Lurbinectedin

Last updated

Lurbinectedin
Lurbinectedin structure.svg
Clinical data
Pronunciation /ˌlɜːrbɪˈnɛktɪdɪn/
LUR-bi-NEK-ti-din
Trade names Zepzelca
Other namesPM-01183
AHFS/Drugs.com Professional Drug Facts
MedlinePlus a620049
License data
Pregnancy
category
Routes of
administration 		Intravenous
Drug class Antineoplastic agent
ATC code
Legal status
Legal status
Identifiers
  • [(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
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
Formula C41H44N4O10S
Molar mass 784.88 g·mol−1
3D model (JSmol)
  • 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=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 for the treatment of small cell lung cancer. [5] [6] [7]

Contents

The most common side effects include leukopenia, lymphopenia, fatigue, anemia, neutropenia, increased creatinine, increased alanine aminotransferase, increased glucose, thrombocytopenia, nausea, decreased appetite, musculoskeletal pain, decreased albumin, constipation, dyspnea, decreased sodium, increased aspartate aminotransferase, vomiting, cough, decreased magnesium and diarrhea. [5] [6] [7]

Lurbinectedin is a synthetic tetrahydropyrrolo [4,3,2-de]quinolin-8(1H)-one alkaloid analogue with potential antineoplastic activity. [8] Lurbinectedin covalently binds to residues lying in the minor groove of DNA, which may result in delayed progression through S phase, cell cycle arrest in the G2/M phase and cell death. [8]

Lurbinectedin was approved for medical use in the United States in June 2020. [9] [5] [6] [7] [10]

Medical uses

Lurbinectedin is indicated for the treatment of adults with metastatic small cell lung cancer (SCLC) with disease progression on or after platinum-based chemotherapy. [7]

Structure

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. [11]

Synthesis

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%. [12]

Mechanism of action

According to PharmaMar, [13] 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. Macrophages can contribute to tumor growth and progression by promoting tumor cell proliferation and invasion, fostering tumor angiogenesis and suppressing antitumor immune cells. [14] [15] 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.

History

Lurbinectedin was approved for medical use in the United States in June 2020. [9] [5] [6] [7] [10]

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. [7] [10] Participants received lurbinectedin 3.2 mg/m2 by intravenous infusion every 21 days until disease progression or unacceptable toxicity. [7] The trial was conducted at 26 sites in the United States, Great Britain, Belgium, France, Italy, Spain and Czech Republic. [10]

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. [7] [16]

Research

Clinical Trials

Lurbinectedin can be used as monotherapy in the treatment of SCLC.[ medical citation needed ] 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. [17]
  • 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). [17]

Lurbinectedin is also being investigated in combination with doxorubicin as second-line therapy in a randomized Phase III trial.[ medical citation needed ] 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. [18] [19]

Lurbinectedin is available in the U.S. under Expanded Access Program (EAP). [18] [20]

Related Research Articles

<span class="mw-page-title-main">Small-cell carcinoma</span> Type of malignant cancer

Small-cell carcinoma is a type of highly malignant cancer that most commonly arises within the lung, although it can occasionally arise in other body sites, such as the cervix, prostate, and gastrointestinal tract. Compared to non-small cell carcinoma, small cell carcinoma is more aggressive, with a shorter doubling time, higher growth fraction, and earlier development of metastases.

Bevacizumab, sold under the brand name Avastin among others, is a monoclonal antibody medication used to treat a number of types of cancers and a specific eye disease. For cancer, it is given by slow injection into a vein (intravenous) and used for colon cancer, lung cancer, ovarian cancer, glioblastoma, hepatocellular carcinoma, and renal-cell carcinoma. In many of these diseases it is used as a first-line therapy. For age-related macular degeneration it is given by injection into the eye (intravitreal).

<span class="mw-page-title-main">Trabectedin</span> Chemical compound

Trabectedin, sold under the brand name Yondelis, is an antitumor chemotherapy medication for the treatment of advanced soft-tissue sarcoma and ovarian cancer.

Spectrum Pharmaceuticals, Inc. is an American biopharmaceutical company located in Boston, MA. It develops and markets drugs for treatments in hematology and oncology.

Treatment of lung cancer refers to the use of medical therapies, such as surgery, radiation, chemotherapy, immunotherapy, percutaneous ablation, and palliative care, alone or in combination, in an attempt to cure or lessen the adverse impact of malignant neoplasms originating in lung tissue.

<span class="mw-page-title-main">Crizotinib</span> ALK inhibitor for treatment of non-small-cell lung cancer

Crizotinib, sold under the brand name Xalkori among others, is an anti-cancer medication used for the treatment of non-small cell lung carcinoma (NSCLC). Crizotinib inhibits the c-Met/Hepatocyte growth factor receptor (HGFR) tyrosine kinase, which is involved in the oncogenesis of a number of other histological forms of malignant neoplasms. It also acts as an ALK and ROS1 inhibitor.

<span class="mw-page-title-main">TIGIT</span> Protein-coding gene in the species Homo sapiens

TIGIT is an immune receptor present on some T cells and natural killer cells (NK). It is also identified as WUCAM and Vstm3. TIGIT could bind to CD155 (PVR) on dendritic cells (DCs), macrophages, etc. with high affinity, and also to CD112 (PVRL2) with lower affinity.

<span class="mw-page-title-main">Nivolumab</span> Anticancer medication

Nivolumab, sold under the brand name Opdivo, is an anti-cancer medication used to treat a number of types of cancer. This includes melanoma, lung cancer, malignant pleural mesothelioma, renal cell carcinoma, Hodgkin lymphoma, head and neck cancer, urothelial carcinoma, colon cancer, esophageal squamous cell carcinoma, liver cancer, gastric cancer, and esophageal or gastroesophageal junction cancer. It is administered intravenously.

<span class="mw-page-title-main">Pembrolizumab</span> Pharmaceutical drug used in cancer treatment

Pembrolizumab, sold under the brand name Keytruda, is a humanized antibody, more specifically a PD-1 Inhibitor, used in cancer immunotherapy that treats melanoma, lung cancer, head and neck cancer, Hodgkin lymphoma, stomach cancer, cervical cancer, and certain types of breast cancer. It is administered by slow intravenous injection.

<span class="mw-page-title-main">Ceritinib</span> ALK inhibitor for treatment of non-small-cell lung cancer

Ceritinib is a prescription-only drug used for the treatment of non-small cell lung cancer (NSCLC). It was developed by Novartis and received FDA approval for use in April 2014.

<span class="mw-page-title-main">Binimetinib</span> Chemical compound

Binimetinib, sold under the brand name Mektovi, is an anti-cancer medication used to treat various cancers. Binimetinib is a selective inhibitor of MEK, a central kinase in the tumor-promoting MAPK pathway. Inappropriate activation of the pathway has been shown to occur in many cancers. In June 2018 it was approved by the FDA in combination with encorafenib for the treatment of patients with unresectable or metastatic BRAF V600E or V600K mutation-positive melanoma. In October 2023, it was approved by the FDA for treatment of NSCLC with a BRAF V600E mutation in combination with encorafenib. It was developed by Array Biopharma.

<span class="mw-page-title-main">Durvalumab</span> Pharmaceutical drug

Durvalumab, sold under the brand name Imfinzi, is an FDA-approved immunotherapy for cancer, developed by Medimmune/AstraZeneca. It is a human immunoglobulin G1 kappa (IgG1κ) monoclonal antibody that blocks the interaction of programmed cell death ligand 1 (PD-L1) with the PD-1 (CD279).

<span class="mw-page-title-main">Atezolizumab</span> Monoclonal anti-PD-L1 antibody

Atezolizumab, sold under the brand name Tecentriq among others, is a monoclonal antibody medication used to treat urothelial carcinoma, non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), hepatocellular carcinoma and alveolar soft part sarcoma, but discontinued for use in triple-negative breast cancer (TNBC). It is a fully humanized, engineered monoclonal antibody of IgG1 isotype against the protein programmed cell death-ligand 1 (PD-L1).

Avelumab, sold under the brand name Bavencio, is a fully human monoclonal antibody medication for the treatment of Merkel cell carcinoma, urothelial carcinoma, and renal cell carcinoma.

<span class="mw-page-title-main">Capmatinib</span> Chemical compound

Capmatinib, sold under the brand name Tabrecta, is an anticancer medication used for the treatment of metastatic non-small cell lung cancer whose tumors have a mutation that leads to the exon 14 skipping of the MET gene, which codes for the membrane receptor HGFR.

<span class="mw-page-title-main">Lorlatinib</span> Kinase inhibitor for treatment of non-small-cell lung cancer

Lorlatinib, sold under the brand name Lorbrena in the United States, Canada, and Japan, and Lorviqua in the European Union, is an anti-cancer medication used for the treatment of non-small cell lung cancer. It is an orally administered inhibitor of anaplastic lymphoma kinase (ALK) and C-ros oncogene 1 (ROS1), two enzymes that play a role in the development of cancer. It was developed by Pfizer.

Cemiplimab, sold under the brand name Libtayo, is a monoclonal antibody medication for the treatment of squamous cell skin cancer. Cemiplimab belongs to a class of drugs that binds to the programmed death receptor-1 (PD-1), blocking the PD-1/PD-L1 pathway.

<span class="mw-page-title-main">Trastuzumab deruxtecan</span> Medication

Trastuzumab deruxtecan, sold under the brand name Enhertu, is an antibody-drug conjugate consisting of the humanized monoclonal antibody trastuzumab (Herceptin) covalently linked to the topoisomerase I inhibitor deruxtecan. It is licensed for the treatment of breast cancer or gastric or gastroesophageal adenocarcinoma. Trastuzumab binds to and blocks signaling through epidermal growth factor receptor 2 (HER2/neu) on cancers that rely on it for growth. Additionally, once bound to HER2 receptors, the antibody is internalized by the cell, carrying the bound deruxtecan along with it, where it interferes with the cell's ability to make DNA structural changes and replicate its DNA during cell division, leading to DNA damage when the cell attempts to replicate itself, destroying the cell.

<span class="mw-page-title-main">G1 Therapeutics</span> Pharmaceutical company

G1 Therapeutics, Inc. is an American biopharmaceutical company headquartered in Research Triangle Park, North Carolina. The company specializes in developing and commercializing small molecule therapeutics for the treatment of patients with cancer.

Infigratinib is an kinase inhibitor in development for the treatment of achondroplasia and hypochondroplasia.

References

  1. 1 2 "Zepzelca". Therapeutic Goods Administration (TGA). 22 September 2021. Archived from the original on 30 September 2021. Retrieved 30 September 2021.
  2. 1 2 "AusPAR: lurbinectedin". Therapeutic Goods Administration (TGA). 4 May 2022. Archived from the original on 4 May 2022. Retrieved 4 May 2022.
  3. ↑ "Updates to the Prescribing Medicines in Pregnancy database". Therapeutic Goods Administration (TGA). 12 May 2022. Archived from the original on 3 April 2022. Retrieved 13 May 2022.
  4. ↑ "Summary Basis of Decision (SBD) for Zepzelca". Health Canada. 23 October 2014. Archived from the original on 29 May 2022. Retrieved 29 May 2022.
  5. 1 2 3 4 5 "Zepzelca- lurbinectedin injection, powder, lyophilized, for solution". DailyMed. 15 June 2020. Archived from the original on 24 January 2021. Retrieved 24 September 2020.
  6. 1 2 3 4 "Jazz Pharmaceuticals Announces U.S. FDA Accelerated Approval of Zepzelca (lurbinectedin) for the Treatment of Metastatic Small Cell Lung Cancer" (Press release). Jazz Pharmaceuticals. 15 June 2020. Archived from the original on 15 June 2020. Retrieved 15 June 2020– via PR Newswire.
  7. 1 2 3 4 5 6 7 8 "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.PD-icon.svg This article incorporates text from this source, which is in the public domain .
  8. 1 2 "Lurbinectedin". National Cancer Institute. Archived from the original on 16 May 2020. Retrieved 15 June 2020.PD-icon.svg This article incorporates text from this source, which is in the public domain .
  9. 1 2 "Zepzelca: FDA-Approved Drugs". U.S. Food and Drug Administration (FDA). Archived from the original on 19 October 2020. Retrieved 15 June 2020.
  10. 1 2 3 4 "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.PD-icon.svg This article incorporates text from this source, which is in the public domain .
  11. ↑ Takahashi R, Mabuchi S, Kawano M, Sasano T, Matsumoto Y, Kuroda H, et al. (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.
  12. ↑ He W, Zhang Z, Ma D (March 2019). "A Scalable Total Synthesis of the Antitumor Agents Et-743 and Lurbinectedin". Angewandte Chemie. 58 (12): 3972–3975. doi:10.1002/anie.201900035. PMID   30689274. S2CID   59306678.
  13. ↑ PharmaMar presentation of Lurbinectedin's Mechanism of Action Lurbinectedin Mechanisim[sic] of Action | https://www.youtube.com/watch?v=8daELhxAXcQ Archived 18 November 2020 at the Wayback Machine
  14. ↑ 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.
  15. ↑ Engblom C, Pfirschke C, Pittet MJ (July 2016). "The role of myeloid cells in cancer therapies". Nature Reviews. Cancer. 16 (7): 447–462. doi:10.1038/nrc.2016.54. PMID   27339708. S2CID   21924175.
  16. ↑ "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.
  17. 1 2 Paz-Ares LG, Trigo Perez JM, Besse B, Moreno V, Lopez R, Sala MA, et al. (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. S2CID   190884224.
  18. 1 2 Calvo E, Moreno V, Flynn M, Holgado E, Olmedo ME, Lopez Criado MP, et al. (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.
  19. ↑ "PharmaMar and Bionical Emas Launch Expanded Access Program for Lurbinectedin in Relapsed Small Cell Lung Cancer in the U.S." (Press release). Bionical Emas. 27 January 2020. Archived from the original on 18 August 2022. Retrieved 4 May 2022– via PR Newswire.
  20. ↑ Farago AF, Drapkin BJ, Lopez-Vilarino de Ramos JA, Galmarini CM, Núñez R, Kahatt C, Paz-Ares L (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.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.