Patients

Patients who were at least 18 years of age were eligible for enrollment if they had pathologically confirmed metastatic nonsquamous NSCLC without sensitizing EGFR or ALK mutations; 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)8; had at least one measurable lesion according to the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.19; and had provided a tumor sample for 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. Because of an increased risk of pneumonitis,10 patients were also excluded if they had received more than 30 Gy of radiotherapy to the lung in the previous 6 months. Full eligibility criteria are listed in the trial protocol, available with the full text of this article at NEJM.org.

Trial Design and Treatment

In this double-blind trial, patients were randomly assigned, in a 2:1 ratio, to receive either 200 mg of pembrolizumab or saline placebo, both administered intravenously every 3 weeks for up to 35 cycles. Randomization was performed by means of an integrated interactive voice-response and Web-response system (i.e., treatment assignments could be provided by following a series of prompts on a touch-tone phone or by following the same prompts in a Web-based portal). Randomization was stratified according to PD-L1 expression (tumor proportion score, ≥1% vs. <1%), choice of platinum-based drug (cisplatin vs. carboplatin), and smoking history (never vs. former or current).

All the patients received four cycles of the investigator’s choice of intravenously administered cisplatin (75 mg per square meter of body-surface area) or carboplatin (area under the concentration–time curve, 5 mg per milliliter per minute) plus pemetrexed (500 mg per square meter), all administered intravenously every 3 weeks, followed by pemetrexed (500 mg per square meter) every 3 weeks. All the patients received premedication with folic acid, vitamin B 12 , and glucocorticoids administered according to local guidelines for pemetrexed use.

Treatment was continued until radiographic progression, unacceptable toxic effects, investigator decision, or patient withdrawal of consent. If toxicity was clearly attributed to one agent, that drug alone could be discontinued. Patients in the placebo-combination group in whom disease progression was verified by blinded, independent central radiologic review were eligible to cross over to receive pembrolizumab monotherapy. Additional details regarding treatment decisions, including the management of adverse events, are provided in the protocol.

Assessments

PD-L1 expression was assessed during screening at a central laboratory by means of the PD-L1 IHC 22C3 pharmDx assay (Agilent) in formalin-fixed tumor samples obtained by core-needle or excisional biopsy or from tissue resected at the time that metastatic disease was diagnosed. Expression was categorized according to the tumor proportion score (i.e., the percentage of tumor cells with membranous PD-L1 staining).11 Investigators, patients, and representatives of the sponsor were unaware of the patients’ tumor proportion scores. Adverse events and laboratory abnormalities were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0. Tumor imaging was scheduled for weeks 6 and 12, then every 9 weeks through week 48 and every 12 weeks thereafter. Response was assessed according to RECIST, version 1.1.9 Patients were contacted every 12 weeks to assess survival during follow-up.

End Points

The two primary end points were overall survival (time from randomization to death from any cause) and progression-free survival (time from randomization to disease progression, as assessed by blinded, independent central radiologic review, or death from any cause, whichever occurred first). The secondary end points were the response rate (the percentage of patients with a confirmed complete or partial response), the duration of response (time from first documented complete or partial response to disease progression or death), and safety. Both the response rate and the duration of response were assessed by blinded, independent central radiologic review. Exploratory end points included the effect of PD-L1 expression on efficacy and patient-reported outcomes. The full list of end points and the statistical analysis plan are available in the protocol.

Trial Oversight

The trial was designed by a panel of academic advisors and employees of Merck (in Kenilworth, New Jersey), the trial sponsor. An external 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 panel at each center. All the patients provided written informed consent before enrollment. Eli Lilly provided the pemetrexed but otherwise had no role in the trial.

All the authors attest that the trial was conducted in accordance with the protocol and all its amendments and with Good Clinical Practice standards. All the authors had access to the data and participated in the writing or reviewing and editing of the manuscript. The first draft of the manuscript was written by the first author with input from authors employed by the sponsor. Assistance in the preparation of the manuscript was provided by a medical writer employed by the sponsor. The investigators agreed to keep all aspects of the trial confidential. All the authors vouch for the accuracy and completeness of the data and analyses.

Statistical Analysis

Efficacy was assessed in the intention-to-treat population, which included all the patients who had undergone randomization. Safety was assessed in the as-treated population, which included all patients who had undergone randomization and received at least one dose of the assigned combination therapy. The Kaplan–Meier method was used to estimate overall and progression-free survival. Data for patients who were alive or lost to follow-up were censored for overall survival at the time they were last known to be alive; data for patients who crossed over were not censored at the time of crossover. Data for patients who were alive and did not have disease progression or who were lost to follow-up were censored for the analysis of progression-free survival at the time of the last imaging assessment. The stratified log-rank test was used to assess between-group differences in overall and progression-free survival. Hazard ratios and associated 95% confidence intervals were calculated with the use of a stratified Cox proportional-hazards model and Efron’s method for handling tied events to assess the magnitude of the treatment difference. Differences in response rate were assessed with the stratified method of Miettinen and Nurminen. The randomization stratification factors were applied to all stratified efficacy analyses.

The full statistical analysis plan specified the performance of two interim analyses and a final analysis. The family-wise type I error rate was strictly controlled at a one-sided alpha level of 0.025 with the use of the graphical method of Maurer and Bretz (Fig. S1 in the Supplementary Appendix, available at NEJM.org). If a significant benefit with regard to one of the primary end points was found in the pembrolizumab-combination group, the corresponding alpha level would be rolled over for testing of the other primary end point. The Lan–DeMets O’Brien–Fleming spending function was used to control the type I error in the interim and final analyses.

We determined that the trial would have a power of 90% to show a hazard ratio for disease progression or death of 0.70 at a one-sided alpha level of 0.0095 (based on 468 events) and a hazard ratio of 0.70 for death at a one-sided alpha level of 0.0155 (based on 416 deaths) for the comparison between the pembrolizumab-combination group and the placebo-combination group. The planned enrollment was 570 patients.

The first interim analysis was to be performed after enrollment was complete and approximately 370 events of progression or death had occurred; it was estimated that approximately 242 deaths would have occurred at this time. As of November 8, 2017, there were 410 events of disease progression or death and 235 deaths. On the basis of the observed number of events, the multiplicity-adjusted, one-sided alpha levels at the first interim analysis were 0.00559 for progression-free survival and 0.00128 for overall survival. Results were reviewed by the external monitoring committee on January 10, 2018. The monitoring committee reported that the efficacy boundaries for overall survival and progression-free survival had been met. The trial is continuing in order to evaluate outcomes with additional follow-up. All data reported here are based on the first interim analysis.