Immune checkpoint inhibitors have revolutionized the treatment of metastatic non-small cell lung cancer (NSCLC). In patients progressing on first-line therapy, immunotherapy with the PD-1/PD-L1 inhibitors pembrolizumab, nivolumab, and atezolizumab has become standard second-line therapy. While these agents are associated with durable responses and long-term improvements in overall survival (OS), only a small proportion of patients respond to treatment. Relatively little is known about the factors that predispose patients to response on checkpoint inhibitors, and there is an unmet need for improved patient selection criteria.
A new meta-analysis of 5 randomized clinical trials (N = 3025) comparing a checkpoint inhibitor (either nivolumab, pembrolizumab, or atezolizumab) to docetaxel in patients with previously treated advanced NSCLC evaluated the clinical and molecular features that were associated with improved outcomes on checkpoint inhibitors. In the overall patient cohort, treatment with checkpoint inhibitors was associated with a significant improvement in OS (HR 0.69, P<.001). This survival benefit was consistent in patients with EGFR wild-type tumors (HR 0.67, P<.001), but not in patients with EGFR mutated NSCLC (HR 1.11, P = .54). Similarly, patients with KRAS mutated tumors had improved OS on checkpoint inhibitors (HR 0.65, P = .03), but patients with KRAS wild-type tumors did not (HR 0.86, P = .24). None of the other patient or disease factors included in this analysis influenced the treatment benefit of checkpoint inhibitors, including smoking status, performance status (0 or 1), age, histology, brain metastases, and sex.
The authors noted that major limitation of the study is that EGFR and KRAS mutations were not determined universally by centralized testing, with EGFR not being assessed in 25.3% and
KRAS in 82.8% of patients. Additionally, the status of potential other mutations was unknown. The results only apply for patients that were eligible for the trials and do not include patients with poor performance status that are common in daily practice.
In their conclusions, the investigators highlighted that checkpoint inhibitors are more effective than chemotherapy in previously treated patients with metastatic NSCLC, and confirm previous observations that these agents are less effective in EGFR mutated NSCLC. They suggest that immunotherapy in patients with EGFR-mutant NSCLC should be used only when other treatment options have been exhausted. They pointed out that in absence of statistically significant interaction between KRAS status and treatment effect, KRAS cannot be considered as a predictive biomarker and larger studies are needed to further investigate its predictive value. However, the findings from this meta-analysis may be helpful for economic analyses and for the design and interpretation of future clinical trials.