Abstract
Simple SummaryTreatment strategies in advanced, metastatic small cell lung cancer have been recently implemented by the combination of chemotherapy and immunotherapy. Nevertheless, the magnitude of survival benefit observed in clinical trials does not reproduce the major improvements observed in non-small cell lung cancer and other malignant diseases. By performing a systematic review and gathering the available data in a meta-analysis, we aim to compare the outcomes of patients treated with standard chemotherapy alone or with PD-1/PD-L1 inhibitors immunotherapy across clinical trials, in order to sustain treatment decisions. The addition of PD-1/PD-L1 inhibitors to standard chemotherapy improves all activity and efficacy outcomes, with a manageable safety profile. The benefit in overall survival is more evident if considering long-term analysis, compared to median estimations. Survival outcomes in extensive-stage small cell lung cancer (ES SCLC) are dismal, with median overall survival (OS) less than 12 months. The combination of PD-1/PD-L1 immune checkpoint inhibitors (ICIs) with first-line platinum-etoposide chemotherapy has been recently evaluated in randomized clinical trials. We performed a systematic literature review through PubMed and conference proceedings. Randomized trials evaluating chemotherapy +/− PD-1/PD-L1 ICIs were included in the meta-analysis. Efficacy (OS), activity [progression-free survival (PFS) and objective response rate (ORR)] outcomes and toxicities were analyzed. For selected endpoints, we focused on patients’ subgroups (OS) and on landmark analyses (OS, PFS). Four randomized trials were identified; globally, 1553 patients were randomized to receive chemotherapy +/− PD-1/PD-L1 ICIs. Adding a PD-1/PD-L1 ICI to chemotherapy led to a significant benefit in OS [hazard ratio (HR) 0.76, 95% confidence interval (CI) 0.68–0.85, p < 0.00001), PFS [HR 0.75, 95% CI 0.68–0.84, p < 0.00001] and ORR [odds ratio 1.28, 95% CI 1.04–1.57, p = 0.02]. No unexpected toxicity emerged. At 12, 18, 24 months for OS, and at 12, 18 months for PFS, experimental arms retained significant improvement in event-free rates, with absolute gain of approximately 10% compared with standard treatment. Albeit the magnitude of the benefit is less impacting compared to other settings of immunotherapy, the addition of PD-1/PD-L1 ICIs to chemotherapy in ES SCLC provided significant improvements in survival outcomes with the known toxicity profile. Biomarkers predicting which patients are suitable to derive long-term benefits are eagerly awaited.
Highlights
Small cell lung cancer (SCLC) is a poorly differentiated neuroendocrine neoplasm accounting for about 15% of lung malignancies [1]
Adding a PD-1/PD-L1 ICI to chemotherapy led to a significant benefit in overall survival (OS) [hazard ratio (HR) 0.76, 95% confidence interval (CI) 0.68–0.85, p < 0.00001), progression-free survival (PFS) [HR 0.75, 95% CI 0.68–0.84, p < 0.00001] and ORR [odds ratio 1.28, 95% CI 1.04–1.57, p = 0.02]
In the search performed in June 2020, three trials were found eligible for inclusion [22,23,24]
Summary
Small cell lung cancer (SCLC) is a poorly differentiated neuroendocrine neoplasm accounting for about 15% of lung malignancies [1]. Its peculiar clinical features are represented by the strong etiopathogenic association with smoking history, the central thoracic localization and the rapid proliferation index, impacting on the highly symptomatic forms often observed already at disease diagnosis [2]. SCLC high proliferation index defines this tumor as chemo- and radio-sensitive, as rapid, relevant and symptomatic disease regression with chemotherapy +/− radiotherapy are normally achieved (the combination of the two treatments being administered with curative intent in limited-stage forms, LS SCLC). In extensive-stage (i.e., metastatic, ES SCLC), disease progression is virtually unavoidable, with a median progression-free survival (PFS) shorter than six months [3]. Median overall survival (OS) estimations in clinical trials of ES SCLC are dismal, being approximately 10 months (since first-line initiation) [3]
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