It was estimated that approximately 830 patients, including approximately 580 patients with PD-L1–positive tumors (70%), would undergo randomization. The overall type I error rate was maintained at or below a one-sided significance level of 0.025 by allocating an alpha level of 0.004 to the progression-free survival comparison and an alpha level of 0.021 to the overall survival comparison among the patients with PD-L1–positive tumors. A gatekeeping procedure to control for the overall type I error rate was used to allow further testing of progression-free and overall survival in the overall population (Fig. S1 in the Supplementary Appendix ). The trial was considered to have met its success criteria if avelumab plus axitinib was superior to sunitinib in prolonging progression-free or over-all survival among the patients with PD-L1–positive tumors. Sensitivity analyses were also performed to explore the robustness of the primary analysis results.
For the primary analysis of progression-free survival among the patients with PD-L1–positive tumors, we estimated that 336 events would provide the trial with 90% power to detect a hazard ratio of 0.65 with the use of a one-sided log-rank test at a significance level of 0.004. A two-look group-sequential design with a Lan–DeMets (O’Brien–Fleming) alpha-spending function was used to determine the efficacy boundary.21 For the primary analysis of overall survival among the patients with PD-L1–positive tumors, we estimated that 368 events would provide the trial with 90% power to detect a hazard ratio of 0.70 with the use of a one-sided log-rank test at a significance level of 0.021. A four-look group-sequential design with a Lan–DeMets (O’Brien–Fleming) alpha-spending function was used to determine the efficacy boundary. This sample size would also allow assessment of progression-free and overall survival in the overall population. The preplanned interim analysis was based on a data-cutoff point of approximately 235 events of disease progression or death (70% information fraction) in the patients with PD-L1–positive tumors. The results of the interim analysis were reviewed by an external data monitoring committee on August 20, 2018. The committee reported that the efficacy boundaries for progression-free survival among the patients with PD-L1–positive tumors and in the overall population had been crossed. The trial continued to evaluate overall survival. All data reported here are based on the first interim analysis.
Efficacy end points were assessed in all patients who underwent randomization, and safety was evaluated in all patients who received at least one dose of a trial drug (avelumab, axitinib, or sunitinib). We calculated the objective response rate according to treatment group, along with corresponding exact two-sided 95% confidence intervals, using the Clopper–Pearson method.22 Progression-free and overall survival and duration of response were estimated with the use of the Kaplan–Meier method, and two-sided P values are reported.23 To account for the group-sequential design in this trial, the repeated confidence interval method24 was used for the hazard ratio at the interim analysis for progression-free survival and overall survival. In addition, the unadjusted 95% confidence interval for the hazard ratio was reported.
For the primary analysis of progression-free survival among the patients with PD-L1–positive tumors, we estimated that 336 events would provide the trial with 90% power to detect a hazard ratio of 0.65 with the use of a one-sided log-rank test at a significance level of 0.004. A two-look group-sequential design with a Lan–DeMets (O’Brien–Fleming) alpha-spending function was used to determine the efficacy boundary.21 For the primary analysis of overall survival among the patients with PD-L1–positive tumors, we estimated that 368 events would provide the trial with 90% power to detect a hazard ratio of 0.70 with the use of a one-sided log-rank test at a significance level of 0.021. A four-look group-sequential design with a Lan–DeMets (O’Brien–Fleming) alpha-spending function was used to determine the efficacy boundary. This sample size would also allow assessment of progression-free and overall survival in the overall population. The preplanned interim analysis was based on a data-cutoff point of approximately 235 events of disease progression or death (70% information fraction) in the patients with PD-L1–positive tumors. The results of the interim analysis were reviewed by an external data monitoring committee on August 20, 2018. The committee reported that the efficacy boundaries for progression-free survival among the patients with PD-L1–positive tumors and in the overall population had been crossed. The trial continued to evaluate overall survival. All data reported here are based on the first interim analysis.
Efficacy end points were assessed in all patients who underwent randomization, and safety was evaluated in all patients who received at least one dose of a trial drug (avelumab, axitinib, or sunitinib). We calculated the objective response rate according to treatment group, along with corresponding exact two-sided 95% confidence intervals, using the Clopper–Pearson method.22 Progression-free and overall survival and duration of response were estimated with the use of the Kaplan–Meier method, and two-sided P values are reported.23 To account for the group-sequential design in this trial, the repeated confidence interval method24 was used for the hazard ratio at the interim analysis for progression-free survival and overall survival. In addition, the unadjusted 95% confidence interval for the hazard ratio was reported.
