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JAMA Oncol. 2018 Feb 1;4(2):210-216. doi: 10.1001/jamaoncol.2017.4427.

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.

Lee CK1,2, Man J2, Lord S1,3, Cooper W4,5,6, Links M2, Gebski V1, Herbst RS7,8, Gralla RJ9,10, Mok T11, Yang JC12,13.

Author information

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

Abstract

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.

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