Stage IV NSCLC Treatment
EGFR tyrosine kinase inhibitors in patients with NSCLC EGFR mutations
Selective patients may benefit from single-agent EGFR tyrosine kinase inhibitors.
- A phase III multicenter, randomized trial compared gefitinib with carboplatin plus paclitaxel as first-line treatment in clinically selected patients in East Asia who had advanced adenocarcinoma of the lung and had never smoked or were former light smokers.
- The study met its primary objective of demonstrating the superiority of gefitinib as compared with the carboplatin-paclitaxel combination for PFS (HR for progression or death = 0.74; 95% CI, 0.65-0.85; P < .001).
- The median PFS was 5.7 months in the gefitinib group and 5.8 months in the carboplatin-paclitaxel group.[Level of evidence: 1iDiii]
- Following the time that chemotherapy was discontinued and while gefitinib was continued, the PFS curves clearly separated and favored gefitinib.
- The 12-month PFS rates were 24.9% with the gefitinib group and 6.7% with the carboplatin-paclitaxel group.
- More than 90% of the patients in the trial with mutations had either del19 or exon 21 L858R mutations, which have been shown to be sensitive to EGFR inhibitors. In the subgroup of patients with a mutation, PFS was significantly longer among those who received gefitinib (HR = 0.48; 95% CI, 0.36-0.64; P < .001), whereas, in the subgroup of patients who were negative for a mutation, PFS was significantly longer in those who received the carboplatin-paclitaxel combination (HR with gefitinib = 2.85; 95% CI, 2.05-3.98; P < .001). There was a significant interaction between treatment and EGFR mutation with respect to PFS (P < .001).
- An early analysis of OS showed similar OS in the whole study population (HR for death with gefitinib = 0.91; 95% CI, 0.76-1.10); however HRs with gefitinib were 0.78 (95% CI, 0.50-1.20) in the mutation-positive subgroup and 1.38 (95% CI, 0.92-2.09) in the mutation-negative subgroup. Although the OS results are not mature, they are concerning as they suggest that patients with NSCLC with wild-type EGFR may have inferior survival if their initial treatment is with an EGFR inhibitor rather than combination chemotherapy.
The above trial demonstrated that gefitinib is superior to the carboplatin-paclitaxel combination as an initial treatment for pulmonary adenocarcinoma among nonsmokers or former light smokers in East Asia. The presence of EGFR mutations is a strong predictor of a better outcome with gefitinib and gefitinib may be inferior to chemotherapy for treating patients with NSCLC with wild-type EGFR, even in patients with favorable-risk clinical features. The applicability of these results to non-Asian populations, rare EGFR mutations, and other EGFR inhibitors is uncertain as there may be additional environmental or molecular features that may modify the clinical benefit to EGFR inhibitors or chemotherapy in other populations or with other agents.