Patients

Eligibility criteria, as reported previously,18 included histologically or cytologically documented stage III, unresectable NSCLC according to the Staging Manual in Thoracic Oncology, version 7, of the International Association for the Study of Lung Cancer.21 Patients also had to have received at least two cycles of platinum-based chemotherapy (containing etoposide, vinblastine, vinorelbine, a taxane [paclitaxel or docetaxel], or pemetrexed) concurrently with definitive radiation therapy.18 Eligible patients must not have had progression after chemoradiotherapy and had to have received their last radiation dose within 1 to 42 days before randomization. (Details are provided in the Supplementary Methods section in the Supplementary Appendix, available with the full text of this article at NEJM.org.)

Trial Design and Interventions

This multicenter, randomized, double-blind, placebo-controlled, phase 3 trial was conducted at 235 investigative sites in 26 countries, including centers in Asia, Australia, Europe, North America, South America, and South Africa. Patients were randomly assigned in a 2:1 ratio to receive durvalumab intravenously, at a dose of 10 mg per kilogram of body weight, or matching placebo every 2 weeks up to 12 months or until confirmed disease progression, the initiation of alternative cancer therapy, unacceptable toxic events, or withdrawal of consent. Randomization was stratified according to age of the patient (<65 years vs. ≥65 years), sex, and smoking history (current or former smoker vs. never smoked). After the discontinuation or completion of the trial regimen, patients were followed for survival. Patients could receive their assigned trial regimen again if disease control had occurred at the end of 12 months and if progression occurred during follow-up.

End Points and Assessments

The primary end points were overall survival and progression-free survival, assessed according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1, and evaluated by means of blinded independent central review. Overall survival was defined as the time from randomization until death from any cause. Progression-free survival was defined as the time from randomization until the date of objective disease progression or death from any cause in the absence of progression.

Secondary efficacy end points included the rate of overall survival at 24 months after randomization, the objective response rate, duration of response, the rates of progression-free survival at 12 and 18 months, the time to death or distant metastasis (defined as any new lesion outside the radiation field, according to RECIST, version 1.1, or proven by biopsy) (see the Supplementary Methods section in the Supplementary Appendix), and the time to second progression (defined as the time from randomization to the earliest of the progression events subsequent to that used for the analysis of progression-free survival). The time to second progression was defined according to local standard practice and assessed by investigators and could include any of the following: objective assessment of progression as assessed radiologically, symptomatic progression, or death. The time to the first subsequent therapy or death and the time to the second subsequent therapy or death were supportive assessments for progression-free survival and the time to second progression, respectively.

In addition to the estimates for progression-free survival, the objective response rate, duration of response, and the time to death or distant metastasis were based on RECIST, version 1.1, according to blinded independent central review assessments. RECIST assessments were not collected for the analysis of time to second progression. Efficacy was assessed every 8 weeks for the first 12 months and every 12 weeks thereafter. All reported efficacy end points are for durvalumab or placebo only and were derived from the time of randomization (i.e., did not include the previous chemoradiotherapy period).

Safety assessments included adverse events, serious adverse events, vital signs, and physical and laboratory examinations. Also assessed were adverse events of special interest and immune-mediated adverse events, which were defined as adverse events of special interest that led to the use of systemic glucocorticoids, endocrine therapy, or other immunosuppressants, that were consistent with an immune-mediated mechanism, and that had no clear alternative cause. Adverse events and serious adverse events were classified according to system organ class and preferred term in the Medical Dictionary for Regulatory Activities, version 19.1, and were graded according to the Common Terminology Criteria for Adverse Events, version 4.03.

Patients provided archived tumor tissue samples (if available), which had been obtained before chemoradiotherapy, for PD-L1 testing with the use of the Ventana SP263 immunohistochemical assay. However, patients were enrolled regardless of PD-L1 expression status. Prespecified analyses of outcomes as a function of PD-L1 expression levels on tumor cells with the use of a 25% cutoff were conducted. In addition, at the request of health regulatory authorities, an exploratory post hoc analysis was conducted that used a PD-L1 expression-level cutoff of 1%. (An additional PD-L1 subgroup with a cutoff of 1 to 24% was also analyzed; see the Supplementary Appendix.)

Trial Oversight

As reported previously,18 the trial was designed by representatives of the sponsor (AstraZeneca) and academic advisors. The trial was conducted in accordance with ethical principles that have their origin in the Declaration of Helsinki and are consistent with the International Council on Harmonisation guidelines for Good Clinical Practice, with any applicable laws and requirements, and with any conditions that were required by a regulatory authority, institutional review board, or independent ethics committee that had approved this trial to be conducted in its territory. (For details, see the Supplementary Methods section in the Supplementary Appendix.)

The data were collected and analyzed by the sponsor after review and a recommendation by the independent data and safety monitoring committee to unblind the data. The manuscript was written by the authors, with editorial assistance funded by the sponsor and conducted in accordance with Good Publication Practice guidelines. The authors had access to the data and vouch for the accuracy and completeness of the data and analyses and for the adherence of the trial to the protocol, available at NEJM.org.

Statistical Analysis

The sample size that was required for the analysis of the primary end points and the statistical methods have been described previously.18 For overall survival, the final analysis was planned to be conducted when approximately 491 deaths had occurred among 713 patients who had undergone randomization (69% maturity). If the true hazard ratio for death in the analysis of overall survival was 0.73, this number of deaths would provide the trial with at least 85% power to show a significant difference, assuming a 2.5% two-sided significance level in the intention-to-treat population; this translates to an 8-month benefit in the median overall survival in the durvalumab group over 22 months in the placebo group (i.e., 30 months in the durvalumab group) if overall survival is exponentially distributed. In addition, two interim analyses for overall survival were planned to be conducted when approximately 285 and 393 deaths had occurred. The Lan–DeMets spending function that approximates an O’Brien−Fleming approach was used to account for multiple comparisons, which were introduced by including interim analyses for superiority.22

The data cutoff for the first interim analysis of overall survival occurred on March 22, 2018, after 299 deaths had occurred (61% of the expected 491 events). The results of this interim analysis were reviewed by an independent data and safety monitoring committee that concluded that the prespecified criteria for unblinding of the data had been fulfilled (i.e., that the P value had crossed the efficacy boundary of 0.00274) and recommended unblinding of the data. Since the trial reached statistical significance on the basis of this interim analysis, the results presented herein are to be considered final for overall survival.

Analyses of the efficacy end points included all the patients who underwent randomization, according to the intention-to-treat principle. For time-to-event end points, such as progression-free survival and overall survival, the effect of durvalumab as compared with placebo was estimated by the hazard ratio (together with its corresponding confidence interval of 100[1−α]%, with adjustment for the interim analysis, or with a 95% confidence interval and P value) in the intention-to-treat population. Between-group comparisons were performed by a stratified log-rank test; the stratification factors were those that had been used for randomization (age, sex, and smoking history). The Kaplan–Meier method was used to calculate medians and their associated 95% confidence intervals. Sensitivity analyses for overall survival included the assessment of attrition bias.

For all the planned analyses of overall survival in prespecified subgroups, an unstratified Cox regression model was used to calculate hazard ratios and 95% confidence intervals. No adjustment for multiple comparisons was planned for these subgroup analyses. Response rates were estimated with the use of the Clopper–Pearson method and compared with the use of Fisher’s exact test. The type I error was controlled for the primary end points, the overall survival rate at 24 months, and the objective response rate, as described previously,18 but not for other secondary end points; therefore, P values are not reported. Safety data were summarized for the as-treated population. Details are provided in the statistical analysis plan, which is available with the protocol.