Non-Small Cell Lung Cancer Treatment (PDQ®): Treatment - Health Professional Information [NCI] - Stage IV NSCLC Treatment
The above trials demonstrated that EGFR tyrosine kinase inhibitors such as gefitinib or erlotinib are superior to the platinum combination chemotherapy as an initial treatment for pulmonary adenocarcinoma among nonsmokers or former light smokers in East Asia. It is likely that these results are applicable to non-Asian populations.
- In a European study (EURTAC), 1,227 patients with advanced NSCLC were screened for EGFR mutations. Of these, 174 patients with EGFR mutations were randomly assigned to receive erlotinib or platinum-based chemotherapy. The primary endpoint was PFS.
- In an interim analysis of the first 153 patients, PFS in the chemotherapy arm was 5.2 months (95% CI, 4.5–5.8) compared to 9.7 months (95% CI, 8.4–12.3) in the erlotinib arm (HR, 0.37; P < .0001). Median survival was 19.3 months in the chemotherapy arm and 19.5 months in the erlotinib arm (HR, 0.80; P = .42).[Level of evidence: 1iiDiii]
Maintenance therapy following first-line chemotherapy
One treatment strategy that has been investigated extensively in NSCLC is maintenance therapy following initial response to chemotherapy. Options for maintenance therapy that have been investigated include the following:
- Continuing the initial combination chemotherapy regimen.
- Continuing only single-agent chemotherapy.
- Introducing a new agent as "maintenance."
Multiple randomized trials have evaluated the efficacy of continuing first-line combination cytotoxic chemotherapy beyond three to four cycles.
Evidence (maintenance therapy following first-line chemotherapy):
- None of the trials of continued cytotoxic combinations showed a significant OS advantage with additional or longer durations beyond four cycles.
- Three trials found statistically significantly improved PFS or time to progression with additional chemotherapy.[42,43,44]
- No consistent improvement in quality of life was reported.[43,45,46]
- Chemotherapy-related toxicities were greater with prolonged chemotherapy.[45,46]
These data suggest that PFS, but not OS, may be improved either by continuing an effective chemotherapy beyond four cycles or by immediate initiation of alternative chemotherapy. The improvement in PFS, however, is tempered by an increase in adverse events from additional cytotoxic chemotherapy and no consistent improvement in quality of life. For patients who have stable disease or who respond to first-line therapy, evidence does not support the continuation of cytotoxic chemotherapy until disease progression or the initiation of a different chemotherapy prior to disease progression. Collectively, these trials suggest that first-line cytotoxic combination chemotherapy should be stopped at disease progression or after four cycles in patients whose disease is not responding to treatment; it can be administered for no more than six cycles.[42,43,45,46]
Evidence (first-line platinum-based combination chemotherapy followed by pemetrexed):
- The findings of two randomized trials (NCT00102804 and NCT00789373) have shown outcomes with the addition of pemetrexed following standard first-line platinum-based combination chemotherapy.[44,47]
- In the first trial, 663 patients with stage IIIB or stage IV disease who had not progressed on four cycles of nonpemetrexed platinum-based chemotherapy were randomly assigned (2:1 ratio) to receive pemetrexed or placebo until disease progression.
- Both the primary endpoint of PFS and the secondary endpoint of OS were statistically significantly prolonged with the addition of maintenance pemetrexed (median PFS, 4.3 months vs. 2.6 months; HR, 0.50; 95% CI, 0.42–0.61; P < .0001; median OS, 13.4 months vs. 10.6 months; HR, 0.79; 95% CI, 0.65–0.95; P = .012).
- Benefit was not seen in patients with squamous histology.
- Higher than grade 3 toxicity and treatment discontinuations resulting from drug-related toxic effects were higher in the pemetrexed group than in the placebo group.
- No pemetrexed-related deaths occurred.
- Relatively fewer patients in the pemetrexed group than in the placebo group received systemic post-discontinuation therapy (227 [51%] vs. 149 [67%]; P = .0001).
- Quality of life during maintenance therapy with pemetrexed was similar to placebo, except for a small increase in loss of appetite and significantly delayed worsening of pain and hemoptysis as assessed using the Lung Cancer Symptom Scale. The quality-of-life results should be evaluated with caution as there was a high degree of censoring (> 50%) for the primary quality-of-life endpoint of time to worsening of symptoms.
- Trials have not evaluated maintenance pemetrexed versus pemetrexed at progression.
- In the second trial, 539 patients with NSCLC with nonprogression following treatment with pemetrexed and cisplatin were randomly assigned to continued pemetrexed or placebo.
- There was a statistically significant improvement in the primary endpoint of PFS (4.1 months vs. 2.8 months (HR, 0.62; 95% CI, 0.49–0.79) but no improvement in OS.[Level of evidence: 1iDiii]