Lurbinectedin

In a dedicated drug-drug interaction study (n=8) with itraconazole, a strong CYP3A4 inhibitor, systemic exposure of total lurbinectedin was increased by approximately 2.7-fold (AUC_0-∞) and total plasma clearance was reduced by 63%, when lurbinectedin was given concomitantly with itraconazole (total daily dose of 200 mg during 12 days, 4 days before up to 8 days after the lurbinectedin administration).

Co-administration of lurbinectedin with strong or moderate CYP3A inhibitors should be avoided. If co-administration with strong CYP3A inhibitors (e.g., ketoconazole, itraconazole, posaconazole, voriconazole, clarithromycin, telithromycin, lopinavir, ritonavir, saquinavir, nelfinavir, atazanavir, indinavir, boceprevir, telaprevir) or moderate CYP3A inhibitors (e.g., aprepitant, ciprofloxacin, erythromycin, cyclosporine, fluconazole, diltiazem, verapamil) cannot be avoided, the dose of lurbinectedin should be reduced by 50% of the approved dose. In case of adverse reactions with the reduced initial dose, up to two subsequent dose reductions by 20% each are allowed.

In a dedicated drug-drug interaction study (n=8) with bosentan, a moderate CYP3A4 inducer, systemic exposure of total lurbinectedin was decreased by approximately 20% (AUC_0-∞) and total plasma clearance was increased by 25% when lurbinectedin was given concomitantly with bosentan (125 mg twice daily during 5 days). Therefore, the magnitude of these changes precludes a clinically relevant effect of co-administration of moderate CYP3A4 inducers (e.g., bosentan, cenobamate, dabrafenib, efavirenz, etravirine, lorlatinib, pexidartinib, phenobarbital, primidone, sotorasib) on lurbinectedin exposure and no dose adjustment is required.

Co-administration of strong CYP3A inducers (e.g., carbamazepine, phenobarbital, phenytoin, rifampicin, rifabutin, rifapentine, St. John's Wort (Hypericum perforatum)) with lurbinectedin should be avoided. Consider alternative agents with less CYP3A induction.

Lurbinectedin has not been evaluated in a sufficient number of patients with severe renal impairment (CrCL <30 mL/min) or end-stage renal disease to estimate the risk; therefore, it should not be administered to these patients.

Treatment with lurbinectedin is not recommended in patients with elevated AST or ALT (AST or ALT >3 × ULN), due to limited clinical experience.

In patients with moderate hepatic impairment (total bilirubin >1.5 to ≤3 × ULN and any AST), the recommended dose of lurbinectedin is 1.6 mg/m² by intravenous infusion over 60 minutes every 21 days until disease progression or unacceptable toxicity. Patients with moderate hepatic impairment should be monitored for increased adverse reactions. In case of adverse reactions with the reduced initial dose, up to two subsequent dose reductions by 20% each are allowed.

Administration of lurbinectedin in patients with severe hepatic impairment (total bilirubin >3 × ULN) should be avoided. If administration of lurbinectedin cannot be avoided, the recommended dose is 1.6 mg/m² by intravenous infusion over 60 minutes every 21 days until disease progression or unacceptable toxicity. Patients with severe hepatic impairment should be monitored for increased adverse reactions. In case of adverse reactions with the reduced initial dose, up to two subsequent dose reductions by 20% each are allowed.

Although no specific studies were conducted to assess fertility with lurbinectedin, and no clear signals of toxicity of reproductive organs were observed in toxicity studies, due to the nature of the compound (cytotoxic and mutagenic) it is likely to affect the reproductive capacity.

Advice on conservation of ovules or sperm should be sought prior to treatment because of the possibility of irreversible infertility due to therapy with lurbinectedin. Genetic counselling is also recommended for patients wishing to have children after therapy.

Patients with ECOG performance status ≥2; central nervous system (CNS) metastases, a history of autoimmune disease, or administration of systemic immunosuppressive medicinal products within 1 week prior to enrolment were excluded in the pivotal study in SCLC. In the absence of data, lurbinectedin in combination with atezolizumab should be used with caution in these populations after careful consideration of the potential benefit/risk on an individual basis.

There are no or limited amount of data from the use of lurbinectedin in pregnant women.

Studies in animals have shown severe embryo-foetal development toxicity.

Lurbinectedin should not be used during pregnancy unless the clinical condition of the woman requires treatment with lurbinectedin.

Pregnant or non-pregnant women of childbearing potential should be advised of the potential risk to a foetus. If lurbinectedin is used during pregnancy, or if a patient becomes pregnant while receiving lurbinectedin, the patient should be apprised of the potential risk to the foetus.

It is unknown whether lurbinectedin/metabolites are excreted in human milk.

A risk to the suckling child cannot be excluded.

Lurbinectedin is contraindicated during breastfeeding.

Women of childbearing potential / Contraception in males and females

Pregnancy testing is recommended in women of childbearing potential prior to starting treatment with lurbinectedin.

Female patients of childbearing potential should use highly effective contraception during treatment and for 7 months after the last dose.

Male patients with female partners of childbearing potential should use condom during treatment and for 4 months after the last dose. Female partners of childbearing potential should use highly effective contraception for the same period.

Fertility

Although no specific studies were conducted to assess fertility with lurbinectedin, and no clear signals of toxicity of reproductive organs were observed in toxicity studies, due to the nature of the compound (cytotoxic and mutagenic) it is likely to affect the reproductive capacity.

Advice on conservation of ovules or sperm should be sought prior to treatment because of the possibility of irreversible infertility due to therapy with lurbinectedin. Genetic counselling is also recommended for patients wishing to have children after therapy.

Lurbinectedin has moderate influence on the ability to drive and use machines. Patients experiencing fatigue, dizziness, vertigo and nausea should be advised not to drive and use machines until symptoms abate.

Summary of the safety profile

The most common adverse reactions were nausea (37.6%), fatigue* (34.3%), anaemia (33.9%), thrombocytopenia (27.7%), and neutropenia (25.2%).

The most frequent grade ¾ adverse reactions were neutropenia (12.4%), thrombocytopenia (11.2%), anaemia (9.5%) and fatigue* (5.0%).

Serious adverse reactions occurred in 34.3% of patients receiving lurbinectedin with atezolizumab. The most frequent serious adverse reactions were thrombocytopenia (2.9%), pneumonia (3.7%), respiratory tract infection (2.5%) and dyspnoea (2.1%). Fatal adverse reactions occurred in 5% of patients receiving lurbinectedin with atezolizumab, in most cases due to pneumonia and other lung infections.

Treatment with lurbinectedin was permanently discontinued due to adverse reactions in 5.8% of patients who were receiving lurbinectedin in combination with atezolizumab. The most frequent adverse reaction requiring permanent discontinuation of lurbinectedin was neutropenia (1.7%).

Adverse reactions leading to interruption of lurbinectedin in patients who received lurbinectedin with atezolizumab occurred in 28.9% of patients; the most common adverse reactions leading to interruption were neutropenia (5.4%), anaemia (5.0%), fatigue* (4.6%) and thrombocytopenia (3.3%).

Dose reductions of lurbinectedin due to an adverse reaction in patients who received lurbinectedin with atezolizumab occurred in 16.1% of patients. The most frequent adverse reactions requiring dose reductions in patients who received lurbinectedin with atezolizumab included thrombocytopenia (4.1%), fatigue* (3.3%), nausea (2.1%) and vomiting (2.1%).

^* For Preferred Terms merged see footnote in the table below.

Tabulated list of adverse reactions

Adverse reactions reported in IMforte clinical study are listed by MedDRA System Organ Class and by frequency in the table below.

The frequencies of adverse reactions are based on all-cause adverse event frequencies identified in 242 patients exposed to lurbinectedin in combination with atezolizumab during a median treatment duration of 4.4 months in the clinical study IMforte. Additional adverse reactions were reported post-marketing.

Frequencies are defined as: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1 000 to <1/100); rare (≥1/10 000 to <1/1 000); very rare (<1/10 000); "not known (cannot be estimated from available data)". Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness.

Adverse reactions experienced by patients treated with lurbinectedin in combination with atezolizumab:

^a including, Urinary tract infection, Cystitis
^b including Skin infection, Cellulitis
^c frequency not known (cannot be estimated from available data), reported in port-marketing setting (information related to grade not available).
^d including Hypoesthesia, Neuropathy peripheral, Paraesthesia, Peripheral sensory neuropathy.
^e including Abdominal discomfort, Abdominal distension, Abdominal pain, Abdominal pain upper.
^f including Back pain, Musculoskeletal chest pain, Musculoskeletal pain, Myalgia, Neck pain, Pain
in extremity
^g including Asthenia, Fatigue.
h including Oedema, Oedema peripheral
ⁱ in few cases tissue necrosis was reported
^j including Alanine aminotransferase increased, Aspartate aminotransferase increased, Transaminases increased

Description of selected adverse reaction

Neutropenia

In IMforte, 25.2% of patients experienced neutropenia (all grades), 12.4% experienced Grade ¾ neutropenia, and 1.7% experienced febrile neutropenia and 0.4% sepsis. The median time to first onset of neutropenia* (all grade) was 10 (range: 7-29) days. The median duration was 11 (range: 1-196) days. Neutropenia* led to dose reduction or interruption in 1.7% or 5.4% of patients, respectively. Treatment was permanently discontinued in 1.7% of patients.

Hepatotoxicity

In IMforte, ALT increase was reported in 6.6% of patients (2.5% ≥Grade 3), while AST increase was reported in 7.0% of patients (1.2% ≥Grade 3). The median time to first onset of ALT increase (all grade) was 7 (range: 3-22) days. The median duration was 17 (range: 7-21) days. ALT increase led to dose reduction or interruption in 0.4% of patients each, respectively. The median time to first onset of AST increased (all grade) was 4 (range: 3-8) days. The median duration was 9 (range: 6-21) days. AST increased led to dose reduction in 0.8% of patients.

Rhabdomyolysis

Cases of rhabdomyolysis have been reported with post-marketing use of lurbinectedin. No fatal cases have been reported.

Extravasation

Cases of extravasation with local irritation have been uncommonly reported with post-marketing use of lurbinectedin. In a few cases, tissue necrosis requiring debridement was reported.

Tumour lysis syndrome

Cases of tumour lysis syndrome have been reported with post-marketing use of lurbinectedin.