Gefitinib vs Chemotherapy for NSCLC: More Data Supporting Targeted Therapies

来源：N Engl J Med. 2010;362:2380-2388

【Summary】

Investigators in Japan randomly assigned 230 chemotherapy-naive patients who had metastatic and epidermal growth factor receptor (EGFR) mutation-positive non-small-cell lung cancer (NSCLC) to treatment with either single-agent gefitinib or combination chemotherapy with carboplatin plus paclitaxel. The primary study endpoint was progression-free survival, although the impact of therapy on response rates, toxicity, and overall survival was also examined.

The study was stopped early when a planned interim analysis of the initial 200 patients revealed a highly statistically significant improvement in progression-free survival (PFS) in favor of treatment on the gefitinib study arm (P < .001; hazard ratio for progression or death, 0.36). At the time of this report, this study arm was associated with improved median PFS (10.8 vs 5.4 months; P < .001) and objective response (73.7% vs 30.7%; P < .001), but not median overall survival (30.5 vs 23.6 months; P = .31). Rash (71%) and abnormal aminotransferase levels (55%) were frequently observed with gefitinib treatment, whereas the most common adverse effects noted with chemotherapy were bone marrow suppression, loss of appetite, and sensory neuropathy.

【Viewpoint】

Previous studies have suggested that patients with metastatic NSCLC and EGFR mutations have a relatively high probability of achieving an objective response to EGFR tyrosine kinase inhibitors.[1] Conversely, in the absence of such mutations, the probability of a patient achieving an objective response is very limited. A critically important question in this area is the relative clinical utility associated with the administration of chemotherapy vs a tyrosine kinase inhibitor of EGFR (without chemotherapy) as primary antineoplastic therapy in individuals with NSCLC and such mutations.

The current study directly, and rather definitively, answers this question by demonstrating the overall superiority in both time to disease progression and response rate of the tyrosine kinase inhibitor gefitinib. In addition, the toxicity associated with this regimen was generally tolerable, although adverse effects (particularly rash) can clearly be problematic. The study was discontinued early at the time of a planned interim analysis based on the major difference in PFS between the arms. This reduced the opportunity for the trial to demonstrate a statistical difference in overall survival, which explains why no significant difference in overall survival was seen between the 2 regimens.

The results support the conclusions reached in other recently reported evidence-based trials comparing gefitinib with cytotoxic chemotherapy.[2] However, unlike in the previous trial, which compared gefitinib with cisplatin and docetaxel, in this trial, gefitinib was compared with carboplatin plus paclitaxel, which is one of the most widely used combination antineoplastic regimens in the Unites States for the treatment of metastatic NSCLC, making these data more applicable to clinicians in the United States.