Lurbinectedin

Chakraborty S, et al. Cell Reports Medicine, 2024, 5(12), 101852.

In this study, lurbinectedin was evaluated for its immunomodulatory effects in small-cell lung cancer (SCLC) models, particularly in the context of PD-L1 blockade. Experimental data demonstrated that lurbinectedin induces DNA damage, generating cytoplasmic DNA fragments that activate the STING (stimulator of interferon genes) pathway. This activation led to a robust tumor-intrinsic type I interferon response, upregulation of MHC-I molecules, and increased expression of damage-associated molecular patterns (DAMPs). In vivo studies in SCLC mouse models showed that lurbinectedin treatment significantly enhanced the anti-tumor efficacy of PD-L1 blockade, resulting in pronounced tumor regression. Immune profiling revealed increased infiltration of CD8⁺ T cells and M1 macrophages, with concurrent suppression of immunosuppressive M2 macrophages. Depletion experiments confirmed that both STING signaling and CD8⁺ T cells were critical to the observed therapeutic synergy. Furthermore, lurbinectedin upregulated MHC-I/II and CD8 expression in clinical SCLC samples, highlighting its translational potential as an immunotherapeutic sensitizer.

Singh A, et al. JTO Clinical and Research Reports, 2025, 6(6), 100807.

In this clinical case series, its application was explored in the context of histologically transformed SCLC derived from EGFR-mutated non-small cell lung cancer (NSCLC), a rare and aggressive resistance mechanism observed in patients previously treated with third-generation EGFR tyrosine kinase inhibitors such as osimertinib.
Three patients with documented transformation from EGFR-mutated NSCLC to SCLC were enrolled. Upon progression, each received combination therapy with lurbinectedin (administered intravenously at standard dosing) alongside continuous osimertinib. The objective was to target both the newly acquired neuroendocrine phenotype via lurbinectedin's DNA-binding cytotoxic mechanism and retain EGFR pathway suppression through osimertinib. Safety and tolerability were assessed through regular hematologic profiling and adverse event monitoring, while response was evaluated via RECIST criteria using serial CT imaging. Despite the small sample size, the dual-agent regimen demonstrated manageable toxicity and signs of clinical stability, underscoring the therapeutic potential of lurbinectedin in this niche setting.

Calles A, et al. Journal of Thoracic Oncology, 2025.

In the Phase I/II LUPER study (NCT04358237), lurbinectedin was experimentally combined with pembrolizumab to evaluate its efficacy and safety in relapsed small cell lung cancer (SCLC) patients without prior immunotherapy exposure. Phase I established the recommended phase II dose as 3.2 mg/m² lurbinectedin and 200 mg pembrolizumab, administered intravenously every three weeks. In Phase II, 28 patients-including 50% platinum-resistant cases-were enrolled. The primary endpoint, objective response rate (ORR), reached 46.4%, with three complete responses, including two complete metabolic responses post-therapy (35 cycles). The median response duration was 7.8 months, and 40% sustained response for over 12 months. Stratification revealed significantly superior progression-free survival (8.0 vs. 2.8 months, p = 0.012) and numerically improved overall survival in platinum-sensitive patients. Grade ≥3 adverse events, primarily transient neutropenia, occurred in 71.4% of participants. These findings underscore the potential of lurbinectedin as a combinatorial agent with immune checkpoint inhibitors for durable responses in relapsed SCLC.

Peters S, et al. Lung Cancer, 2024, 188, 107448.

In a post hoc subgroup analysis from a phase 2 Basket study, lurbinectedin was evaluated for efficacy and safety in patients with extensive-stage small cell lung cancer (SCLC) exhibiting a chemotherapy-free interval (CTFI) ≥30 days and no central nervous system (CNS) metastases. This cohort (n=98) was indirectly compared to a matched population receiving topotecan in the phase 3 ATLANTIS trial. Lurbinectedin was administered intravenously at 3.2 mg/m² every 21 days. Key experimental endpoints included overall response rate (ORR), duration of response (DoR), and overall survival (OS), assessed via investigator assessment (IA) and Independent Review Committee (IRC). Lurbinectedin demonstrated superior ORR (IA: 41.0% vs. 25.5%), prolonged DoR (IA: 5.3 vs. 3.9 months), and improved median OS (10.2 vs. 7.6 months) versus topotecan. Hematologic toxicities were notably lower with lurbinectedin. These findings support lurbinectedin as a safer, more effective option in pre-treated SCLC patients with CTFI ≥30 days and no CNS involvement.