Larotrectinib
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| Non-proprietary name | Larotrectinib | ||||||||||||
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| Molecular formula | C 21 H 22 F 2 N 6 O 2 | ||||||||||||
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| Molar mass | 428.44 g mol −1 | ||||||||||||
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| As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions . | |||||||||||||
Larotrectinib (trade name: Vitrakvi ) is a low molecular weight, highly selective inhibitor of the three tropomyosin receptor kinase proteins TRKA, TRKB and TRKC, which are involved in the nervous system in the areas of pain regulation, proprioception , appetite control and memory. Larotrectinib is approved for the tumor-independent therapy of TRK fusion tumors.
development
It was first described by the American biotech company Array BioPharma and the license was transferred to Loxo Oncology in 2013 . The market launch took place under the trade name Vitrakvi by Bayer .
effect
About one percent of all solid malignant tumors and about 1000 cases annually in the whole of the European Union have a fusion protein in which one of the three genes of the three tropomyosin receptor kinase proteins is involved. The genes are called Neurotrophic receptor tyrosine kinase 1-3, abbreviated NTRK 1-3, which is why a so-called NTRK fusion protein is created. The TRK fusion leads to overexpression of the second protein, which then activates the corresponding signal path permanently and independently of ligands and can trigger malignant growth. This is why TRK fusion tumors are also used.
Since the NTRK fusion protein can occur in different tumors, an analysis of three open, prospective, age and tumor type independent ( basket studies ) studies was carried out in which all patients with a locally advanced or metastatic TRK fusion protein that was primarily unsuccessfully treated with standard therapy was carried out -positive tumor were included. A response rate of 75% was found in 55 patients aged between 4 months and 76 years with 17 different tumor types. After one year, 71% were still responding and 55% were progression-free. No patient had to stop the study because of undesirable effects that were rare (5% had grade 3 or 4 effects). The most common were salivary gland cancer , infantile fibrosarcoma, and other soft tissue sarcomas and thyroid cancer , with no difference in response between the tumor types.
For the European approval, phase I and phase II studies with a total of 122 patients were pooled, all of which showed a high and long-lasting response in adults and children. The response rate was 81% across all age groups after a median of seven to eighteen months and 94% in children. Of the 34 children whose data were included in the analysis, a complete remission was observed in 35%, a partial remission in 59% and a stabilization in 6%.
To date, thirty solid tumors or sarcomas are known in which TRK fusions have been detected. Most belong to the soft tissue sarcomas for which larotrectinib was approved in advance as an orphan drug . In addition, TRK fusion genes are occasionally found in salivary gland cancer and papillary thyroid cancer as well as in gliomas . There was also pre-approval for these three tumor types.
unwanted effects
In addition to the typical effects of cancer immunotherapy , larotrectinib can also cause specific effects that are caused by the inhibition of the TRK signaling pathway, such as weight gain, dizziness , ataxia and paresthesia , since the TRK signaling pathway is involved in the development and maintenance of the nervous system .
Other TRK inhibitors
At the same time as larotrectinib, entrectinib was also approved by the American Food and Drug Administration , which is also a first-generation TRK inhibitor. However, occasional resistance has been observed in both. Therefore, with selitrectinib and repotrectinib, two new next-generation TRK inhibitors have been developed that directly target the resistance mechanisms and are in the clinical test phase.
Admission
Larotrectinib was recognized as an orphan drug by the American Food and Drug Administration in 2015 , and in 2016 the breakthrough therapy status (for particularly effective new drugs) was approved for the treatment of metastatic solid tumors with an NTRK fusion protein. The market approval for the US market took place in November 2018.
Following a positive decision by the Committee for Medicinal Products for Human Use (CHMP) of the European Marketing Authorization Authority (EMA) , larotrectinib was approved by the European Commission on September 19, 2019, subject to the condition that the manufacturer carry out further studies to assess the risks and adverse effects.
This approval is the first with a tumor-independent indication, ie not for a single tumor type, but for the targeted treatment of TRK fusion tumors. The specific treatment of an oncogenic driver in the tumor genome in question is also referred to as "precision oncology".
Larotrectinib has been approved as monotherapy for TRK fusion tumors that are locally advanced or metastatic , or for which surgical resection would be associated with significant morbidity (such as amputation), or for which there is no satisfactory treatment option.
Individual evidence
- ↑ This substance has either not yet been classified with regard to its hazardousness or a reliable and citable source has not yet been found.
- ↑ Alexander Drilon, Theodore W. Laetsch, Shivaani Kummar, Steven G. DuBois, Ulrik N. Lassen, George D. Demetri, Michael Nathenson, Robert C. Doebele, Anna F. Farago, Alberto S. Pappo, Brian Turpin, Afshin Dowlati , Marcia S. Brose, Leo Mascarenhas, Noah Federman, Jordan Berlin, Wafik S. El-Deiry, Christina Baik, John Deeken, Valentina Boni, Ramamoorthy Nagasubramanian, Matthew Taylor, Erin R. Rudzinski, Funda Meric-Bernstam, Davendra PS Sohal , Patrick C. Ma, Luis E. Raez, Jaclyn F. Hechtman, Ryma Benayed, Marc Ladanyi, Brian B. Tuch, Kevin Ebata, Scott Cruickshank, Nora C. Ku, Michael C. Cox, Douglas S. Hawkins, David S Hong, David M. Hyman, et al. a .: Efficacy of Larotrectinib in TRK Fusion – Positive Cancers in Adults and Children . New England Journal of Medicine 2018, Volume 378, Issue 8, Feb. 22, 2018, pages 731-739, doi: 10.1056 / NEJMoa1714448
- ↑ a b c Klaus Fleck: TRK Fusion Cancer: A Remedy for Many Tumors , Deutsches Ärzteblatt 2019, Volume 116, Issue 44 of November 1, 2019, Page A2026, Link
- ↑ a b A. Drilon: TRK inhibitors in TRK fusion-positive cancers , Annals of Oncology 2019, Edition 30, Supplement 8 of November 1, 2019, pages viii23-viii30, [doi: 10.1093 / annonc / mdz282]
- ↑ New Drug Application (NDA): 210861 , accessed February 9, 2019.
- ↑ Link to EMA , accessed December 15, 2019, 1:12 a.m. CEST
