Lurbinectedin

Risk Summary

Based on animal data and its mechanism of action, lurbinectedin can cause fetal harm when administered to a pregnant woman. There are no available data to inform the risk of lurbinectedin use in pregnant women. Intravenous administration of a single lurbinectedin dose (approximately 0.2 times the 3.2 mg/m² clinical dose) to pregnant rats during the period of organogenesis caused embryolethality (see Data).

Advise pregnant women of the potential risk to a fetus.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Data

Animal Data

In a reproductive toxicity study, administration of a single lurbinectedin dose of 0.6 mg/m² (approximately 0.2 times of the human dose of 3.2 mg/m²) to pregnant rats on Gestation Day 10 resulted in 100% post-implantation loss.

Risk Summary

There are no data on the presence of lurbinectedin in human milk or its effects on the breastfed child or on milk production. Because of the potential for serious adverse reactions from lurbinectedin in breastfed children, advise women not to breastfeed during treatment with lurbinectedin and for 2 weeks after the final dose.

Carcinogenicity testing of lurbinectedin has not been performed. Lurbinectedin is genotoxic to mammalian cells in the presence and absence of metabolic activation. Lurbinectedin was not mutagenic in vitro in a bacterial reverse mutation (Ames) assay.

Fertility studies with lurbinectedin were not performed. There were no findings in reproductive organs in general toxicology studies in rats, dogs, or monkeys; however, the highest doses and exposures in these studies were all at levels lower than those at the human dose of 3.2 mg/m².

• Myelosuppression
• Hepatotoxicity
• Extravasation Resulting in Tissue Necrosis
• Rhabdomyolysis

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The pooled safety population described in the WARNINGS AND PRECAUTIONS reflect exposure to lurbinectedin as a single agent at a dose of 3.2 mg/m² intravenously every 21 days in 554 patients with advanced solid tumors. Among 554 patients who received lurbinectedin, including 105 patients with small cell lung cancer (SCLC) in PM1183-B-005-14 (Study B-005), 24% were exposed for 6 months or longer and 5% were exposed for greater than one year.

Small Cell Lung Cancer (SCLC)

The safety of lurbinectedin was evaluated in a cohort of 105 patients with previously treated SCLC in Study B-005. Patients received lurbinectedin 3.2 mg/m² intravenously every 21 days. All patients in this study received a pre-specified anti-emetic regimen consisting of a corticosteroid and serotonin antagonist. Patients could receive G-CSF for secondary prophylaxis (i.e., after patients had an initial decrease in WBC), but not primary prophylaxis. Among patients who received lurbinectedin, 29% were exposed for 6 months or longer and 6% were exposed for greater than one year.

Serious adverse reactions occurred in 34% of patients who received lurbinectedin. Serious adverse reactions in ≥3% of patients included pneumonia, febrile neutropenia, neutropenia, respiratory tract infection, anemia, dyspnea, and thrombocytopenia.

Permanent discontinuation due to an adverse reaction occurred in two patients (1.9%) who received lurbinectedin. Adverse reactions resulting in permanent discontinuation in ≥1% of patients who received lurbinectedin, which included peripheral neuropathy and myelosuppression.

Dosage interruptions due to an adverse reaction occurred in 30.5% of patients who received lurbinectedin. Adverse reactions requiring dosage interruption in ≥3% of patients who received lurbinectedin included neutropenia, and hypoalbuminemia.

Dose reductions due to an adverse reaction occurred in 25% of patients who received lurbinectedin. Adverse reactions requiring dosage reductions in ≥3% of patients who received lurbinectedin included neutropenia, febrile neutropenia and fatigue.

The most common adverse reactions, including laboratory abnormalities, (≥20%) were 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.

Table 1 summarizes the adverse reactions in the SCLC cohort of Study B-005.

Table 1. Adverse Reactions (≥10%) in Patients with SCLC Who Received Lurbinectedin in Study B-005:

^a Graded per NCI CTCAE 4.0.
^b No grade 5 adverse reactions were reported.
^c Includes abdominal pain, abdominal pain upper and abdominal discomfort.
^d Includes musculoskeletal pain, back pain, arthralgia, pain in extremity, musculoskeletal chest pain, neck pain, bone pain and myalgia.
^e Includes cough and productive cough.
^f Includes upper respiratory tract infection, viral upper respiratory tract infection, respiratory tract infection and bronchitis.
^g Includes pneumonia and lung infection.
^h Includes neuropathy peripheral, neuralgia, paresthesia, peripheral sensory neuropathy, hypoesthesia, and hyperesthesia.

Clinically relevant adverse reactions in <10% of patients who received lurbinectedin include dysgeusia, febrile neutropenia and pneumonitis.

Table 2 summarizes the laboratory abnormalities in Study B-005.

Table 2. Select Laboratory Abnormalities (≥20%) Worsening from Baseline in Patients with SCLC Who Received Lurbinectedin in Study B-005:

^a The denominator used to calculate the rate varied from 95 to 105 based on the number of patients with a baseline value and at least one post-treatment value.
^b Graded per NCI CTCAE 4.0.