Background: Immunochemotherapy (ICT) is the standard first-line treatment for extensive stage (ES)-SCLC. However, progression-free survival for patients (pts) treated with ICT as first-line therapy is approximately 5 months, and half of the pts will relapse within 6 months. Several drugs have been approved for the treatment after relapse, and amrubicin has been used as a second-line treatment in Japan for 20 years. However, the efficacy of pts treated with amrubicin is unsatisfactory, the median survival was 9.2 months (pts with sensitive relapse (SR-pts)) and 2.6 months (pts with refractory relapse (RR-pts)), indicating an urgent need for new therapeutic strategies in the treatment of post-relapse SCLC pts. A retrospective study showed significant improvement in survival for patients who progress on immunochemotherapy, treated with same ICI plus chemotherapy as second-line therapy (Trans Lung Cancer Rec. 2020). Cytotoxic chemotherapy introduced immunogenic cell death and the addition of chemotherapy to ICI might have a synergistic effect. Based on these assumptions, the combination of amrubicin with ICI may provide additional benefit for post-progression pts and we are therefore initiating this study. Methods: This is an open-label, single-arm, multicenter, physician-initiated Phase 2 study of amrubicin plus durvalumab in Japanese pts with relapsed SCLC. The study is divided into a lead-in cohort (LIC) and a Phase 2 part; the LIC will use a 3+3 design to ensure safety and will proceed to the Phase 2 part if the first 3 pts have no dose limiting toxicity (DLT) or the first 6 pts have only 1 DLT. Eligibility criteria include pts with ES-SCLC who relapse after platinum-containing chemotherapy with durvalumab as first-line therapy, age ≥20, ECOG 0-1. The primary endpoint is 1-year survival. Patients were treated with intravenous amrubicin 40 mg/m2 on day 1-3 and durvalumab 1500 mg/body on day 1 every 3 weeks until PD or unacceptable toxicity. The planned number of pts was 18 each with sensitive relapse (SR-pts) and refractory relapse (RR-pts) which was calculated based on the results of a previous randomized controlled trial (J Clin Oncol. 2008). In this trial, the point estimates and two-sided 90% confidence intervals (Clopper Peason method) for 1-year survival corresponding to the expected 1-year survival were: SR-pts (11/18 patients): 0.611 (90% CI: 0.392-0.801), RR-pts (8/18 0.444 (90% CI: 0.244-0.659). Enrollment began in October 2022, and will be completed by March 2025. Clinical trial information: jRCT2061220036.