Background: Chemotherapy plus immunotherapy (CT-IO) is now the standard first-line for ES-SCLC patients (pts). The impact of prior IO on 2L therapies remains unclear. This study aims to assess the real-word efficacy of 2L therapies in ES-SCLC pts, previously treated with CT-IO. Methods: All patients from 8 French hospitals initially treated with CT-IO were screened, and those who received 2L after progression were included and divided into 3 groups: platinum-based, lurbinectedin or others (topotecan, cyclophosphamide/adriamycine/vincristine or taxanes). We assessed overall survival (OS) from 2L initiation, 2L progression-free survival (2L-PFS) and objective response rate (ORR), considering treatment group and treatment free-interval (TFI) < or ≥ 90 days (platinum-resistant and platinum-sensitive, respectively). The aim was not to compare efficacy between groups, given significant inherent selection biases. Results: Of the 132 screened ES-SCLC pts, 72 received 2L. At 2L initiation, median age was 67.0, 31.9% had a Performans Status (PS) ≥ 2, 40% had brain progression at 1L, with half of them undergoing brain radiotherapy. Regarding TFI, 66.7% were platinum-sensitive and 33.3% platinum-resistant. Only 5 pts had a TFI > 180 days. Platinum-doublet was the 2L for 33/72 (45.8%), lurbinectedin for 17/72 (23.6%) and others for 22/72 (30.6%). Pts with a TFI ≥ 90 days mainly received platinum rechallenge (30/48, 62.5%), while those with a TFI < 90 days received lurbinectedin (41.7%) or others (45.8%). With a median follow-up of 17.3 months, the median OS was 4.8 months (95%CI, 1.7-7.9) and 6.1 months (95%CI, 5.0-8.2) for platinum-resistant and platinum-sensitive, respectively. Median OS was 7.9 months (95%CI, 5.7-11.8) with platinum rechallenge, 4.5 months (95%CI, 3.0-6.8) with lurbinectedin and 4.7 months (95%CI, 2.0-6.3) with other chemotherapies (log rank p = 0.02). Median 2L-PFS was 1.8 months (95%CI, 1.2-4.5) and 3.7 months (95%CI, 2.8-6.0) for platinum-resistant and platinum-sensitive, respectively. Median 2L-PFS was 4.6 months (95%CI, 3.2-7.5) with platinum rechallenge, 2.5 months (95%CI, 1.6-4.7) with lurbinectedin and 1.9 months (95%CI, 1.4-3.8) with other chemotherapies (log rank p = 0.024). The 6-months PFS in platinum-sensitive pts was 45.6%/16.7%/11.1% with platinum/lurbinectedin/other respectively. ORR was 61%/23%/18% with platinum/lurbinectedin/other respectively. Conclusions: Platinum rechallenge following first-line CT-IO showed noteworthy results within a real-word ES-SCLC population, including patients with altered PS and brain metastases. 2L lurbinectedin efficacy appeared limited, similar to other platinum-free regimens, yet I was mostly used in platinum-resistant pts. Further data is needed to explore the potential of first-line IO in enhancing sensitivity to platinum rechallenge.