Extensive-stage small cell lung cancer (ES-SCLC) - combination treatment

Active Ingredient: Lurbinectedin

Indication for Lurbinectedin

Population group: only adults (18 years old or older)

Therapeutic intent: Curative procedure

Lurbinectedin, in combination with atezolizumab, is indicated for the maintenance treatment of adult patients with extensive-stage small cell lung cancer (ES-SCLC) whose disease has not progressed after first-line induction therapy with atezolizumab, carboplatin and etoposide.

For this indication, competent medicine agencies globally authorize below treatments:

3.2 mg/m² every 21 days

For:

Dosage regimens

Intravenous, 3.2 milligrams lurbinectedin per square meter of body surface, once every 21 days.

Detailed description

The recommended dose of lurbinectedin is 3.2 mg/m² every 21 days until disease progression or unacceptable toxicity when it is administered in combination with atezolizumab.

When administering lurbinectedin on the same day, atezolizumab should be administered first.

For the recommended intravenous or subcutaneous dose of atezolizumab, as well as for recommendations regarding dose modification due to toxicity, refer to their prescribing information.

Treatment with lurbinectedin should be initiated only if absolute neutrophil count (ANC) is at least 1.5 x 10⁹/L and platelet count is at least 100 x 10⁹/L.

Treatment continuation and treatment delays

Further treatment cycles (i.e., cycle 2 or subsequent) will be administered every 21 days if the patient fulfils all the treatment continuation criteria listed above (see also Table 2 for dose modifications criteria for lurbinectedin adverse reactions).

If a patient does not meet the requirements for treatment continuation on Day 1 of any cycle after Cycle 1, treatment will be withheld until appropriate recovery, for a maximum of 21 days after the treatment due date. If there is no recovery after a 21-days delay, treatment must be stopped.

In case atezolizumab is discontinued due to an immune-related severe adverse reaction, treatment with lurbinectedin may be continued at its current dose as a single agent. If immune toxicity re-occurs despite discontinuation of atezolizumab, treatment with lurbinectedin should also be discontinued.

Pre-infusion medicinal products

The following pre-infusion medicinal products should be administered for antiemetic prophylaxis:

Corticosteroids (intravenous dexamethasone 8 mg or equivalent)
Serotonin antagonists (intravenous ondansetron 8 mg or equivalent)

Post-infusion medicinal products

Primary prophylaxis with granulocyte colony-stimulating factor (G-CSF) is recommended to reduce the risk of severe neutropenia/febrile neutropenia.

If needed, post-medication can include administration of extended antiemetic treatment for 2 days:

Corticosteroids (oral dexamethasone 4 mg or equivalent), or
Serotonin antagonists (oral ondansetron 8 mg or equivalent) or
Metoclopramide (intravenous or oral 10 mg or equivalent every 8 hours)

Dose adjustment for adverse reactions

The recommended dose reductions for adverse reactions are listed in Table 1.

Table 1. Dose reduction for lurbinectedin for adverse reactions:

Recommended starting dose	1^st Dose reduction	2^nd Dose reduction	3^rd Dose reduction
3.2 mg/m²	2.6 mg/m²	2.0 mg/m²	Stop
1.6 mg/m²*	1.3 mg/m²	1.0 mg/m²	Stop

^* Dose reduction schedule applicable to the 50% reduced dose (i.e., 1.6 mg/m²) used in cases of moderated hepatic impairment or co-administration with strong or moderate CYP3A inhibitors.

The recommended dose modifications for adverse reactions are presented in Table 2.

Table 2. Dose modifications criteria for lurbinectedin for adverse reactions:

Adverse reaction	Severity^a	Dose modification
Neutropenia^b	Grade 4 OR any grade febrile neutropenia OR associated with infection/sepsis at any grade	• Withhold lurbinectedin until Grade ≤1 and resolution of any associated fever/infection/sepsis, AND • Resume lurbinectedin at a reduced dose^b
Thrombocytopenia	Grade 3 with bleeding OR Grade 4	• Withhold lurbinectedin until platelet ≥100 x 10⁹/L, AND • Resume lurbinectedin at reduced dose
Hepatotoxicity and other adverse reactions	Grade 2	• Withhold lurbinectedin until Grade ≤1 (for AST and ALT until ≤3 ULN), AND • Resume lurbinectedin at same dose
Hepatotoxicity and other adverse reactions	Grade ≥3	• Withhold lurbinectedin until Grade ≤1 (for AST and ALT until ≤3 ULN). AND • Resume lurbinectedin at reduced dose
Rhabdomyolysis	Grade 2	• Withhold lurbinectedin until Grade ≤1, AND • Resume lurbinectedin at same dose
Rhabdomyolysis	Grade ≥3	• Permanently discontinue lurbinectedin
Non-haematological toxicity	Grade 2	• Withhold lurbinectedin until Grade ≤1, AND • Resume lurbinectedin at same dose
Non-haematological toxicity	Grade ≥3	• Withhold lurbinectedin until Grade ≤1, AND • Resume lurbinectedin at reduced dose
Tumour Lysis Syndrome	Grade 2	• Withhold lurbinectedin until Grade ≤1, AND • Resume lurbinectedin at same dose
Tumour Lysis Syndrome	Grade ≥3	• Permanently discontinue lurbinectedin
Any adverse reaction that requires frequent or prolonged (>2 weeks) dose delays	-	• Reduce the dose of lurbinectedin or discontinue

^a National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0.
^b Patients with isolated Grade 4 neutropenia (neutrophil count less than 500 cells/mm³) and who had not received G-CSF as primary prophylaxis, may receive G-CSF prophylaxis rather than undergo lurbinectedin dose reduction.

Dose adjustment for co-administration with strong or moderate CYP3A inhibitors

Co-administration of lurbinectedin with strong or moderate CYP3A inhibitors should be avoided. If co-administration cannot be avoided, 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 (see Table 1).

Active ingredient

Lurbinectedin
Lurbinectedin inhibits the oncogenic transcription process through (i) its binding to CG-rich sequences of DNA, located within promoters of protein-coding genes; (ii) the eviction of oncogenic transcription factors from their binding sites; and (iii) the stalling of elongating RNA polymerase II and its specific degradation by the ubiquitin/proteasome machinery with all these processes leading to subsequent cell cycle arrest and tumour cell apoptosis. Read more about Lurbinectedin

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