Statistical analysis
REGRESSION, EVENTS
The planned sample size was 540 patients, with 339 PFS events and 388 OS events needed to achieve a power of 80% to show an HR of 0.68 for PFS at a one-sided α level of 0.005 and an HR of 0.73 for OS at a one-sided α level of 0.02 for comparison between the serplulimab plus chemotherapy group and the placebo plus chemotherapy group. The primary efficacy analyses were conducted in the ITT population. All randomized patients who received at least one dose of study medication were included in the analysis of safety. The Kaplan–Meier method was used to estimate OS, PFS and DOR. The reverse Kaplan–Meier method was used to estimate the median follow-up duration. Between-group differences in OS and PFS were assessed using the stratified log-rank test and the Cox proportional hazards model. The Schoenfeld residual test was planned to check the proportional hazard assumption. Differences in ORR were assessed using the Cochran–Mantel–Haenszel test and logistic regression.The statistical analysis plan specified one interim analysis and a final analysis of OS. The interim analysis of OS was planned to be performed during the final analysis of PFS, when approximately 339 IRRC-assessed PFS events had been observed in the ITT population.The protocol prespecified two primary hypotheses that were tested in parallel: (1) the superiority of serplulimab plus chemotherapy over placebo plus chemotherapy for PFS (assessed by the IRRC in accordance with RECIST v1.1) in all randomized patients; and (2) the superiority of serplulimab plus chemotherapy over placebo plus chemotherapy for OS in all randomized patients. The study was considered successful if serplulimab plus chemotherapy was superior to placebo plus chemotherapy for any primary endpoint. The threshold for statistical significance was 0.01 (two-sided) for the final log-rank analysis of PFS and 0.01 (two-sided) for the interim log-rank analysis of OS (adjusted according to the actual 266 OS events and O’Brien–Fleming-like α-spending function). An O’Brien–Fleming-like α-spending function (Lan–DeMets approximation) was used to control the overall type I error rate. The significance level for each analysis could be modified based on the actual number of PFS and OS events reached at the analytical time point.The independent data monitoring committee confirmed that the study met the specified efficacy endpoints after reviewing the results of the final analysis of PFS and the interim analysis of OS conducted by an unblinded external statistician. The trial is continuing in order to evaluate outcomes with additional follow-up. All data reported here are based on the interim analysis, with a data cutoff date of 15 April 2022. The statistical analysis plan is available in the Supplementary Information. Sample size calculation and statistical analyses were done using SAS (v9.4). This trial is registered with ClinicalTrials.gov (NCT03958890).