Efficacy and Safety of First-Line Immunotherapy in Combination with Chemotherapy for Patients with Extensive-Stage Small Cell Lung Cancer: A Systematic Review and Network Meta-Analysis

Abstract

Background: The prognosis of patients with extensive-stage small cell lung cancer (SCLC) is poor. Adding an immune checkpoint inhibitor (ICI) to chemotherapy may exert a synergistic effect and improve survival outcomes. However, for treatment-naive extensive-stage SCLC patients, the efficacy of immunotherapy in combination with cytotoxic chemotherapy remains controversial.

Objective: To evaluate the benefits and risks of the combination of immunotherapy and chemotherapy and to assess the comparative effectiveness of different first-line treatment strategies for extensive-stage SCLC.

Methods: PubMed, Web of Science, EMBASE, and Cochrane Library were searched for randomized clinical trials studying different immunotherapeutics for patients with previously untreated extensive-stage SCLC up to Feb 16, 2020. The primary outcomes were overall survival (OS) and progression-free survival (PFS), and the secondary outcomes were objective response rate (ORR), disease control rate (DCR), and adverse events.

Results: We identified 141 published records, and 4 studies (comprising 2202 patients) were included in the analysis. Immunotherapy (including ipilimumab, atezolizumab, and durvalumab) plus chemotherapy was associated with better OS (hazard ratio (HR) 0.84, 95% confidence interval (CI) 0.75-0.93; risk ratio (RR) 0.90, 95% CI 0.81-1.00) and PFS (HR: 0.81, 95% CI 0.74-0.88; RR 0.96, 95% CI 0.93-0.99) than placebo plus chemotherapy. The addition of immunotherapy to chemotherapy showed similar improvement in ORR, DCR, and adverse events versus placebo plus chemotherapy. On the surface under the cumulative ranking (SUCRA) analysis, the anti-PD-L1 agent, atezolizumab, had the highest likelihood of achieving improved OS (93.4%) and PFS (95.0%).

Conclusion: In the first-line setting, combining immunotherapy with chemotherapy is better than standard chemotherapy in terms of OS and PFS. Across the eligible studies, PD-L1 inhibitors might be preferred. Further explorations of more ICIs in the first-line treatment for extensive-stage SCLC patients should be needed.

Figure 1

Flow chart of the screening and selection process.

Figure 2

Meta-analyses of the hazard ratios for the included studies examining overall survival (a) and progression-free survival (b) for immunotherapy plus chemotherapy vs. chemotherapy alone. ATE: atezolizumab; DUR: durvalumab; IPI: ipilimumab; PLA: placebo. All these treatments were combined with chemotherapy. (a) indicates phased-IPI, and (b) indicates concurrent-IPI.

Figure 3

Network meta-analysis of comparisons on different outcomes of first-line treatments in different groups of small cell lung cancer patients. (a) Comparison of overall survival and progression-free survival. (b) Comparison of objective response rate and disease control rate. (c) Comparison of any grade and grade 3 or more adverse events. Direct comparisons are represented by the color lines connecting the treatments. Line width is proportional to the number of trials including every pair of treatments, whereas circle size is proportional to the total number of patients for each treatment in the network. ATE = atezolizumab; DUR = durvalumab; IPI = ipilimumab; PLA = placebo. All these treatments were combined with chemotherapy.

Figure 4

Risk ratios for the pairwise comparisons of the network meta-analysis. Direct and indirect comparisons should be read from left to right. For overall survival, progression-free survival, and adverse events, a risk ratio of less than 1 favors the left treatment. For the objective response rate and disease control rate, a risk ratio of less than 1 favors the right treatment. ATE indicates atezolizumab; DUR indicates durvalumab; IPI indicates ipilimumab; PLA indicates placebo. All these treatments were combined with chemotherapy.

Figure 5

Ranking probabilities of the different comparisons for overall survival (a), progression-free survival (b), objective response rate (c), and disease control rate (d). ATE means atezolizumab; DUR means durvalumab; IPI means ipilimumab; PLA means placebo. All these treatments were added to chemotherapy.

Figure 6

Risk of bias graph (a) and summary (b).