Patients

Patients were eligible for enrollment if they were 18 years of age or older, had pathologically confirmed stage IV squamous NSCLC (as classified according to the seventh edition of the Cancer Staging Manual of the American Joint Committee on Cancer12), had received no previous systemic therapy for metastatic disease, had an Eastern Cooperative Oncology Group (ECOG) performance-status score of 0 or 1 (on a 5-point scale, with higher scores indicating increasing disability; a score of 0 indicates no symptoms, and 1 mild symptoms),13 had at least one measurable lesion according to version 1.1 of the Response Evaluation Criteria in Solid Tumors (RECIST),14 and provided a tumor sample for the determination of PD-L1 status. Patients were excluded if they had symptomatic central nervous system metastases, had a history of noninfectious pneumonitis that required the use of glucocorticoids, had active autoimmune disease, or were receiving systemic immunosuppressive treatment. Full eligibility criteria are listed in the trial protocol, available with the full text of this article at NEJM.org.

Trial Design and Treatments

In this double-blind trial, randomization was performed with the use of an interactive voice-response and integrated Web-response system. Randomization was stratified according to PD-L1 tumor proportion score (≥1% vs. <1%; tumor proportion score is the percentage of tumor cells with membranous PD-L1 staining, with <1% indicating PD-L1–negative), choice of taxane (paclitaxel vs. nab-paclitaxel), and geographic region of enrollment (East Asia vs. the rest of the world). Patients were randomly assigned, in a 1:1 ratio, to receive 200 mg of pembrolizumab or saline placebo on day 1 for up to 35 cycles. For the first 4 cycles, all the patients also received carboplatin (at a dose calculated to produce an area under the concentration–time curve of 6 mg per milliliter per minute) on day 1 and either paclitaxel (200 mg per square meter of body-surface area) on day 1 or nab-paclitaxel (100 mg per square meter) on days 1, 8, and 15. All treatments were administered intravenously in 3-week cycles. The patients who received paclitaxel also received premedication with a glucocorticoid, a type 1 antihistamine, and a type 2 antihistamine according to local guidelines; premedication with a glucocorticoid and antihistamines was not required for patients who received nab-paclitaxel.

The assigned treatment was continued until radiographic disease progression, the occurrence of unacceptable toxic effects, an investigator’s decision to discontinue the treatment, or withdrawal of patient consent. If toxic effects were clearly attributed to one component of the treatment, that component alone could be discontinued. Patients who had radiographic disease progression but were clinically stable could continue to receive treatment at the discretion of an investigator until disease progression was confirmed by imaging performed at least 28 days after the imaging assessment that first showed disease progression. The trial-group assignment could be unblinded for a patient who had disease progression confirmed by blinded, independent review of radiologic images at a central laboratory; such patients in the placebo-combination group were eligible to cross over to receive pembrolizumab monotherapy if all protocol-specified criteria were met. Patients in the pembrolizumab-combination group who were deemed to have clinical benefit from treatment despite radiographically confirmed disease progression were permitted to continue open-label pembrolizumab monotherapy. Additional details regarding treatment decisions, management of adverse events, and eligibility criteria for crossover are available in the protocol.

Assessments

The PD-L1 IHC 22C3 pharmDx assay (Agilent Technologies) was used to assess PD-L1 expression in formalin-fixed tumor samples obtained at the time metastatic disease was diagnosed. PD-L1 expression was assessed during screening at a central laboratory and was characterized according to the tumor proportion score.15 Investigators and patients were unaware of the tumor proportion score. Adverse events and abnormal laboratory findings were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.03. Tumor imaging was scheduled for weeks 6, 12, and 18 and then every 9 weeks through week 45 and every 12 weeks thereafter. Response was assessed according to RECIST, version 1.1.14 Patients were contacted to assess survival every 12 weeks during follow-up.

Trial Oversight

The trial was designed by a panel of academic advisors and employees of Merck Sharp & Dohme, the sponsor of the trial. An external, independent monitoring committee oversaw the trial and assessed efficacy and safety at prespecified interim analyses. The trial protocol and all amendments were approved by the appropriate ethics committee at each participating center. All patients provided written informed consent before enrollment.

The authors vouch for the accuracy and completeness of the data and for the fidelity of the trial to the protocol. The trial was conducted in accordance with the provisions of the International Conference on Harmonisation Good Clinical Practice guidelines. All the authors had access to the data. Assistance in the preparation of the manuscript was provided by a medical writer employed by the sponsor, and all the authors participated in writing or reviewing and editing the manuscript.

Statistical Analysis

The trial had dual primary end points of overall survival and progression-free survival, which was assessed by means of blinded, independent central review of radiologic images. The secondary end points were response rate and duration of response, which were assessed by means of blinded, independent central radiologic review, and safety. The effects of PD-L1 expression on overall survival, progression-free survival, and response rate were prespecified exploratory end points. Efficacy was assessed in the intention-to-treat population, which included all patients who underwent randomization. Safety was assessed in the as-treated population, which included all patients who underwent randomization and received at least one dose of the assigned combination treatment.

The Kaplan–Meier method was used to estimate overall survival, progression-free survival, and duration of response. The stratified log-rank test was used to assess between-group differences in overall and progression-free survival. A stratified Cox proportional-hazards model and Efron’s method of tie handling were used to assess the magnitude of the difference between the trial groups. There was no violation of the proportional-hazards model in the intention-to-treat population. In some subgroups, there was a delayed separation of the survival curves, suggesting a possible deviation from the proportional-hazards assumption. The stratified method of Miettinen and Nurminen was used to assess differences in response rate. The randomization stratification factors were applied to all stratified analyses.

The full statistical analysis plan is available with the protocol. The graphical method of Maurer and Bretz was used to control the family-wise type I error rate at a one-sided alpha level of 0.025 across all hypotheses and interim analyses (Fig. S1 in the Supplementary Appendix, available at NEJM.org). We determined that with a sample of 560 patients, the trial would have 90% power to show a hazard ratio for disease progression or death of 0.70 at a one-sided alpha level of 0.01 (as calculated on the basis of 415 events of disease progression or death) and 85% power to show a hazard ratio for death of 0.70 at a one-sided alpha level of 0.01 (as calculated on the basis of 361 deaths) for the comparison between the pembrolizumab-combination group and the placebo-combination group.

The original protocol specified the performance of two interim analyses and a final analysis (Table S1 in the Supplementary Appendix). To improve the ability of the trial to identify long-term treatment effects, the protocol was amended to specify the performance of three interim analyses and a final analysis (Table S1 in the Supplementary Appendix). The second interim analysis was to be performed after enrollment was complete and approximately 332 events of disease progression or death had been observed; it was estimated that approximately 212 deaths would be observed at this time. As of April 3, 2018, there were 349 events of disease progression or death and 205 deaths, and the multiplicity-adjusted, one-sided alpha spent at this interim analysis (as determined on the basis of the Lan–DeMets O’Brien–Fleming spending function) was 0.008 for progression-free survival and 0.0029 for overall survival. The external monitoring committee reviewed the results of the second interim analysis on May 21, 2018. Because the committee reported that the efficacy boundaries for the primary hypotheses of overall survival and progression-free survival had been met, the decision was made to report the results of the second interim analysis. The trial is continuing in order to evaluate outcomes with additional follow-up.