Zepzelca (lurbinectedin)

P1/2, N=62, Recruiting, Massachusetts General Hospital | Phase classification: P1b/2 --> P1/2

P=N/A, N=300, Recruiting, Jazz Pharmaceuticals | Active, not recruiting --> Recruiting | Trial completion date: Jan 2026 --> Jun 2030 | Trial primary completion date: Oct 2025 --> Jun 2030

P2, N=35, Recruiting, National Cancer Institute (NCI) | Not yet recruiting --> Recruiting

P1, N=9, Terminated, H. Lee Moffitt Cancer Center and Research Institute | Phase classification: P1/2 --> P1

As single agent, M1774 suppressed cancer cell viability at nanomolar concentrations, showing greater activity than ceralasertib and berzosertib, but less potency than gartisertib and elimusertib in the small-cell lung cancer H146, H82, and DMS114 cell lines. Low dose of M1774 was found highly synergistic with a broad spectrum of clinical DDAs including TOP1 inhibitors (SN-38/irinotecan, topotecan, exatecan, and exatecan), the TOP2 inhibitor etoposide, cisplatin, the RNA polymerase II inhibitor lurbinectedin, and the PARP inhibitor talazoparib in various models including cancer cell lines, patient-derived organoids, and mouse xenograft models. Furthermore, we demonstrate that M1774 reverses chemoresistance to anticancer DDAs in cancer cells lacking SLFN11 expression, suggesting that SLFN11 can be utilized for patient selection in upcoming clinical trials.

P=N/A, N=300, Active, not recruiting, Jazz Pharmaceuticals | Recruiting --> Active, not recruiting

In the SAINT phase 2 study using ipi, nivo and trabectedin as first line therapy for advanced soft tissue sarcomas (STS; n=79), there were 6 complete responses, 14 partial responses, 49 stable disease, 25.3% best response rate, 87.3% disease control rate; median PFS, 6.7 months, median OS, 24.6 months (Gordon et al, Cancers vol. Eligible patients are 18 years of age or older, previously treated in phase 1 and previously untreated in phase 2 with confirmed diagnosis of advanced STS, adequate hematologic and organ function, and no history of autoimmune disorder. To date, 6 patients in phase 1 have been dosed.

P2, N=47, Completed, Jazz Pharmaceuticals | Active, not recruiting --> Completed

No differences in terms of toxicity were found between LRB with and without BOS. In summary, the magnitude of the observed changes precludes a clinically relevant effect of BOS co-administration on LRB exposure and its safety profile.

P3, N=490, Recruiting, Amgen | N=700 --> 490 | Trial primary completion date: Sep 2025 --> Aug 2027

P1/2, N=28, Active, not recruiting, Antonio Calles Blanco | Trial primary completion date: Feb 2024 --> Sep 2023

P3, N=690, Active, not recruiting, Hoffmann-La Roche | Recruiting --> Active, not recruiting

This review delves into the current and evolving treatment landscape for ES-SCLC, focusing on the most promising therapeutic strategies under investigation. We discuss the latest developments in the use of newer ICIs, antiangiogenic agents, PARP inhibitors (PARPi), lurbinectedin, and anti-DLL3 agents, offering insights into potential future directions in the management of this aggressive cancer.

P2, N=35, Not yet recruiting, National Cancer Institute (NCI)

P1/2, N=70, Not yet recruiting, University of California, San Francisco

P3, N=468, Not yet recruiting, Daiichi Sankyo, Inc.

P3, N=700, Recruiting, Amgen | Trial primary completion date: Nov 2024 --> Sep 2025

P3, N=705, Recruiting, PharmaMar

P2, N=47, Active, not recruiting, Jazz Pharmaceuticals | Trial primary completion date: Nov 2023 --> Mar 2024

P1/2, N=75, Recruiting, National Cancer Institute (NCI) | Trial completion date: Dec 2026 --> Dec 2027 | Trial primary completion date: Aug 2025 --> Aug 2026

P2/3, N=240, Recruiting, PharmaMar | Phase classification: P2b/3 --> P2/3

P2/3, N=240, Recruiting, PharmaMar

P1, N=34, Recruiting, M.D. Anderson Cancer Center | Not yet recruiting --> Recruiting | Phase classification: P1b --> P1

P1b/2, N=62, Recruiting, Massachusetts General Hospital | Trial completion date: Jan 2025 --> Jul 2025 | Trial primary completion date: Jan 2024 --> Jul 2024

P2, N=82, Recruiting, Institut Bergonié | Not yet recruiting --> Recruiting

 These findings suggest improved OS with lurbinectedin monotherapy versus the historical standard of care in Alberta, Canada.

This analysis confirms a manageable safety profile for lurbinectedin in patients with advanced solid tumours. Findings are consistent with those reported in patients with relapsed SCLC, Ewing sarcoma, germline BRCA1/2 metastatic breast cancer, neuroendocrine tumours and ovarian cancer.

Our study provides a mechanistic insight into lurbinectedin response in SCLC and the first demonstration that lurbinectedin is a potential therapeutic target after SCLC transformation.

The management paradigm of advanced/metastatic EP-NEC has been extrapolated from small cell lung cancer (SCLC) and commonly consists of 1st line therapy with etoposide and platinum (cisplatin or carboplatin), followed by alternative cytotoxic regimens at the time of progression. Only a minority of patients are able to receive 2nd line therapy, and cytotoxics derived from the SCLC paradigm such as topotecan or lurbinectedin have very limited activity...After a long period of stagnation in treatment options and outcomes, more promising regimens are gradually being utilized in the 2nd line setting including systemic therapy combinations such as FOLFIRI, FOLFOX, modified FOLFIRINOX, CAPTEM, and, more recently, novel checkpoint inhibitors such as nivolumab and ipilimumab. Simultaneously, advances in the understanding of disease biology are helping to refine patient selection and identify commonalities between NEC and their sites of origin which may eventually lead to additional targeted therapy options. While many questions remain, contemporary developments give grounds for optimism that improved outcomes for EP-NEC will soon be within reach.

Importantly, MYC-driven non-neuroendocrine tumors which are resistant to first-line therapies show reduced CDKN1A/p21 expression and increased ERCC5/XPG indicating they are primed for response to lurbinectedin-berzosertib combination. The combination is being assessed in a clinical trial NCT04802174.

P2, N=47, Active, not recruiting, Jazz Pharmaceuticals | Recruiting --> Active, not recruiting

P1/2, N=56, Recruiting, Children's Hospital of Philadelphia | Not yet recruiting --> Recruiting

Lurbinectedin, metformin, celecoxib, and 5-azacytidine have reported preclinical effects on MDSC and clinical evidence in OC. They have all been approved for a different indication, characterizing them as the most promising candidates for repurposing to treat patients with OC.

P2, N=106, Recruiting, Mayo Clinic | Trial completion date: Nov 2024 --> Nov 2025 | Trial primary completion date: Nov 2023 --> Nov 2024

Recent and ongoing examples of multi-site studies include EGFR Exon 20 mutation clinicopathology and treatment outcomes, intracranial outcomes in first-line chemoimmunotherapy, outcomes after long-term immunotherapy, ROS1 study demonstrating near 50% thrombosis rate in real-world treatment settings, real-world experiences of newly approved therapeutics (IMpower150, Lorlatinib, Lurbinectedin, Ipilimumab/Nivolumab) demonstrating translation of trial outcomes to the general population, and dynamic profiling of ctDNA in ALK-positive NSCLC and CTCs in SCLC to evaluate impact on treatment outcomes and clinical decision making. The AURORA platform effectively and efficiently captures RWD and generates RWE at a national level, with a framework encouraging of international collaboration. The prospective cohort provides highly granular information to completement clinical quality and population registries. It provides value to investigators through data ownership, flexible contribution and networking for research collaborations, and to industry through cost-effective targeted real-world investigations.

ATLANTIS was a phase 3 study in SCLC with lurbinectedin 2.0 mg/m plus doxorubicin 40 mg/m q3wk vs physician's choice, with overall survival (OS) as the primary endpoint and objective response rate (ORR) as the secondary endpoint. Head-to-head comparisons with predicted 3.2 mg/m lurbinectedin resulted in a positive outcome in ATLANTIS, with hazard ratio (95% prediction intervals [95% PI]) for OS of 0.54 (0.41, 0.72), and odds ratio (95% PI) for ORR of 0.35 (0.25, 0.5). These results support the superiority of lurbinectedin monotherapy for relapsed SCLC over other approved therapies.

P1/2, N=56, Not yet recruiting, Children's Hospital of Philadelphia

No abstract available

P1/2, N=40, Recruiting, ERLINDA M GORDON | Not yet recruiting --> Recruiting

P3, N=700, Recruiting, Amgen | Not yet recruiting --> Recruiting

P1/2, N=40, Not yet recruiting, ERLINDA M GORDON

In platinum-sensitive patients, lurbinectedin demonstrated a survival benefit and favorable safety profile versus oral and IV topotecan and platinum re-challenge (overall survival, hazard ratio [HR]: 0.43; 95% credible interval [CrI]: 0.27, 0.67; HR: 0.43; 95% CrI: 0.26, 0.70; HR: 0.42; 95% CrI: 0.30, 0.58 respectively). Lurbinectedin showed a robust survival benefit and favorable safety versus other SCLC treatments in 2L platinum-sensitive SCLC.