Lurbinectedin with immunotherapy in extensive-stage small cell lung cancer: Current insights and future prospects—A systematic review.

Abstract

e20100 Background: Extensive-stage small cell lung cancer (ES-SCLC) is an aggressive malignancy with limited treatment options and a poor prognosis. Combining lurbinectedin (LUR), a novel RNA polymerase II inhibitor, with immunotherapy (IO) has emerged as a promising strategy to enhance therapeutic outcomes. This systematic review evaluates current evidence and ongoing trials of LUR-IO combinations in ES-SCLC. Methods: A systematic literature search was conducted in PubMed, Scopus, Cochrane Library, and ClinicalTrials.gov for studies published between January 2018 and the present, focusing on LUR combined with IO in ES-SCLC. The search yielded 120 articles, of which two open-label studies, LUPER/Phase I-II (NCT04358237) and 2SMALL/Phase I (NCT04253145), met the criteria and were included. Additionally, three ongoing trials investigating LUR-IO combinations were identified and included in this review for future perspectives. Results: A total of 54 patients from two studies investigating the role of LUR in combination with pembrolizumab and atezolizumab (ATZ) were included in this systematic review. The median age of pts ranges from 41-78 years, and 54% were male. 82.1% have ECOG status 1. Across both studies, 50% (n=27) had a platinum-free interval <90 days and 21.4% had brain metastases. Efficacy outcome shows an Overall response rate (ORR) of 46.4% (2 complete responses [CR] and 11 partial responses [PR]) and 57.7% (2 CR and 13 PR) in LUPER AND 2SMALL studies, respectively. Stable disease (SD) was observed in 14.3% of LUPER patients and 26.9% of 2SMALL patients, leading to disease control rates (DCR) of 60.7% and 80.8%, respectively. Median PFS was 5.3 months (95% CI: 2.7–12.0) in LUPER and 4.93 months (range: 3.37–7.67) in 2SMALL. Median OS was reported in LUPER as 11.1 months (95% CI: 6.9–NR), and the median duration of response (DoR) was 11.4 months (range: 0–21.2), with 7.1% achieving durable responses >12 months. Eight patients in 2SMALL were censored for progression. Neutropenia (>20 % and 42.86%) and Anemia (>20% and 19.05%) were the most common hematological adverse events in LUPER and 2SMALL, respectively. No treatment-related deaths occurred in either study. Dose-limiting toxicities (DLTs) in 2SMALL were noted in 20.83% of patients receiving LUR 3.2 mg/m² with atezolizumab, primarily due to febrile neutropenia (9.52%; 2/21) and prolonged Grade 4 neutropenia (9.52%; 2/21). Three ongoing trials (NCT04607954, NCT04253145, NCT06497530), including 230 recruiting patients and 30 not yet recruiting patients, are going to explore LUR combination with durvalumab, ATZ, and sarilumab, respectively. Conclusions: LUR-IO shows promising efficacy and manageable safety profiles in extensive-stage small-cell lung cancer. However, further results from ongoing trials are essential to understand its long-term potential and broader applicability better.