On June 15, 2020, the alkylating drug lurbinectedin was granted accelerated approval for treatment of adult patients with metastatic small cell lung cancer (SCLC) with disease progression during or after platinum-based chemotherapy.1,2
Supporting Efficacy Data
Accelerated approval was based on findings in the multicenter, multicohort PM1183-B-005-14 trial (Study B-005; ClinicalTrials.gov identifier NCT02454972).2,3 A total of 105 patients with metastatic SCLC who had disease progression during or after platinum-based chemotherapy received lurbinectedin at 3.2 mg/m2 by intravenous (IV) infusion every 21 days until disease progression or unacceptable toxicity.
Median patient age was 60 years (range = 40–83 years; 35% ≥ 65 years). Overall, 60% were male, 75% were white, and the Eastern Cooperative Oncology Group performance status was 0 or 1 in 92%. In addition, 92% were former or current smokers. All patients received one or two lines of platinum-based chemotherapy, 71% had prior radiotherapy, 8% had prior immunotherapy in addition to platinum-based chemotherapy, and 57% had platinum-sensitive SCLC.
The main efficacy outcome measures were confirmed overall response rate on investigator assessment using Response Evaluation Criteria in Solid Tumors version 1.1 and response duration. Among all patients, the overall response rate (all partial responses) was 35%; the median response duration was 5.3 months (95% confidence interval [CI] = 4.1– 6.4 months), with 35% of responders responding for at least 6 months. On independent review committee assessment, the overall response rate was 30% (all partial responses). The median response duration was 5.1 months (95% CI = 4.9–6.4 months), with 25% of responders showing a response for at least 6 months.
On investigator assessment, the overall response rate was 45% among platinum-sensitive patients and 22% among platinum-resistant patients, with median response durations of 6.2 and 4.7 months, respectively. On independent review committee assessment, the overall response rate was 43% among platinum-sensitive patients and 13% among platinum-resistant patients, with median response durations of 5.3 and 4.8 months, respectively.
How It Works
Lurbinectedin is an alkylating drug that binds guanine residues in the minor groove of DNA, forming adducts and resulting in a bending of the DNA helix toward the major groove. Adduct formation triggers a cascade of events that can affect the subsequent activity of DNA binding proteins, including some transcription factors, and DNA repair pathways, resulting in perturbation of the cell cycle and eventual cell death. Lurbinectedin inhibited human monocyte activity in vitro and reduced macrophage infiltration in implanted tumors in mice.
How It Is Used
The recommended dosage of lurbinectedin is 3.2 mg/m2 via 60-minute IV infusion every 21 days until disease progression or unacceptable toxicity. Treatment should be initiated only if the absolute neutrophil count is ≥ 1,500 cells/mm3 and the platelet count is ≥ 100,000/mm3. Administration of preinfusion medications for antiemetic prophylaxis should be considered, including corticosteroids and serotonin antagonists.
Recommended dose reductions for adverse reactions are sequentially to 2.6 mg/m2 every 21 days and 2.0 mg/m2 every 21 days. Treatment should be permanently discontinued in patients who cannot tolerate 2.0 mg/m2 or who require a dose delay of more than 2 weeks.
Prescribing information provides instructions on dosage modification, including withholding treatment and dose reduction for adverse reactions including neutropenia, thrombocytopenia, hepatotoxicity, and other grade 2 to 4 adverse reactions. Coadministration with strong or moderate CYP3A inhibitors (eg, ketoconazole, conivaptan, clarithromycin) or with strong or moderate CYP3A inducers (eg, phenytoin, rifampin, carbamazepine, St. John’s wort) should be avoided.
All patients in Study B-005 received a prespecified antiemetic regimen consisting of a corticosteroid and serotonin antagonist. Patients could receive granulocyte colony-stimulating factor as secondary (but not primary) prophylaxis. Among the 105 patients, 29% were exposed to treatment for at least 6 months and 6% for more than 1 year.
The most common adverse events of any grade (≥ 20%), including laboratory abnormalities, were myelosuppression (decreases in leukocytes in 79%, lymphocytes in 79%, hemoglobin in 74%, neutrophils in 71%, and platelets in 37%), fatigue (77%), increased creatinine (69%), increased alanine aminotransferase (66%), increased glucose (52%), nausea (37%), decreased appetite (33%), musculoskeletal pain (33%), decreased albumin (32%), constipation (31%), dyspnea (31%), decreased sodium (31%), increased aspartate aminotransferase (26%), vomiting (22%), decreased magnesium (22%), cough (20%), and diarrhea (20%).
The most common grade 3 or 4 adverse events were fatigue (12%), pneumonia (7%), dyspnea (6%), and respiratory tract infection (5%). The most common grade 3 or 4 laboratory abnormalities were decreased neutrophils (46%), decreased lymphocytes (43%), decreased leukocytes (29%), and decreased hemoglobin (10%).
Serious adverse events occurred in 34% of patients, with those occurring in at least 3% including pneumonia, febrile neutropenia, neutropenia, respiratory tract infection, anemia, dyspnea, and thrombocytopenia. Adverse events required dose reduction in 25% of patients (most commonly due to neutropenia, febrile neutropenia, and fatigue) and treatment interruption in 31% (most commonly due to neutropenia and hypoalbuminemia). Adverse events led to discontinuation of treatment in two patients (1.9%), with causes consisting of peripheral neuropathy and myelosuppression.
Lurbinectedin has warnings/precautions for myelosuppression, hepatotoxicity, and embryofetal toxicity. Blood cell counts should be monitored prior to each administration. Liver function tests should be monitored prior to initiating treatment, periodically during treatment, and as clinically indicated. Patients should be advised not to breastfeed while receiving lurbinectedin.
1. U.S. Food and Drug Administration: FDA grants accelerated approval to lurbinectedin for metastatic small cell lung cancer. Available at https://www.fda.gov/drugs/drug-approvals-and-databases/fda-grants-accelerated-approval-lurbinectedin-metastatic-small-cell-lung-cancer. Accessed June 22, 2020.
2. Zepzelca (lurbinectedin) for injection prescribing information, Jazz Pharmaceutials, June 2020. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/213702s000lbl.pdf. Accessed July 9, 2020.
3. Trigo J, Subbiah V, Besse B, et al: Lurbinectedin as second-line treatment for patients with small-cell lung cancer: A single-arm, open-label, phase II basket trial. Lancet Oncol 21:645-654, 2020.