Axitinib

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.

The study design and patient eligibility criteria have been described in detail previously.^{2 (link)} Briefly, JAVELIN Renal 101 (NCT02684006) is a multicenter, randomized, open-label, phase 3 trial comparing avelumab + axitinib with sunitinib. Randomization (1:1) was stratified according to Eastern Cooperative Oncology Group performance status (ECOG PS) score (0 vs 1) and geographic region (United States vs Canada and Western Europe vs rest of the world). Eligible patients were aged ≥ 18 years (≥ 20 years in Japan) with previously untreated advanced RCC with a clear-cell component. Additional inclusion criteria included the presence of ≥1 measurable lesion according to the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1; ECOG PS score of 0 or 1; a fresh or archival tumor specimen; and adequate renal, cardiac, and hepatic function. Patients across all Memorial Sloan Kettering Cancer Center (MSKCC) and International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) prognostic risk groups were included.
The 2 independent primary end points were PFS as determined by blinded independent central review (BICR) according to RECIST 1.1 and overall survival in patients with PD-L1+ tumors (≥1% of immune cells staining positive within the tumor area of the tested tissue sample). PD-L1 expression was assessed at a central laboratory with the use of the Ventana PD-L1 (SP263) assay (Ventana Medical Systems). Key secondary end points were PFS as determined by BICR according to RECIST 1.1 and overall survival in patients in the overall population, irrespective of PD-L1 expression. Other secondary end points included investigator-assessed PFS, ORR, adverse events, pharmacokinetic measures, tumor tissue biomarkers, and patient-reported outcomes. All data are reported per investigator assessment, unless otherwise stated.
The trial was conducted in accordance with the ethics principles of the Declaration of Helsinki and the Good Clinical Practice guidelines, defined by the International Council for Harmonisation. All the patients provided written informed consent. The protocol, amendments, and informed-consent forms were approved by the institutional review board or independent ethics committee at each trial site. An independent external data monitoring committee reviewed efficacy and safety.