Systematic Review and Network Meta-Analysis of Immune Checkpoint Inhibitors in Combination with Chemotherapy as a First-Line Therapy for Extensive-Stage Small Cell Carcinoma

Simple Summary Patients with extensive-stage small cell lung cancer (ED-SCLC) have a very short survival time even if they receive standard chemotherapy. Currently, the combination of chemotherapy plus immune checkpoint inhibitors (ICIs) as the first line treatment had superior survival than chemotherapy alone in randomized control trials. However, there is a lack of head-to-head comparisons for these combination regimens. We conducted a systematic review and network meta-analysis to provide a treatment ranking of ICIs for ED-SCLC. In summary, the probability of nivolumab was associated with the best ranking for overall survival, followed by atezolizumab, durvalumab, pembrolizumab, and ipilimumab. The ranking of progression free survival from the best to the worst was as follows: nivolumab, pembrolizumab, atezolizumab, durvalumab, and ipilimumab. However, nivolumab had the highest probability of grade 3-4 adverse events in our study. Further head-to head large-scale phase III randomized controlled studies are needed to verify our conclusions. Patients with extensive-stage small cell lung cancer (ED-SCLC) have a very short survival time even if they receive standard cytotoxic chemotherapy with etoposide and platinum (EP). Several randomized controlled trials have shown that patients with ED-SCLC who received a combination of EP plus immune checkpoint inhibitors (ICIs) had superior survival compared with those who received EP alone. We conducted a systematic review and network meta-analysis to provide a ranking of ICIs for our primary endpoints in terms of overall survival (OS), progression free survival (PFS), and objective response rate (ORR), as well as our secondary endpoint in terms of adverse events. The fractional polynomial model was used to evaluate the adjusted hazard ratios for the survival indicators (OS and PFS). Treatment rank was estimated using the surface under the cumulative ranking curve (SUCRA), as well as the probability of being best (Prbest) reference. EP plus nivolumab, atezolizumab or durvalumab had significant benefits compared with EP alone in terms of OS (Hazard Ratio HR = 0.67, 95% Confidence Interval CI = 0.46-0.98 for nivolumab, HR = 0.70, 95% CI = 0.54-0.91 for atezolizumab, HR = 0.73, 95% CI = 0.59-0.90 for durvalumab) but no significant differences were observed for pembrolizumab or ipilimumab. The probability of nivolumab being ranked first among all treatment arms was highest (SCURA = 78.7%, Prbest = 46.7%). All EP plus ICI combinations had a longer PFS compared with EP alone (HR = 0.65, 95% CI = 0.46-0.92 for nivolumab, HR = 0.77, 95% CI = 0.61-0.96 for atezolizumab, HR = 0.78, 95% CI = 0.65-0.94 for durvalumab, HR = 0.75, 95% CI = 0.61-0.92 for pembrolizumab), and nivolumab was ranked first in terms of PFS (SCURA = 85.0%, Prbest = 66.8%). In addition, nivolumab had the highest probability of grade 3-4 adverse events (SUCRA = 84.8%) in our study. We found that nivolumab had the best PFS and OS in all combinations of ICIs and EP, but nivolumab also had the highest probability of grade 3-4 adverse events in our network meta-analysis. Further head-to head large-scale phase III randomized controlled studies are needed to verify our conclusions.