Zepzelca (lurbinectedin)

Collectively, these findings reveal a previously unknown mechanism of action of ecteinascidins that merits further investigation for potential clinical applications in the treatment of MPM, as new first line treatment in monotherapy or in association with immunotherapy.

P3, N=180, Recruiting, Luye Pharma Group Ltd. | Not yet recruiting --> Recruiting

Interestingly, our study shows that lurbinectedin treatment upregulates MHC-I/II genes and CD8 in SCLC clinical samples. We provide mechanistic insights into the effect of lurbinectedin on STING-mediated multimodal immune activation and demonstrate that lurbinectedin treatment represents a promising therapeutic strategy to potentiate the efficacy of immunotherapy in SCLC.

P1/2, N=62, Active, not recruiting, Massachusetts General Hospital | Recruiting --> Active, not recruiting | Trial primary completion date: Jul 2024 --> Jul 2025

P1/2, N=0, Withdrawn, University of California, San Francisco | N=70 --> 0 | Not yet recruiting --> Withdrawn

P2, N=152, Not yet recruiting, VA Office of Research and Development

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

P1/2, N=70, Not yet recruiting, University of California, San Francisco | Trial completion date: Jul 2027 --> Oct 2027 | Initiation date: Jul 2024 --> Oct 2024 | Trial primary completion date: Jan 2026 --> May 2026

P1/2, N=28, Active, not recruiting, Antonio Calles Blanco | Trial completion date: Feb 2024 --> Mar 2025

P3, N=509, Active, not recruiting, Amgen | Recruiting --> Active, not recruiting

P2, N=0, Withdrawn, AdventHealth | N=36 --> 0 | Recruiting --> Withdrawn

Taken together, the data shows that (1) lurbinectedin combined with ipilimumab and nivolumab is a safe regimen with a MTD of 3.2 mg/m2 for lurbinectedin and (2) there were no serious treatment related adverse events reported. The phase II part of the study is currently open for previously untreated patient enrollment.

P2, N=9, Not yet recruiting, Cancer Institute and Hospital, Chinese Academy of Medical Sciences

P3, N=180, Not yet recruiting, Luye Pharma Group Ltd.

Current available treatments in the second-line setting are limited, and topotecan has long been the only FDA-approved drug in relapsed or refractory ES-SCLC, until the recent approval of lurbinectedin, a selective inhibitor of RNA polymerase II. Several studies have revealed the synergistic activity of temozolomide with poly-ADP-ribose polymerase (PARP) inhibitors, that prevent repair of TMZ-induced DNA damage. This review focuses on the rationale for the use of TMZ in ES-SCLC and provides an overview of the main trials that have evaluated and are currently investigating its role, both as a single-agent and in combinations, in relapse or refractory disease.

P2, N=30, Recruiting, UNC Lineberger Comprehensive Cancer Center | Trial completion date: Jul 2026 --> Dec 2027 | Trial primary completion date: Jul 2024 --> Dec 2025

P3, N=468, Recruiting, Daiichi Sankyo | Not yet recruiting --> Recruiting

We report a patient with SCBC who achieved an objective and prolonged response to lurbinectedin, which has been approved for metastatic small cell lung cancer, after developing disease progression on cisplatin/etoposide and nivolumab/ipilimumab. A repeat biopsy following the development of lurbinectedin resistance showed a new actionable ERBB2 alteration without significant change in the tumor mutation burden (six mutations/Mb). The present report suggests that lurbinectedin may be active and should be further explored in SCBC harboring TP53 mutations and amplifications in E2F3 and MYC family complexes.

P1, N=32, Completed, Luye Pharma Group Ltd. | Recruiting --> Completed | Trial completion date: Dec 2024 --> Nov 2023 | Trial primary completion date: Dec 2024 --> Nov 2023

Flow cytometric analyses further confirm the induction of cellular death in lung cancer cells following administration of the nanoformulation. Our findings show that quercetin/lurbinectedin-loaded GO NPs may be a promising lung cancer treatment, opening new avenues for targeted and effective therapies.

P2, N=0, Withdrawn, Institut Bergonié | N=82 --> 0 | Trial completion date: Apr 2026 --> May 2024 | Recruiting --> Withdrawn | Trial primary completion date: Oct 2024 --> May 2024

P2/3, N=360, Recruiting, PharmaMar | N=240 --> 360

P1/2, N=120, Recruiting, National Cancer Institute (NCI) | N=75 --> 120

P3, N=705, Recruiting, PharmaMar | Trial completion date: Jun 2025 --> Apr 2026 | Trial primary completion date: Jun 2025 --> Apr 2026

P1/2, N=320, Recruiting, PharmaMar | Trial completion date: Nov 2023 --> Mar 2026 | Trial primary completion date: Nov 2023 --> Mar 2026

P1/2, N=15, Not yet recruiting, Vall d'Hebron Institute of Oncology

P1/2, N=70, Not yet recruiting, University of California, San Francisco | Trial completion date: Oct 2031 --> Jul 2027 | Initiation date: Apr 2024 --> Jul 2024 | Trial primary completion date: Oct 2026 --> Jan 2026

P3, N=468, Not yet recruiting, Daiichi Sankyo | Trial completion date: Jan 2028 --> Feb 2029 | Trial primary completion date: Jul 2026 --> Apr 2027

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)