Lurbinectedin

Lurbinectedin is a cytotoxic antineoplastic agent that attaches to DNA and interferes with gene transcription. It is used in extensive-stage small cell lung cancer together with atezolizumab, an antibody that blocks PD-L1.

Mechanism of Action

• DNA binding: lurbinectedin binds to CG-rich sequences in the promoter regions of protein-coding genes. It forms covalent adducts with guanine in the minor groove of DNA, which bend the helix toward the major groove.
• Transcription block: it evicts oncogenic transcription factors from their binding sites and stalls elongating RNA polymerase II, which is then broken down by the ubiquitin–proteasome system.
• Cell death: the result is cell-cycle arrest and apoptosis of tumour cells. Impaired DNA repair and double-strand DNA breaks add to the cytotoxic effect.
• Tumour microenvironment: in vitro, at low nanomolar concentrations, it lowers the expression of inflammatory and motility-related genes and reduces cell migration and adhesion; at higher concentrations it triggers apoptosis of monocytes and macrophages through caspase-8. In mouse models, antitumour doses (0.18–0.20 mg/kg) slowed tumour growth, reduced specific immune cell populations and lowered tumour vascularity.
• Cardiac electrophysiology: in 39 patients with advanced cancer, no large effect (more than 10 ms) on the QTc interval was found at 3.2 mg/m² every 21 days.

Pharmacokinetics

• Exposure: after a 3.2 mg/m² one-hour infusion, the geometric mean total plasma Cmax is 107 µg/L and AUC∞ 551 µg·h/L. Pharmacokinetics are linear over 0.02–6.9 mg/m², and there is no accumulation with dosing every 21 days.
• Distribution: steady-state volume of distribution about 504 L; about 99% bound to plasma proteins (albumin and α-1-acid glycoprotein); blood-to-plasma ratio 0.68.
• Metabolism: hepatic, mainly by CYP3A4 (shown in human liver preparations in vitro). In vitro, lurbinectedin does not inhibit CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1 or 3A4 and does not induce CYP1A2 or CYP3A4. It is a substrate of the efflux transporter P-glycoprotein (MDR1).
• Elimination: terminal half-life 51 hours; total plasma clearance 11 L/h. About 89% of the dose is excreted in faeces (less than 0.2% as unchanged drug) and 6% in urine (1% unchanged).
• Special populations: body weight (39–154 kg), age (18–85 years) and sex have no clinically meaningful effect on exposure. A dedicated study examined different degrees of hepatic impairment in patients with advanced solid tumours; the resulting dose recommendations are given under Administration and Dosage.

• Extensive-stage small cell lung cancer (ES-SCLC), maintenance treatment: lurbinectedin is used in combination with atezolizumab in adults whose disease has not progressed after first-line induction therapy with atezolizumab, carboplatin and etoposide.

• Hypersensitivity to lurbinectedin or to any of the excipients (sucrose, lactic acid, sodium hydroxide).
• Breastfeeding.

The frequencies below come from the IMforte study, in which 242 patients received lurbinectedin with atezolizumab for a median of 4.4 months, together with post-marketing reports. The most common reactions are nausea (37.6%), fatigue (34.3%, including asthenia), anaemia (33.9%), thrombocytopenia (27.7%) and neutropenia (25.2%). The most frequent grade 3 or 4 reactions are neutropenia (12.4%), thrombocytopenia (11.2%), anaemia (9.5%) and fatigue (5.0%).

Very common (≥1/10): anaemia, thrombocytopenia, neutropenia, leukopenia, decreased appetite, dyspnoea, nausea, diarrhoea, vomiting, constipation, musculoskeletal pain (back, neck, chest and limb pain, myalgia), fatigue (including asthenia).

Common (≥1/100 to <1/10): pneumonia, urinary tract infection (including cystitis), infection, skin infection (including cellulitis), lymphopenia, febrile neutropenia, hypothyroidism, hypomagnesaemia, hypocalcaemia, peripheral neuropathy (including hypoaesthesia, paraesthesia and peripheral sensory neuropathy), headache, dysgeusia, phlebitis, thrombophlebitis, cough, pneumonitis, productive cough, abdominal pain (including discomfort and distension), dyspepsia, stomatitis, pruritus, rash, arthralgia, oedema (including peripheral oedema), pyrexia, peripheral swelling, extravasation, mucosal inflammation, increased transaminases (ALT, AST), increased blood creatinine, increased gamma-glutamyltransferase, increased blood creatine phosphokinase, weight decreased.

Uncommon (≥1/1,000 to <1/100): sepsis, pancytopenia.

Not known: tumour lysis syndrome and rhabdomyolysis (reported after marketing; the frequency cannot be estimated).

Important and serious reactions: serious reactions occurred in 34.3% of patients, most often pneumonia (3.7%), thrombocytopenia (2.9%), respiratory tract infection (2.5%) and dyspnoea (2.1%). Fatal reactions occurred in 5%, mostly pneumonia and other lung infections. Adverse reactions led to permanent discontinuation in 5.8% of patients (neutropenia most often, 1.7%), to interruption in 28.9% and to dose reduction in 16.1%. Neutropenia began a median of 10 days after the first dose (range 7–29 days) and lasted a median of 11 days. ALT rose in 6.6% and AST in 7.0% of patients (grade 3 or higher in 2.5% and 1.2%). Extravasation caused tissue necrosis requiring debridement in a few cases.

Lurbinectedin is metabolised mainly by CYP3A4, so medicines that inhibit or induce this enzyme can change its exposure.

• Strong or moderate CYP3A inhibitors: itraconazole, a strong inhibitor, raised total lurbinectedin exposure (AUC) about 2.7-fold and cut total plasma clearance by 63% in a study of 8 subjects. Avoid the combination. If it cannot be avoided, give 50% of the approved dose (1.6 mg/m²); up to two further reductions of 20% each are then allowed if needed. The SmPC names as strong inhibitors ketoconazole, itraconazole, posaconazole, voriconazole, clarithromycin, telithromycin, lopinavir, ritonavir, saquinavir, nelfinavir, atazanavir, indinavir, boceprevir and telaprevir, and as moderate inhibitors aprepitant, ciprofloxacin, erythromycin, ciclosporin, fluconazole, diltiazem and verapamil.
• Strong CYP3A inducers: co-administration should be avoided (for example rifampicin, carbamazepine, phenytoin or St John’s wort), because they can lower lurbinectedin exposure.
• Moderate CYP3A inducers: bosentan lowered lurbinectedin exposure by about 20% and raised clearance by 25%, which is not clinically relevant, so no dose adjustment is needed with moderate inducers such as bosentan, efavirenz or etravirine.
• Medicines linked to rhabdomyolysis (for example statins): use with caution, because the risk of rhabdomyolysis may be higher.
• Transporters: lurbinectedin is a P-glycoprotein substrate. Its inhibitory effects on several transporters seen in vitro are not considered clinically relevant.

Treatment should be started and supervised by health professionals experienced in anticancer medicines. Lurbinectedin is given only as an intravenous infusion over one hour. The powder is reconstituted and then diluted before use (see section 6.6 of the SmPC). A central venous catheter should be considered to lower the risk of extravasation and thrombophlebitis, especially in patients with limited venous access.

Recommended Dose

• 3.2 mg/m² every 21 days, in combination with atezolizumab, until disease progression or unacceptable toxicity.
• On days when both are given, atezolizumab is given first. For the dose of atezolizumab (intravenous or subcutaneous) and for its dose changes, refer to its own prescribing information.
• Treatment is started only if the absolute neutrophil count is at least 1.5 × 10⁹/L and the platelet count is at least 100 × 10⁹/L.

Treatment Continuation and Delays

• Later cycles are given every 21 days when the continuation criteria are met.
• If the criteria are not met on day 1 of a cycle after cycle 1, treatment is withheld until recovery, for no more than 21 days after the due date. Without recovery after a 21-day delay, treatment is stopped.
• If atezolizumab is stopped because of a severe immune-related reaction, lurbinectedin may continue at its current dose as a single agent. If immune toxicity returns despite stopping atezolizumab, lurbinectedin is stopped too.

Medicines Before and After the Infusion

• Before each infusion (antiemetic prophylaxis): a corticosteroid (intravenous dexamethasone 8 mg or equivalent) and a serotonin antagonist (intravenous ondansetron 8 mg or equivalent).
• After the infusion: primary prophylaxis with G-CSF is recommended to lower the risk of severe or febrile neutropenia. If needed, antiemetic treatment can be extended for 2 days with oral dexamethasone 4 mg (or equivalent), oral ondansetron 8 mg (or equivalent), or metoclopramide 10 mg by mouth or intravenously every 8 hours (or equivalent).

Dose Adjustments for Side Effects

Severity grades follow NCI CTCAE version 5.0.

• Dose levels: the starting dose of 3.2 mg/m² is reduced to 2.6 mg/m² (first reduction) and then to 2.0 mg/m² (second reduction); after that, treatment is stopped. When the starting dose is already halved to 1.6 mg/m² (see below), the steps are 1.3 mg/m², then 1.0 mg/m², then stop.
• Neutropenia: for grade 4 neutropenia, any febrile neutropenia, or neutropenia of any grade with infection or sepsis, treatment is withheld until the neutropenia is grade 1 or lower and any fever, infection or sepsis has resolved, then resumed at a reduced dose. A patient with isolated grade 4 neutropenia (below 500 cells/mm³) who did not receive G-CSF as primary prophylaxis may be given G-CSF prophylaxis instead of a dose reduction.
• Thrombocytopenia: for grade 3 with bleeding, or grade 4, treatment is withheld until platelets are at least 100 × 10⁹/L, then resumed at a reduced dose.
• Hepatotoxicity and other adverse reactions: grade 2, withhold until grade 1 or lower (for AST and ALT, until no more than 3 × ULN), then resume at the same dose; grade 3 or higher, withhold until grade 1 or lower (for AST and ALT, no more than 3 × ULN), then resume at a reduced dose.
• Rhabdomyolysis and tumour lysis syndrome: grade 2, withhold until grade 1 or lower, then resume at the same dose; grade 3 or higher, stop permanently.
• Other non-haematological toxicity: grade 2, withhold until grade 1 or lower, then resume at the same dose; grade 3 or higher, withhold until grade 1 or lower, then resume at a reduced dose.
• Repeated or long delays: any reaction that needs frequent or prolonged (more than 2 weeks) delays calls for a dose reduction or discontinuation.

With CYP3A Inhibitors

Strong or moderate CYP3A inhibitors should be avoided. If they cannot be, the lurbinectedin dose is reduced by 50% of the approved dose, and up to two further reductions of 20% each are allowed.

Special Populations

• Elderly: no dose adjustment in patients aged 65 years and over.
• Renal impairment: no adjustment in mild (creatinine clearance 60–89 mL/min) or moderate (30–59 mL/min) impairment. Lurbinectedin has not been evaluated in enough patients with severe impairment (below 30 mL/min) or end-stage renal disease, so it should not be given to them.
• Hepatic impairment: treatment is not recommended when AST or ALT is above 3 × ULN, because experience is limited. No adjustment in mild impairment (total bilirubin at or below ULN with AST above ULN, or total bilirubin 1 to 1.5 × ULN with any AST). In moderate impairment (total bilirubin above 1.5 and up to 3 × ULN with any AST) the dose is 1.6 mg/m² as a 60-minute infusion every 21 days, with monitoring for increased adverse reactions; up to two further reductions of 20% each are allowed. In severe impairment (total bilirubin above 3 × ULN) the medicine should be avoided; if that is not possible, the same 1.6 mg/m² dose and monitoring apply.
• Children and adolescents: there is no relevant use of lurbinectedin in children for small cell lung cancer.

Myelosuppression

Lurbinectedin can cause severe and life-threatening myelosuppression, including febrile neutropenia and sepsis. It must not be given when the baseline neutrophil count is below 1.5 × 10⁹/L or the platelet count is below 100 × 10⁹/L. Full blood counts, with differential white cell and platelet counts, are checked at baseline and before each cycle. G-CSF is recommended if the neutrophil count falls below 500/mm³, or if any value below the lower limit of normal comes with infection or sepsis. Dose changes may be needed (see Dose Adjustments for Side Effects).

Hepatotoxicity

Increases in ALT and AST have been reported. ALT, AST and bilirubin are checked before treatment and periodically during it as clinically indicated.

Extravasation

Leakage of the infusion into the surrounding tissue can injure skin and soft tissue, including necrosis that has needed surgical debridement. Consider a central venous catheter and watch the infusion site for signs of extravasation. If it happens, stop the infusion at once, remove the infusion catheter and monitor for tissue necrosis, which may appear after a delay. Give supportive care, consult a specialist when needed, and use an unaffected site for later infusions.

Rhabdomyolysis

Creatine phosphokinase (CPK) is checked before treatment and periodically during it as clinically indicated. If rhabdomyolysis occurs, supportive measures such as parenteral hydration, urine alkalinisation and dialysis should be started promptly as indicated, and treatment is withheld or the dose reduced according to severity. Take care when giving medicines known to be associated with rhabdomyolysis, such as statins.

Tumour Lysis Syndrome

Tumour lysis syndrome, which may be fatal, has been reported. Patients, especially those with a high tumour burden, should be monitored closely. Preventing dehydration and managing electrolyte imbalances are the key precautions. If it develops, it is treated promptly and interrupting or stopping treatment should be considered.

Embryo-foetal Toxicity, Pregnancy, Breastfeeding and Fertility

• Pregnancy test: testing is recommended in women of childbearing potential before treatment starts.
• Contraception: women of childbearing potential should use highly effective contraception during treatment and for 7 months after the last dose. Men with female partners of childbearing potential should use a condom during treatment and for 4 months after the last dose, and the partner should use highly effective contraception for the same period.
• Pregnancy: lurbinectedin can cause foetal harm. Animal studies showed severe embryo-foetal toxicity, and human data are absent or limited. It should not be used in pregnancy unless the woman’s condition requires it, and she should be told of the risk to the foetus.
• Breastfeeding: contraindicated. It is not known whether lurbinectedin or its metabolites pass into breast milk, and a risk to the child cannot be excluded.
• Fertility: no specific fertility studies were done, but because the compound is cytotoxic and mutagenic it is likely to affect reproductive capacity.

Effect on Driving

Lurbinectedin has a moderate influence on the ability to drive and use machines. Patients with fatigue, dizziness, vertigo or nausea should not drive or use machines until the symptoms ease.

Store the vials in a refrigerator at 2–8 °C. Keep the cold chain unbroken during transport and delivery to the hospital pharmacy. After reconstitution and dilution, the solution must be used within the in-use periods given under Shelf Life.

• Unopened vial: 18 months for the 2 mg vial; 5 years for the 4 mg vial. Do not use after the expiry date.
• Reconstituted and diluted solution: chemical and physical in-use stability has been shown for 24 hours at either 2–8 °C or 25 °C. From a microbiological point of view the product should be used immediately; if it is not, in-use times and conditions are the user’s responsibility and would normally not exceed 24 hours at 2–8 °C, unless reconstitution and dilution took place under controlled and validated aseptic conditions.

Prescription only (Rx), as a medicinal product subject to restricted medical prescription. Treatment is started and supervised by health professionals experienced in anticancer medicines. Lurbinectedin is given as an intravenous infusion in hospital, so it is supplied to the hospital or clinic that administers it, with refrigerated (2–8 °C) cold-chain delivery.