Lurbinectedin

Lurbinectedin
Names
Pronunciation/ˌlɜːrbɪˈnɛktɪdin/
LUR-bi-NEK-ti-deen
Trade namesZepzelca
Other namesPM-01183
IUPAC name
  • [(1R,2R,3R,11S,12S,14R,26R)-5,12-dihydroxy-6,6'-dimethoxy-7,21,30-trimethyl-27-oxospiro[17,19,28-trioxa-24-thia-13,30-diazaheptacyclo[12.9.6.13,11.02,13.04,9.015,23.016,20]triaconta-4(9),5,7,15,20,22-hexaene-26,1'-2,3,4,9-tetrahydropyrido[3,4-b]indole]-22-yl] acetate
Clinical data
Drug classAlkylating agent[1]
Main usesSmall cell lung cancer (SCLC)[1]
Side effectsLow white blood cells, low red blood cells, kidney problems, low platelets, nausea, muscle pain, shortness of breath, liver inflammation, constipation[1]
WHO AWaReUnlinkedWikibase error: ⧼unlinkedwikibase-error-statements-entity-not-set⧽
Pregnancy
category
    Routes of
    use    		Intravenous
    Typical dose3.2 mg/m2 q 3 wks[1]
    External links
    AHFS/Drugs.comMonograph
    MedlinePlusa620049
    Legal
    License data
    Legal status
    Chemical and physical data
    FormulaC41H44N4O10S
    Molar mass784.88 g·mol−1
    3D model (JSmol)
    SMILES
    • CC1=CC2=C([C@@H]3[C@@H]4[C@H]5C6=C(C(=C7C(=C6[C@@H](N4[C@H]([C@H](C2)N3C)O)COC(=O)[C@@]8(CS5)C9=C(CCN8)C2=C(N9)C=CC(=C2)OC)OCO7)C)OC(=O)C)C(=C1OC)O
    InChI
    • InChI=1S/C41H44N4O10S/c1-17-11-20-12-25-39(48)45-26-14-52-40(49)41(38-22(9-10-42-41)23-13-21(50-5)7-8-24(23)43-38)15-56-37(31(45)30(44(25)4)27(20)32(47)33(17)51-6)29-28(26)36-35(53-16-54-36)18(2)34(29)55-19(3)46/h7-8,11,13,25-26,30-31,37,39,42-43,47-48H,9-10,12,14-16H2,1-6H3/t25-,26-,30+,31+,37+,39-,41+/m0/s1
    • Key:YDDMIZRDDREKEP-HWTBNCOESA-N

    Lurbinectedin, sold under the brand name Zepzelca, is a medication used to treat small cell lung cancer (SCLC).[1] It is used when the disease has spread despite other treatments.[1] It is given by gradual injection into a vein.[1]

    Common side effects include low white blood cells, low red blood cells, kidney problems, low platelets, nausea, muscle pain, shortness of breath, liver inflammation, and constipation.[1] Other side effects may include infertility.[1] Use in pregnancy may harm the baby.[1] It is an alkylating agent.[1] It works by interfering with DNA duplication required for cell division.[3]

    Lurbinectedin was approved for medical use in the United States in 2020 and Australia in 2021.[4][2] In the United States 4 mg costs about 7,200 USD as of 2021.[5] As of 2021 it is not available in the United Kingdom or Europe.[6]

    Medical uses

    Dosage

    It is generally give at a dose of 3.2 mg/m2 every 3 weeks.[1]

    Mechanism of action

    Lurbinectedin inhibits the active transcription of the encoding genes. This has two consequences. It promotes tumor cell death and normalizes the tumor microenvironment. Active transcription is the process by which there are specific signal where information contained in the DNA sequence is transferred to an RNA molecule. This activity depends on the activity of an enzyme called RNA polymerase II. Lurbinectedin inhibits transcription through a very precise mechanism. Firstly, lurbinectedin binds to specific DNA sequences. It is at these precise spots that slides down the DNA to produce RNA polymerase II that is blocked and degraded by lurbinectedin. Lurbinectedin also has important role in tumor microenvironment. The tumor cells act upon macrophages to avoid them from behaving like an activator of the immune system. Literally, macrophages work in any tumor's favor. Macrophages can contribute to tumor growth and progression by promoting tumor cell proliferation and invasion, fostering tumor angiogenesis and suppressing antitumor immune cells.[7][8] Attracted to oxygen-starved (hypoxic) and necrotic tumor cells they promote chronic inflammation. So, not only that macrophages inhibit immune system avoiding the destruction of tumor cells, but they also create tumor tissue that allows tumor growth. However, macrophages associated with tumors are cells that are addicted to the transcription process. Lurbinectedin acts specifically on the macrophages associated with tumors in two ways: firstly, by inhibiting the transcription of macrophages that leads to cell death and secondly, inhibiting the production of tumor growth factors. In this way, lurbinectedin normalizes the tumor microenvironment.

    Chemistry

    Lurbinectedin is structurally similar to trabectedin, although the tetrahydroisoquinoline present in trabectedin is replaced with a tetrahydro β-carboline which enables lurbinectedin to exhibit increased antitumor activity compared with trabectedin.[9]

    Biosynthesis

    Lurbinectedin a marine agent isolated from the sea squirt species Ecteinascidia turbinata. Synthetic production is necessary because very small amounts can be obtained from sea organisms. For example, one ton (1000 kg) of sea squirts are required to produce one gram of trabectedin, which is analogue of lurbinectedin. Complex synthesis of lurbinectedin starts from small, common starting materials that require twenty-six individual steps to produce the drug with overall yield of 1.6%.[10][11]

    History

    Lurbinectedin was approved for medical use in the United States in June 2020.[12][1][13][14]

    Efficacy was demonstrated in the PM1183-B-005-14 trial (Study B-005; NCT02454972), a multicenter open-label, multi-cohort study enrolling 105 participants with metastatic SCLC who had disease progression on or after platinum-based chemotherapy.[13][14] Participants received lurbinectedin 3.2 mg/m2 by intravenous infusion every 21 days until disease progression or unacceptable toxicity.[13] The trial was conducted at 26 sites in the United States, Great Britain, Belgium, France, Italy, Spain and Czech Republic.[14]

    The U.S. Food and Drug Administration (FDA) granted the application for lurbinectedin priority review and orphan drug designations and granted the approval of Zepzelca to Pharma Mar S.A.[13][15]

    Research

    Lurbinectedin can be used as monotherapy in the treatment of SCLC. Lurbinectedin monotherapy demonstrated the following clinical results in relapsed extensive stage SCLC:

    • For sensitive disease (chemotherapy-free interval of ≥ 90 days) overall response rate (ORR) was 46.6% with 79.3% disease control rate and median overall survival (OS) being increased to 15.2 months.[16]
    • For resistant disease (chemotherapy-free interval of < 90 days) overall response rate (ORR) was 21.3% with 46.8% disease control rate and 5.1 months median overall survival (OS).[16]

    Lurbinectedin is also being investigated in combination with doxorubicin as second-line therapy in a randomized Phase III trial. While overall survival in this trial is not yet known, response rates at second line were

    • 91.7% in sensitive disease with median progression-free survival of 5.8 months, and
    • 33.3% in resistant disease with median progression-free of 3.5 months.[17]

    Lurbinectedin is available in the U.S. under Expanded Access Program (EAP).[17][18]

    References

    1. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 "Zepzelca- lurbinectedin injection, powder, lyophilized, for solution". DailyMed. 15 June 2020. Archived from the original on 24 January 2021. Retrieved 24 September 2020.
    2. 1 2 3 "Zepzelca". Therapeutic Goods Administration (TGA). 22 September 2021. Archived from the original on 30 September 2021. Retrieved 30 September 2021.
    3. ↑ "Lurbinectedin". National Cancer Institute. Archived from the original on 16 May 2020. Retrieved 15 June 2020. Public Domain This article incorporates text from this source, which is in the public domain.
    4. ↑ "Lurbinectedin Monograph for Professionals". Drugs.com. Archived from the original on 26 January 2021. Retrieved 24 November 2021.
    5. ↑ "Zepzelca Prices, Coupons & Patient Assistance Programs". Drugs.com. Retrieved 24 November 2021.
    6. ↑ "Lurbinectedin". SPS - Specialist Pharmacy Service. 13 September 2016. Archived from the original on 8 December 2021. Retrieved 24 November 2021.
    7. ↑ Qian BZ, Pollard JW (April 2010). "Macrophage diversity enhances tumor progression and metastasis". Cell. 141 (1): 39–51. doi:10.1016/j.cell.2010.03.014. PMC 4994190. PMID 20371344.
    8. ↑ Engblom C, Pfirschke C, Pittet MJ (July 2016). "The role of myeloid cells in cancer therapies". Nature Reviews. Cancer. 16 (7): 447–62. doi:10.1038/nrc.2016.54. PMID 27339708. S2CID 21924175.
    9. ↑ Takahashi, Ryoko; Mabuchi, Seiji; Kawano, Mahiru; Sasano, Tomoyuki; Matsumoto, Yuri; Kuroda, Hiromasa; Kozasa, Katsumi; Hashimoto, Kae; Sawada, Kenjiro; Kimura, Tadashi (17 March 2016). "Preclinical Investigations of PM01183 (Lurbinectedin) as a Single Agent or in Combination with Other Anticancer Agents for Clear Cell Carcinoma of the Ovary". PLOS ONE. 11 (3): e0151050. Bibcode:2016PLoSO..1151050T. doi:10.1371/journal.pone.0151050. PMC 4795692. PMID 26986199.
    10. ↑ Total synthesis of marine antitumor agents trabectedin and lurbinectedin | https://www.sciencedaily.com/releases/2019/02/190219111659.htm Total synthesis of marine antitumor agents trabectedin and lurbinectedin -- ScienceDaily at the Wayback Machine (archived 7 November 2020)
    11. ↑ A Scalable Total Synthesis of the Antitumor Agents Et‐743 and Lurbinectedin | https://onlinelibrary.wiley.com/doi/full/10.1002/anie.201900035 A Scalable Total Synthesis of the Antitumor Agents Et‐743 and Lurbinectedin - He - 2019 - Angewandte Chemie International Edition - Wiley Online Library at the Wayback Machine (archived 3 June 2020)
    12. ↑ "Zepzelca: FDA-Approved Drugs". U.S. Food and Drug Administration (FDA). Archived from the original on 19 October 2020. Retrieved 15 June 2020.
    13. 1 2 3 4 "FDA grants accelerated approval to lurbinectedin for metastatic small". U.S. Food and Drug Administration (FDA). 15 June 2020. Archived from the original on 18 June 2020. Retrieved 16 June 2020. Public Domain This article incorporates text from this source, which is in the public domain.
    14. 1 2 3 "Drug Trials Snapshots: Zepzelca". U.S. Food and Drug Administration (FDA). 15 June 2020. Archived from the original on 22 December 2020. Retrieved 28 June 2020. Public Domain This article incorporates text from this source, which is in the public domain.
    15. ↑ "Lurbinectedin Orphan Drug Designation and Approval". U.S. Food and Drug Administration (FDA). 1 August 2018. Archived from the original on 17 June 2020. Retrieved 16 June 2020.
    16. 1 2 Paz-Ares, Luis G.; Trigo Perez, Jose Manuel; Besse, Benjamin; Moreno, Victor; Lopez, Rafael; Sala, Maria Angeles; Ponce Aix, Santiago; Fernandez, Cristian Marcelo; Siguero, Mariano; Kahatt, Carmen Maria; Zeaiter, Ali Hassan; Zaman, Khalil; Boni, Valentina; Arrondeau, Jennifer; Martinez Aguillo, Maite; Delord, Jean-Pierre; Awada, Ahmad; Kristeleit, Rebecca Sophie; Olmedo Garcia, Maria Eugenia; Subbiah, Vivek (20 May 2019). "Efficacy and safety profile of lurbinectedin in second-line SCLC patients: Results from a phase II single-agent trial". Journal of Clinical Oncology. 37 (15_suppl): 8506. doi:10.1200/JCO.2019.37.15_suppl.8506.
    17. 1 2 Calvo, E.; Moreno, V.; Flynn, M.; Holgado, E.; Olmedo, M.E.; Lopez Criado, M.P.; Kahatt, C.; Lopez-Vilariño, J.A.; Siguero, M.; Fernandez-Teruel, C.; Cullell-Young, M.; Soto Matos-Pita, A.; Forster, M. (October 2017). "Antitumor activity of lurbinectedin (PM01183) and doxorubicin in relapsed small-cell lung cancer: results from a phase I study". Annals of Oncology. 28 (10): 2559–2566. doi:10.1093/annonc/mdx357. PMC 5834091. PMID 28961837.
    18. ↑ Farago, Anna F; Drapkin, Benjamin J; Lopez-Vilarino de Ramos, Jose Antonio; Galmarini, Carlos M; Núñez, Rafael; Kahatt, Carmen; Paz-Ares, Luis (January 2019). "ATLANTIS: a Phase III study of lurbinectedin/doxorubicin versus topotecan or cyclophosphamide/doxorubicin/vincristine in patients with small-cell lung cancer who have failed one prior platinum-containing line". Future Oncology. 15 (3): 231–239. doi:10.2217/fon-2018-0597. PMC 6331752. PMID 30362375.
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