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

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.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Lee reported serving on the scientific advisory board of and receiving honorarium from AstraZeneca. Dr Cooper reported serving on the scientific advisory board of and receiving honorarium from Bristol Myers Squibb, MSD, and AstraZeneca. Dr Hersbt reported being a consultant for AstraZeneca, Genentech, Eli Lilly, Merck, and Pfizer and receiving research funding from Genentech and Merck. Dr Mok reported serving on the scientific advisory board of and receiving honorarium and research funding from AstraZeneca, Roche/Genentech, Eli Lilly, Bristol-Myers Squibb, Boehringer Ingelheim, Novartis, Pfizer, Merck Serono, Clovis Oncology, Vertex, SFJ, ACEA BioSciences, MSD, geneDecode, Oncogenex, Celgene, Ignyta, Taiho Pharmaceutical Co Ltd, and Eisai Co Ltd. Dr Yang reported serving as a consultant for Bristol-Myers Squibb and on the scientific advisory board of Astellas Pharma EMEA, Bayer Plc, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene Ltd, Clovis Oncology, Eli Lilly and Company, Merck Serono, Merrimack Pharmaceuticals, MSD, Novartis, Ono Pharmaceutical Co Ltd, Pfizer Inc, Roche/Genentech, and Yuhan Pharmaceuticals. No other disclosures were reported.

Figures

Figure 1.. Flow Diagram of Study Inclusion and Exclusion

Figure 2.. Forest Plot of Hazard Ratios Comparing Overall Survival in Patients Who Received PD-1 (Programmed Cell Death 1) or PD-L1 (Programmed Cell Death 1 Ligand 1) Immune Checkpoint Inhibitors vs Docetaxel

A, Epidermal growth factor receptor (EGFR) wild-type and mutated subgroups. B, Kirsten RAS (KRAS) wild-type and mutated subgroups. Hazard ratios for each trial are represented by the squares, and the horizontal line crossing the square represents the 95% CI. The diamonds represent the estimated overall effect, based on the meta-analysis fixed-effect method. All statistical tests were 2-sided.