lurbinectedin — Drug Monograph

Brand names: Zepzelca

Drug class: Other

Mechanism of Action

Lurbinectedin is a selective inhibitor of oncogenic transcription through covalent binding to the minor groove of DNA at guanine residues flanking transcription factor binding sites, particularly those occupied by activated oncogenic transcription factors. This DNA adduct formation triggers double-strand breaks (DSBs) and stalls RNA polymerase II (RNAPII) elongation complexes, which are subsequently degraded by ubiquitin-proteasome pathways, depleting the RNAPII pool and globally suppressing transcription of oncogenic gene programs. Uniquely, lurbinectedin also induces apoptosis of…

FDA Indications

• Metastatic small cell lung cancer (SCLC) with disease progression on or after platinum-based chemotherapy — approved June 2020 under accelerated approval based on overall response rate (PM1183-B-005-13 basket trial)

Common Side Effects

• Myelosuppression — leukopenia (79%), neutropenia (75%), anemia (49%), thrombocytopenia (38%)
• Fatigue (78%)
• Nausea (37%)
• Decreased appetite (33%)
• Musculoskeletal pain (22%)
• Constipation (31%)
• Dyspnea (22%)
• Vomiting (22%)
• Peripheral edema (16%)
• Diarrhea (14%)
• Alopecia (10%)
• ALT/AST elevation (14%)
• Creatinine elevation (19%)

Clinical Pearl

Lurbinectedin received accelerated FDA approval based on a 35.2% overall response rate (ORR) and 5.3-month median duration of response in a single-arm basket trial, without a randomized confirmatory trial at time of approval — a confirmatory phase III trial (LAGOON) is ongoing to establish overall survival benefit. The drug demonstrates particularly meaningful activity in patients with a platinum-free interval ≥90 days (ORR ~45%), suggesting it may be most beneficial in the sensitive-relapse…

Related Therapies & Mechanisms

• Tarlatamab (Imdelltra) — Other · SCLC
• Adagrasib (Krazati) — Other
• Arsenic Trioxide (Trisenox) — Other
• Asparaginase (L-asparaginase, E. coli) (Elspar) — Other