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Original Investigation
February 2018

Clinical and Molecular Characteristics Associated With Survival Among Patients Treated With Checkpoint Inhibitors for Advanced Non–Small Cell Lung Carcinoma: A Systematic Review and Meta-analysis

Author Affiliations
  • 1National Health and Medical Research Council Clinical Trials Centre, The University of Sydney, Sydney, New South Wales, Australia
  • 2Cancer Care Centre, St George Hospital, Sydney, New South Wales, Australia
  • 3School of Medicine, The University of Norte Dame, Sydney, New South Wales, Australia
  • 4Department of Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia
  • 5Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia
  • 6School of Medicine, Western Sydney University, Sydney, New South Wales, Australia
  • 7Yale Cancer Center, Yale School of Medicine, New Haven, Connecticut
  • 8Smilow Cancer Hospital, New Haven, Connecticut
  • 9Department of Medicine (Oncology), Albert Einstein College of Medicine, New York, New York
  • 10Hematology-Oncology Division, Jacobi Medical Center, New York, New York
  • 11Hong Kong Cancer Institute, Department of Clinical Oncology, Chinese University of Hong Kong, Shatin, China
  • 12Graduate Institute of Oncology, National Taiwan University, Taipei City, Taiwan
  • 13Department of Oncology, National Taiwan University Hospital, Taipei City, Taiwan
JAMA Oncol. 2018;4(2):210-216. doi:10.1001/jamaoncol.2017.4427
Key Points

Question  What is the relative efficacy, overall and in subgroups, of checkpoint inhibitor vs docetaxel for second-line advanced non–small cell lung carcinoma defined by clinicopathological characteristics?

Findings  In this systematic review and meta-analysis of 5 randomized clinical trials involving 3025 patients with advanced non–small cell lung carcinoma, checkpoint inhibitors improved overall survival over docetaxel and had a significantly greater benefit for EGFR wild-type over EGFR mutant tumors.

Meaning  In second-line checkpoint inhibitor therapy for advanced non–small cell lung carcinoma, EGFR mutational status could assist in patient selection, design, and interpretation of future trials and economic analyses.


Importance  Checkpoint inhibitors have replaced docetaxel as the new standard second-line therapy in advanced non–small cell lung carcinoma (NSCLC), but little is known about the potential predictive value of clinical and molecular characteristics.

Objective  To estimate the relative efficacy of checkpoint inhibitor vs docetaxel overall and in subgroups defined by clinicopathological characteristics.

Data Sources  This systematic review and meta-analysis searched MEDLINE, Embase, PubMed, and the Cochrane Central Register of Controlled Trials for randomized clinical trials published in the English language between January 1, 1996, and January 30, 2017.

Study Selection  Randomized clinical trials that compared a checkpoint inhibitor (nivolumab, pembrolizumab, or atezolizumab) with docetaxel. For each trial included in this study, the trial name, year of publication or conference presentation, patients’ clinicopathological characteristics, type of chemotherapy, and type of checkpoint inhibitor were extracted. Data collection for this study took place from February 1 to March 31, 2017.

Data Extraction and Synthesis  Two reviewers performed study selection, data abstraction, and risk of bias assessment. Hazard ratios (HR) and 95% CIs for the overall population and subgroups were extracted. Pooled treatment estimates were calculated using the inverse-variance-weighted method.

Results  In total, 5 trials involving 3025 patients with advanced NSCLC were included in this meta-analysis. These patients were randomized to receive a checkpoint inhibitor (nivolumab, 427 [14.1%]; pembrolizumab, 691 [22.8%]; or atezolizumab, 569 [18.8%]) or docetaxel (1338 [44.2%]). Checkpoint inhibitors were associated with prolonged overall survival, compared with docetaxel (HR, 0.69; 95% CI, 0.63-0.75; P < .001). They prolonged overall survival in the EGFR wild-type subgroup (HR, 0.67; 95% CI, 0.60-0.75; P < .001), but not in the EGFR mutant subgroup (HR, 1.11; 95% CI, 0.80-1.53; P = .54; interaction, P = .005), and they prolonged overall survival in the KRAS mutant subgroup (HR, 0.65; 95% CI, 0.44-0.97; P = .03) but not in the KRAS wild-type subgroup (HR, 0.86; 95% CI, 0.67-1.11; P = .24; interaction, P = .24). The relative treatment benefits were similar according to smoking status (never smokers [HR, 0.79] vs ever smokers [HR, 0.69]; interaction, P = .40), performance status (0 [HR, 0.69] vs 1 [HR, 0.68]; interaction, P = .85), age (<65 years [HR, 0.71] vs ≥65 years [HR, 0.69]; interaction, P = .74), histology (squamous [HR, 0.67] vs nonsquamous [HR, 0.70]; interaction, P = .71), or sex (male [HR, 0.69] vs female [HR, 0.70]; interaction, P = .82).

Conclusion and Relevance  Checkpoint inhibitors, compared with docetaxel, are associated with significantly prolong overall survival in second-line therapy in NSCLC. The finding of no overall survival benefit for patients with EGFR mutant tumors suggests that checkpoint inhibitors should be considered only after other effective therapies have been exhausted. The findings of this meta-analysis could also assist in the design and interpretation of future trials and in economic analyses.