Crizotinib

from Wikipedia, the free encyclopedia
Structural formula
Structural formula of crizotinib
General
Non-proprietary name Crizotinib
other names

3 - [(1 R ) -1- (2,6-dichloro-3-fluorophenyl) ethoxy] -5- (1-piperidin-4-ylpyrazol-4-yl) pyridin-2-amine ( IUPAC )

Molecular formula C 21 H 22 Cl 2 FN 5 O
External identifiers / databases
CAS number 877399-52-5
EC number 638-814-9
ECHA InfoCard 100.166.440
PubChem 11626560
DrugBank DB08700
Wikidata Q5186964
Drug information
ATC code

L01 XE16

Drug class

Cytostatic

Mechanism of action

Tyrosine kinase inhibitor

properties
Molar mass 450.337 g mol −1
Physical state

firmly

Melting point

196-199 ° C

safety instructions
Please note the exemption from the labeling requirement for drugs, medical devices, cosmetics, food and animal feed
GHS labeling of hazardous substances
05 - Corrosive 07 - Warning 08 - Dangerous to health 09 - Dangerous for the environment

danger

H and P phrases H: 317-318-341-400
P: 261-272-280-201-202-280-302 + 352-333 + 313-362 + 364-305 + 351 + 338-310-308 + 313-391
As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Crizotinib is a medicine used to treat a certain type of lung cancer . It was first in 2010 by the pharmaceutical company Pfizer introduced and since October 2012, the trade name Xalkori conditions in Europe for the treatment of advanced stages of a specific subtype of lung cancer admitted .

Crizotinib is an oral aminopyridine and as such is a tyrosine kinase inhibitor that blocks ALK tyrosine kinase and the tyrosine kinases MET and ROS1 (c-ros oncogene 1) . The expression of the tyrosine kinase ALK ( anaplastic lymphoma kinase ) was first described in anaplastic large-cell lymphoma and subsequently also in non-small-cell lung cancer and neuroblastoma in children . In lung cancer, about 5% of all non- small cell lung cancer (NSCLC) show a translocation of this gene , which corresponds to about 60,000 cases annually worldwide.

ALK -positive non-small cell lung cancer

In a 2013, Pfizer-funded, multicentre, open - label phase III study , 347 enrolled patients with locally spread or metastatic ALK-positive non-small cell lung cancer who had previously received platinum-based chemotherapy were compared to subsequent chemotherapy with pemetrexed or Docetaxel , a significantly increased median progression-free survival time of 7.7 months versus 3.0 months ( hazard rate 0.49) and an effect ( response rate , as complete response or partial response ) in 65% versus 20%. The subjective patient parameters also showed that crizotinib was superior to standard therapy, with greater symptom reduction and better quality of life . Frequent side effects were visual disturbances (60%), gastrointestinal disturbances with diarrhea in 60%, nausea in 55%, vomiting in 47% and constipation in 42% as well as increased liver enzyme values (38%). Most of the side effects were mild to moderate (grade 1–2). The side effects were significantly more frequent and stronger than with standard therapy, although treatment with crizotinib was also carried out for longer. On October 13, 2015, Pfizer announced that crizotinib was associated with an increased risk of heart failure (1.1% of those treated). Heart failure deaths have been reported during treatment with crizotinib.

On October 23, 2012, crizotinib was approved by the European Medicines Agency (EMA) under conditions for the treatment of patients with ALK- positive NSCLC. The manufacturing company was obliged to provide further information and study results. The recommended dose is 2 × 250 mg daily.

The PROFILE 1014 study, published in early December 2014 and also sponsored by Pfizer, examined the effectiveness of crizotinib in the first line , i.e. H. in previously untreated chemotherapeutic patients with ALK -positive NSCLC. The effectiveness of crizotinib 2 × 250 mg daily was compared with a standard therapy pemetrexed + cisplatin or carboplatin . The observation period of the study was too short to be able to assess the median survival time (i.e. the point in time at which 50% of the treated patients in the respective study arm had not died), but the progression-free survival was significantly longer with crizotinib (10.9 Months compared to 7.0 months). The authors concluded that in ALK- positive NSCLC crizotinib was superior to the previous first-line standard therapy consisting of pemetrexed + carbo- or cisplatin.

ROS1 -positive non-small cell lung cancer

Another therapeutic study , also published in November 2014 in the New England Journal and co- funded by Pfizer, examined the effectiveness of crizotinib in NSCLC patients with changes in the ROS1 gene. A total of 50 patients with advanced NSCLC were included in the study and received crizotinib 250 mg twice daily. 86% of the patients had already had at least one previous chemotherapy regimen. Histologically, most of the patients had adenocarcinoma and the majority had been non-smokers for life. 6% of the patients achieved a complete remission of the disease, 66% a partial remission and 18% the disease was stable. The overall response rate was 72%. The mean progression-free survival was 19.2 months. The side effects were comparatively minor and comparable to those of the above study.

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) .

In the first early benefit assessment, crizotinib was compared with chemotherapy with docetaxel or pemetrexed - or with best supportive care if chemotherapy is not indicated - in the treatment of adults with previously treated anaplastic lymphoma kinase (ALK) -positive, advanced non-small cell lung cancer in 2013 . The G-BA decision was limited in time and was repealed in 2016 by a new decision. Accordingly, there is a hint of a considerable added benefit for patients for whom chemotherapy is indicated. For those affected for whom chemotherapy is not indicated, an additional benefit has not been proven.

In 2016, an early benefit assessment was carried out in a new application area: the first-line treatment of adults with ALK-positive, advanced non-small cell lung cancer. According to the G-BA decision, there is a hint of a considerable added benefit compared to cisplatin in combination with pemetrexed or carboplatin in combination with pemetrexed.

After crizotinib was also approved for the treatment of adults with ROS1-positive, advanced NSCLC, another benefit assessment followed in 2016 and 2017. According to the G-BA resolution, an additional benefit has not been proven in this indication for either previously untreated or previously treated patients.

Individual evidence

  1. ↑ J. Jean Cui, Michelle Tran-Dube, Hong Shen, Mitchell Nambu, Pei-Pei Kung, Mason Pairish, Lei Jia, Jerry Meng, Lee Funk, Iriny Botrous, Michele McTigue, Neil Grodsky, Kevin Ryan, Ellen Padrique, Gordon Alton, Sergei Timofeevski, Shinji Yamazaki, Qiuhua Li, Helen Zou, James Christensen, Barbara Mroczkowski, Steve Bender, Robert S. Kania, Martin P. Edwards: Structure Based Drug Design of Crizotinib (PF-02341066), a Potent and Selective Dual Inhibitor of Mesenchymal-Epithelial Transition Factor (c-MET) Kinase and Anaplastic Lymphoma Kinase (ALK) . In: Journal of Medicinal Chemistry . tape 54 , no. 18 , September 22, 2011, pp. 6342-6363 , doi : 10.1021 / jm2007613 .
  2. ↑ a b crizotinib (PDF; 30 kB) caymanchem; accessed on December 27, 2019.
  3. ↑ Alice T. Shaw, Dong-Wan Kim, Kazuhiko Nakagawa, Takashi Seto, Lucio Crinó, Myung-Ju Ahn, Tommaso De Pas, Benjamin Besse, Benjamin J. Solomon, Fiona Blackhall, Yi-Long Wu, Michael Thomas, Kenneth J O'Byrne, Denis Moro-Sibilot, D. Ross Camidge, Tony Mok, Vera Hirsh, Gregory J. Riely, Shrividya Iyer, Vanessa Tassell, Anna Polli, Keith D. Wilner, Pasi A. Jänne: Crizotinib versus Chemotherapy in Advanced ALK-Positive Lung Cancer. In: New England Journal of Medicine . Volume 368, Issue 25, June 20, 2013, pp. 2385–2394. doi: 10.1056 / NEJMoa1214886 .
  4. ↑ Rote-Hand-Brief on Xalkori® (crizotinib): New recommendations on the risk of heart failure. (PDF) Retrieved November 5, 2015 .
  5. ↑ Xalkori: crizotinib. Retrieved July 7, 2013 .
  6. ^ BJ Solomon, T. Mok, DW Kim, YL Wu, K. Nakagawa, T. Mekhail, E. Felip, F. Cappuzzo, J. Paolini, T. Usari, S. Iyer, A. Reisman, KD Wilner, J Tursi, F Blackhall; PROFILE 1014 Investigators: First-line crizotinib versus chemotherapy in ALK-positive lung cancer. In: N Engl J Med. 371 (23), 2014, pp. 2167-2177. doi: 10.1056 / NEJMoa1408440 .
  7. ↑ AT Shaw, SH Ou, YJ Bang, DR Camidge, BJ Solomon, R. Salgia, GJ Riely, M. Varella-Garcia, GI Shapiro, DB Costa, RC Doebele, LP Le, Z. Zheng, W. Tan, P. Stephenson, SM Shreeve, LM Tye, JG Christensen, KD Wilner, JW Clark, AJ Iafrate: Crizotinib in ROS1-rearranged non-small-cell lung cancer. In: N Engl J Med. 371 (21), Nov 20, 2014, pp. 1963-1971. doi: 10.1056 / NEJMoa1406766 PMID 25264305 .
  8. ↑ A12-15 Crizotinib - benefit assessment according to Section 35a Social Code Book V (dossier assessment). iqwig.de; accessed on March 27, 2020.
  9. ↑ A13-13 Addendum to Commission A12-15 Crizotinib. iqwig.de; accessed on March 27, 2020.
  10. ↑ A16-41 Crizotinib (NSCLC) - Benefit assessment according to Section 35a SGB V (expiry of time limit). iqwig.de; accessed on March 27, 2020.
  11. ↑ Benefit assessment procedure for the active ingredient crizotinib (reassessment after the deadline - non-small cell lung cancer, ALK +, pretreated patients). g-ba.de; accessed on March 27, 2020.
  12. ↑ A15-59 Crizotinib (new area of ​​application - benefit assessment according to Section 35a SGB V). iqwig.de; accessed on March 27, 2020
  13. ↑ A16-26 Crizotinib - Addendum to Commission A15-59. iqwig.de; accessed on March 27, 2020
  14. ↑ Benefit assessment procedure for the active ingredient crizotinib (new area of ​​application - non-small cell lung cancer, ALK +, first line). g-ba.de; accessed on March 27, 2020.
  15. ↑ A16-59 Crizotinib (lung carcinoma) - benefit assessment according to § 35a SGB V. iqwig.de; accessed on March 27, 2020.
  16. ↑ Benefit assessment procedure for the active ingredient crizotinib (new area of ​​application - non-small cell lung cancer, ROS1 +). g-ba.de; accessed on March 27, 2020.