Revisiting Platinum Sensitivity in Relapsed Small-Cell Lung Cancer: Outcomes of Platinum-Containing Doublet Chemotherapy in the 3–6 Month Relapse Window

Background: Second-line treatment selection in relapsed extensive-stage small-cell lung cancer (ES-SCLC) is commonly guided by the platinum-free interval, but the optimal approach for patients progressing 3–6 months after first-line platinum-based therapy remains uncertain. We compared platinum-containing doublet chemotherapy with single-agent chemotherapy in this clinically ambiguous subgroup. Methods: This multicenter retrospective real-world cohort study included patients with ES-SCLC or recurrent metastatic SCLC after prior limited-stage disease who received first-line platinum-based chemotherapy, achieved disease control, and progressed within a platinum-free interval of 90–180 days. Treatment allocation was at the discretion of the treating physician and was not randomized. The primary endpoint was progression-free survival (PFS); secondary endpoints were overall survival (OS), objective response rate (ORR), disease control rate (DCR), and safety. Because of the non-randomized design, the treatment effect was examined across multiple analytic approaches, including multivariable Cox regression, propensity score adjustment, and stabilized inverse probability of treatment weighting (IPTW). Results: Of 105 patients, 54 received single-agent chemotherapy and 51 received platinum-containing doublet therapy; 39 (37.1%) had received first-line atezolizumab. Baseline characteristics were imbalanced in favor of the doublet group, which had a longer platinum-free interval, fewer pleural metastases, and a higher rate of objective response to first-line therapy. ORR was higher with doublet therapy (31.4% vs. 11.1%, p = 0.016), as was DCR (62.7% vs. 33.3%, p = 0.003). Median PFS was 4.4 months (95% CI 3.4–5.8) with doublet therapy versus 3.1 months (95% CI 2.7–3.7) with single-agent chemotherapy (unadjusted HR 0.53, 95% CI 0.36–0.80; p = 0.002). Median OS was 6.5 months (95% CI 5.4–8.0) versus 5.4 months (95% CI 4.1–6.0), a difference that was not statistically significant (HR 0.68, 95% CI 0.46–1.01; p = 0.054). The PFS estimate favored doublet therapy in all sensitivity analyses but was attenuated with increasingly complete adjustment for treatment selection (multivariable HR 0.46, 95% CI 0.29–0.72; propensity-adjusted HR 0.58, 95% CI 0.38–0.88; IPTW HR 0.68, 95% CI 0.38–1.20, p = 0.184). No OS estimate reached statistical significance in any model. Grade ≥ 3 adverse events were similar between groups (66.7% vs. 64.8%, p = 0.842). Conclusions: In this non-randomized cohort of patients relapsing within a 90–180-day platinum-free interval, platinum-containing doublet chemotherapy was associated with higher response rates and longer PFS, without an increase in severe toxicity, but no overall survival benefit was demonstrated. Because baseline prognostic factors consistently favored the doublet group and the PFS advantage was attenuated after propensity-based adjustment, these findings should be regarded as hypothesis-generating. They are nonetheless consistent with randomized data showing improved PFS but not OS with platinum rechallenge, and support platinum-containing rechallenge as a reasonable option in carefully selected patients rather than as a demonstrated survival-prolonging strategy.