALK-positive, advanced NSCLC. The G-BA endorsed the assessment result. For adults previously treated with crizotinib and chemotherapy , for whom treatment with docetaxel or pemetrexed is an option, there is a hint of considerable added benefit. If treatment with docetaxel or pemetrexed is not an option after pretreatment with platinum-based chemotherapy, an additional benefit has not been proven in the absence of suitable study data. An added benefit has also not been proven for crizotinib-pretreated patients who have not yet received chemotherapy.

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 Zilan Song, Meining Wang, Ao Zhang: Alectinib: a novel second generation anaplastic lymphoma kinase (ALK) inhibitor for overcoming clinically-acquired resistance . In: Acta Pharmaceutica Sinica B . tape 5 , no. 1 , January 2015, p. 34–37 , doi : 10.1016 / j.apsb.2014.12.007 (English).
  3. ↑ FDA approves new oral therapy to treat ALK-positive lung cancer. FDA, December 11, 2015, accessed September 22, 2017 .
  4. ↑ Media release: Roche receives EU approval of Alecensa (alectinib) for people with previously treated ALK-positive non-small cell lung cancer. Roche, February 21, 2017, accessed on September 22, 2017 .
  5. ↑ a b Annex I: Summary of the product characteristics. (PDF) EMA, accessed on September 22, 2017 .
  6. ↑ a b Solange Peters, D. Ross Camidge, Alice T. Shaw, Shirish Gadgeel, Jin S. Ahn, Dong-Wan Kim, Sai-Hong I. Ou, Maurice Pérol, Rafal Dziadziuszko, Rafael Rosell, Ali Zeaiter, Emmanuel Mitry , Sophie Golding, Bogdana Balas, Johannes Noe, Peter N. Morcos, Tony Mok, for the ALEX Trial Investigators: Alectinib versus Crizotinib in Untreated ALK-Positive Non – Small-Cell Lung Cancer . In: The New England Journal of Medicine . tape 377 , August 31, 2017, p. 829-838 , doi : 10.1056 / NEJMoa1704795 (English).
  7. ↑ A17-67 Alectinib (non-small cell lung carcinoma) - benefit assessment according to Section 35a SGB V , accessed on August 31, 2018.
  8. ↑ Resolution of the Federal Joint Committee of June 21, 2018 on an amendment to the Drugs Directive (AM-RL): Annex XII - Alectinib (new field of application: first-line treatment of non-small cell lung cancer) , accessed on August 31, 2018.
  9. ↑ A17-44 Alectinib (non-small cell lung cancer) - Addendum to Commission A17-19 , accessed on August 31, 2018.
  10. ^ Resolution of the Federal Joint Committee of October 19 , 2017 on an amendment to the Drugs Directive (AM-RL): Annex XII - Alectinib , accessed on August 31, 2018.
  11. ↑ A17-19 Alectinib (NSCLC) - Benefit assessment according to Section 35a SGB V , accessed on September 3, 2018.
  12. ↑ Decision of the Federal Joint Committee of April 6 , 2017 on an amendment to the Drugs Directive (AM-RL): Annex XII - Alectinib , accessed on September 3, 2018.