What is lurbinectedin?
Lurbinectedin is an alkylating agent given intravenously and has selective inhibition of oncogenic transcription.
How does lurbinectedin work?
Lurbinectedin binds to guanine residues in the minor groove of DNA forming adducts, resulting in a bending of the DNA towards the major groove. The adduct formation triggers a cascade of events that affect subsequent activity of the DNA binding. These include transcription factors and DNA repair pathways, resulting in cell death.
What is this approved for?
Lurbinectedin was granted accelerated approval for adult patients who have metastatic small cell lung cancer (SCLC) and have progressed on or after platinum-based chemotherapy.
What is the basis for this approval?
Lurbinectedin was approved based upon the results of the PM1183-B-005-14 trial, which was an open-label, multi-cohort study. A total of 105 patients with metastatic SCLC who had progression on or after platinum-based chemotherapy were enrolled. Patients received lurbinectedin 3.2 mg/m2 IV every 21 days until disease progression. The primary efficacy measure was confirmed overall response rate (ORR), as well as response duration. The ORR was 35 percent (95% CI: 26-45%) with a median response duration of 5.3 months (95% CI: 4.1-6.4 months). The ORR per independent review committee was 30 percent (95% CI: 22-40%) and a median response duration of 5.1 months (95% CI: 4.9-64.months) (Lancet Oncol 2020;21:645-654).
How do you administer lurbinectedin?
Lurbinectedin is dosed as a 3.2 mg/m2 intravenous infusion over 60 minutes every 21 days until disease progression. Total volume of diluent is dependent on venous access.
Are there any pre-medications needed?
Standard premedication for lurbinectedin is not required for prevention of infusion-related reactions; however, adequate antiemesis prophylaxis should be considered with a corticosteroid and serotonin antagonist prior to each infusion.
What are the common side effects associated with lurbinectedin (> or =20%)?
The most common adverse events were leukopenia (79%), lymphopenia (79%), fatigue (77%), anemia (74%), neutropenia (71%), increased creatinine (69%), increased alanine aminotransferase (66%), increased glucose (52%), thrombocytopenia (37%), nausea (37%), decreased appetite (33%), musculoskeletal pain (33%), decreased albumin (32%), constipation (31%), dyspnea (31%), decreased sodium (31%), increased aspartate aminotransferase (26%), vomiting (22%), cough (20%), decreased magnesium (22%), and diarrhea (20%).
What are the uncommon side effects associated with lurbinectedin (less than 20%)?
Pyrexia (13%), chest pain (10%), abdominal pain (11%), respiratory tract infections (18%), pneumonia (10%), peripheral neuropathy (11%), and headache (10%) were also seen in studies. A rare but serious adverse effect related to lurbinectedin is embryo-fetal toxicity.
Are there any important drug interactions I should be aware of?
Lurbinectedin is primarily metabolized by CYP3A4. Co-administration with strong or moderate CYP3A4 inhibitors and inducers should be avoided.
How do I adjust the dose in the setting of renal or hepatic insufficiency?
No dose adjustments are needed in patients with mild-to-moderate renal dysfunction. Additionally, no dose adjustments are recommended for mild-moderate hepatic impairment; however, patients with severe hepatic function have not been evaluated in clinical trials.
What should my patients know about lurbinectedin?
* Patients should be monitored for myelosuppression prior to each infusion and notify their provider for signs and symptoms of infection.
* Adequate education related to management of chemotherapy-induced nausea and vomiting is warranted as lurbinectedin is listed as moderately emetogenic. Breakthrough antiemetics should be prescribed to patients.
What else should I know about lurbinectedin?
* Initiation of lurbinectedin should only occur if the baseline neutrophil count is >= 1,500 cells/mm3 and platelet count is >= 100,000/mm3. Treatment should be withheld for any grade 4 neutropenia and any grade febrile neutropenia until the severity of the adverse effect is <= grade 1. Dose reduction by one dose level would be warranted at the time therapy is resumed.
* Therapy should be withheld for grade 3 thrombocytopenia with bleeding or grade 4 thrombocytopenia until the platelets are >= 100,000/mm3.
* Monitor liver function tests prior to initiating therapy and periodically as indicated. Therapy should be held for grade >= 2 hepatotoxicity. Therapy may be resumed at the same dose or may require dose reductions.
* Dose reductions include the first reduction to 2.6 mg/m2 then the second reduction of 2 mg/m2.
What useful links are available regarding lurbinectedin?
* FDA Approval Announcement: https://bit.ly/2GdSUa2
* Prescribing Information: https://bit.ly/3jvzgES
Any ongoing clinical trials related to lurbinectedin?
Lurbinectedin is also being studied as a single agent or in combination with chemotherapy in phase I-II clinical trials in patients with advanced cancers, such as non-small cell lung carcinoma, mesothelioma, breast cancer, sarcoma, ovarian, etc. More information is available about these trials at http://clinicaltrials.gov.
JANELLE E. MANN, PHARMD, BCOP, is Clinical Oncology Pharmacist/ Manager, Clinical Pharmacy Services at Washington University School of Medicine, Saint Louis, Mo. She serves as the Pharmacy Forum column editor. RAMASWAMY GOVINDAN, MD, Professor of Medicine; Anheuser Busch Chair in Medical Oncology; Director, Section of Medical Oncology, Division of Oncology, Washington University School of Medicine, serves as the Pharmacy Forum column physician advisor.