ORRs for the two treatment groups were compared on the basis of the Miettinen and Nurminen method. For subgroup analysis of OS and PFS, patients with unassessable PD-L1 TPS were not included. Between-group differences in OS and PFS were evaluated by the stratified log-rank test. The magnitude of difference between the treatment groups (HRs and 95% CIs) was assessed using the stratified Cox proportional hazards model and the Efron method of tie handling. OS and PFS were estimated using the nonparametric Kaplan-Meier method. Safety was assessed in the as-treated population and included all patients who received at least one dose of study treatment. Patients’ postbaseline PRO scores were defined as “stable,” “improved,” or “deteriorated” according to a greater than or equal to 10-point change for each of the instruments or scales from baseline, as perceived to be clinically meaningful by patients.Įfficacy was assessed in the intention-to-treat population, which included all randomized patients. Supportive PRO end points included mean score changes and the proportion of patients with “deteriorated,” “stable,” or “improved” scores from baseline to weeks 9 and 18 in the subscales of EORTC QLQ-C30 and EORTC QLQ-LC13. TTD was defined as the time to first onset of greater than or equal to 10-point increase from baseline and confirmed by another adjacent greater than or equal to 10-point increase in any of the three symptoms under the right-censoring rule. Key PRO end points were the mean score change from baseline to week 9 and week 18 using the EORTC QLQ-C30 global health status (GHS)/quality of life (QoL) scale and the time to deterioration (TTD) in the composite end point of cough (EORTC QLQ-LC13-Q1), chest pain (EORTC QLQ-LC13-Q10), or dyspnea (EORTC QLQ-C30-Q8). Patients in the pembrolizumab–chemotherapy group with confirmed radiographic progression (i.e., two scans at least 4 wk apart revealing progressive disease) on the basis of the immune-related RECIST, but were achieving a clinically meaningful benefit, and with no further increase in the tumor burden at the confirmatory tumor imaging visit, could continue treatment with pembrolizumab to complete a total of 35 treatment cycles. ![]() Because positive results for PFS and OS (dual primary end points) were observed in the final analysis in the global study and in the interim analysis in the China extension study, this study was unblinded, allowing patients in the placebo–chemotherapy group with documented disease progression verified by blinded independent central review (BICR) per RECIST version 1.1 to cross over to receive open-label pembrolizumab monotherapy for up to 35 treatment cycles if they met all eligibility criteria. Patients with unassessable PD-L1 status were included in the group with TPS less than 1%. Randomization was stratified by PD-L1 expression (TPS ≥1% versus <1%), by choice of taxane (paclitaxel versus nab-paclitaxel), and, in the global study, by geographic region (East Asia versus non-East Asia). Treatment with pembrolizumab or placebo continued until completion of 35 cycles, documented disease progression, unacceptable adverse events (AEs), intercurrent illness, investigator’s decision, or withdrawal of consent. ![]() For the first four cycles, all patients received pembrolizumab or placebo intravenously on day 1 of each 21-day cycle and carboplatin (area under the concentration–time curve, 6 mg/mL/min) plus paclitaxel (200 mg/m 2 on d 1 of each cycle) or nab-paclitaxel (100 mg/m 2 on d 1, 8, and 15 of each cycle). Patients were randomized 1:1 to receive pembrolizumab 200 mg every 3 weeks or saline placebo for up to 35 cycles. ![]() Patients were excluded if they had major surgery within 3 weeks of treatment received radiation therapy to the lung of greater than 30 Gy within 6 months of first study dose or completed palliative radiotherapy within 7 days before treatment had a known history of previous malignancy, active central nervous system metastases, or carcinomatous meningitis had peripheral neuropathy of grade 2 or higher (assessed by the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0) had active autoimmune disease had received previous treatment with an anti–PD-(L)1 or anti–PD-L2 agent or had interstitial lung disease or a history of pneumonitis that required steroid therapy. Briefly, eligible patients were at least 18 years of age with histologically or cytologically confirmed diagnosis of stage IV squamous NSCLC, measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, an Eastern Cooperative Oncology Group performance status of 0 or 1, adequate organ function, and had provided a tumor tissue sample for PD-L1 evaluation and not received systemic treatment previously.
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