Background: Although the combination of an anti-PD-L1 antibody and platinum-based chemotherapy has become the standard care for ES-SCLC patients (pts), its safety and efficacy for those with a poor PS are unclear. Since SCLC is highly sensitive to chemotherapy, we hypothesized that ES-SCLC pts with a poor PS may benefit from anti-PD-L1 antibody therapy because tumor shrinkage by cytotoxic agents is expected to improve PS and tumor immune responses. This study aims to assess the safety and efficacy of durvalumab plus carboplatin (CBDCA) and etoposide (ETP) in ES-SCLC with a poor PS. Methods: This is an open-label, single-arm, multicenter phase II study. Previously untreated ES-SCLC pts with a poor PS (PS 2–3) were enrolled. Eligible pts received 1500 mg durvalumab plus CBDCA and ETP every 3 to 4 weeks for up to 4 cycles, followed by 1500 mg durvalumab every 4 weeks until progression or unacceptable toxicity. Initial dosages of CBDCA and ETP were AUC 4 and 80 mg/m² in PS 2 cohort and AUC 3 and 60 mg/m² in PS 3. The dosages for the second and subsequent cycles were adaptively determined based on the adverse events of the first cycle allowing for dose escalation to a maximum CBDCA AUC of 5 and ETP of 100 mg/m². The primary endpoint was the tolerability, which was evaluated based on the percentage of pts who completed four cycles of durvalumab plus CBDCA and ETP. The expected completion rates were 50% for each cohort, and the threshold completion rates were 33% for PS2 and 20% for PS3. Results: From April 2021 to October 2023, 57 pts (43 pts with PS 2 and 14 pts with PS 3) were enrolled. At data cutoff (Dec 31th, 2023), the median follow-up period was 7 months (range 1.1-32) in the ITT population. The median age is 74 years old (range 55-86), 79% male. 68% (80% CI, 56-77) in PS2 and 50% (80% CI, 27-73) in PS3 pts completed four cycles of durvalumab plus CBDCA and ETP. The ORRs in PS 2 and PS 3 were 52% (95% CI, 36-68) and 45% (95% CI, 17-77). The median PFSs in PS 2 and PS 3 were 4.7 months (95% CI, 3.8-6.4) and 5.1 months (95% CI, 1.4-10.6). The median OS in PS 2 and PS 3 were 9.5 months (95% CI, 6.6-26.7) and 5.1 months (95% CI, 1.4-not reached). The ratios of PS improvement in PS2 and PS3 were 57% (95% CI, 42-71) and 45% (95% CI, 21-72). Grade ≥3 adverse events (AEs) were reported in 93% in PS 2 and 100% in PS 3 pts, and 11 pts (20%) had discontinued study treatment due to AE. Conclusions: The current study met its primary endpoint. Durvalumab plus CBDCA and ETP showed tolerability and promising efficacy as first-line treatment for ES-SCLC pts with a poor PS. These data support the combination therapy of immune checkpoint inhibitor and chemotherapy with dosage adjustment for ES-SCLC with a poor PS. Clinical trial information: jRCTs031200319.