Abstract 5837: Lurbinectedin-induced transcriptional reprogramming: A pathway to sensitise SCLC to immunotherapy

Abstract Background: For decades, platinum-based chemotherapy plus etoposide (ChT+E) has remained unchallenged at the first-line treatment for extensive-stage-SCLC (ES-SCLC), that is, until the introduction of immune-checkpoint blockade (ICB) anti-PD-L1. ChT+E susceptibility of SCLC relies in the high genomic instability observed in SCLC, further increased by ChT+E and surpassing DNA Damage Repair (DDR) capabilities. In the context of DNA damage and cell-intrinsic immunity, the addition of ICB improves the response of SCLC to ChT+E through tumour immunogenicity. Although initially responding to treatment, almost all patients relapse within the first 6 months, leading to limited options at second-line treatment, Lurbinectedin (LUR) among them. While LUR acts by degrading RNA polymerase II and, therefore, inhibiting transcription, it also causes DNA damage synergising with ICB. 2SMALL is a phase 1/2 study assessing the safety, tolerability and efficacy of LUR plus atezolizumab (ATZ) as second-line treatment for ES-SCLC. Methods: 2SMALL Phase-I was a dose exploration trial combining increasing doses of LUR plus a fixed dose of ATZ every 3 weeks. Study endpoints included safety profile and LUR recommended dose, as well as, Objective Response Rate (ORR), Progression-Free Survival (PFS) and Overall Survival (OS). Pre-clinically, efficacy of LUR plus anti-PD-L1 mAb was evaluated in vivo in a syngeneic immunocompetent mice model for SCLC (Rb1-/-Trp53-/-), and in vitro/ex vivo in several SCLC cell lines and PDX-derived-spheroids. Results: LUR+ATZ was well tolerated, without unexpected toxicities. ORR were observed in 16/24 patients, including: 3/24 Complete Responses; 13/24 Partial Responses; 5/24 Stable Disease; and 3/24 Progressive Disease. Median PFS was 4.7 months (3.37-7.4) and median OS 14.5 months (9.5-23.4). In pre-clinical in vivo experiments, LUR+anti-PD-L1 achieved tumour rejection in 16/28 mice and 13/16 mice did not show tumour growth when exposed to a rechallenge. At the tumour, LUR increases Antigen Processing and Presentation (APP), activates IFN type-I signalling and promotes immune infiltration when combined with anti-PD-L1, particularly CD8+ T lymphocytes, at Tumour Immune Microenvironment (TIME). Finally, anti-tumour effect was mainly mediated by CD8+ T-cells. Conclusions: LUR+ATZ anti-tumour activity is remarkable both in patients and pre-clinical in vivo experiments. Our results show effective tumour-activating IFN type-I, which increases immunity against tumours and provides the rationale to combine LUR with ICBs. Citation Format: Joan Salvador Russo-Cabrera, Santiago Ponce-Aix, Patricia Cozar, Alicia Luengo, Belén Revuelta, Laura García-Redondo, Alejandro Navarro, Reyes Bernabé, María Eugenia Olmedo, José Manuel Trigo, Jon Zugazagoitia, Luis Paz-Ares, Itziar Otano. Lurbinectedin-induced transcriptional reprogramming: A pathway to sensitise SCLC to immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5837.