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]
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 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 with disease progression on or after platinum-based chemotherapy.[7]
In October 2025, the indication for lurbinectedin was expanded to include using lurbinectedin in combination with atezolizumab or in combination with atezolizumab/hyaluronidase for the maintenance treatment of adults with extensive-stage small cell lung cancer whose disease has not progressed after first-line induction therapy with atezolizumab or atezolizumab and hyaluronidase, carboplatin, and etoposide.[11]
Adverse effects
The US prescribing information for lurbinectedin includes warnings and precautions for myelosuppression, hepatotoxicity, extravasation resulting in tissue necrosis, rhabdomyolysis, and embryo-fetal toxicity.[11] The prescribing information for atezolizumab and for atezolizumab/hyaluronidase include warnings and precautions for severe and fatal immune-mediated adverse reactions, infusion-related reactions, complications of allogeneic hematopoietic stem cell transplantation, and embryo-fetal toxicity.[11]
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.[12]
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%.[13]
Mechanism of action
According to PharmaMar,[14][unreliable medical source?] 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 RNA polymerase II slides down the DNA to produce RNA 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.[15][16]
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 multi-center open-label, multi-cohort study enrolling 105 participants with metastatic small cell lung cancer who had disease progression on or after platinum-based chemotherapy.[7][10] Participants received lurbinectedin 3.2mg/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 US 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][17]
The efficacy of lurbinectedin used in combination with atezolizumab or in combination with atezolizumab/hyaluronidase was evaluated in IMforte (NCT05091567), a randomized, multi-center, open-label trial in participants receiving first-line treatment for extensive-stage small cell lung cancer.[11] In IMforte, 483 participants with extensive-stage small cell lung cancer whose disease had not progressed after completion of four cycles of atezolizumab, carboplatin, and etoposide (induction treatment) were randomized (1:1) to receive either lurbinectedin in combination with atezolizumab administered intravenously or atezolizumab intravenously alone until disease progression or unacceptable toxicity.[11]
Lurbinectedin can be used as monotherapy in the treatment of small cell lung cancer.[medical citation needed] Lurbinectedin monotherapy demonstrated the following clinical results in relapsed extensive stage small cell lung cancer:
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.[19]
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).[19]
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.[20][21]
Lurbinectedin is available in the US under Expanded Access Program (EAP).[20][22]
1 2 "Lurbinectedin". National Cancer Institute. Archived from the original on 16 May 2020. Retrieved 15 June 2020. This article incorporates text from this source, which is in the public domain.
↑ 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. PMID30689274. S2CID59306678.
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