Stage IV NSCLC Treatment
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]
Evidence (maintenance erlotinib following platinum-based doublet chemotherapy):
- One trial (NCT00556712) reported favorable outcomes with maintenance erlotinib after four cycles of platinum-based doublet chemotherapy in patients with stable disease.
- In this trial, 889 patients with NSCLC but without progressive disease were randomly assigned to receive erlotinib (150 mg/day) or placebo until they experienced progressive disease or unacceptable toxicity.
- Median PFS was significantly longer with erlotinib than with placebo: 12.3 weeks for patients in the erlotinib group versus 11.1 weeks for those in the placebo group (HR, 0.71; 95% CI, 0.62–0.82; P < .0001).
- In the overall population, patients whose tumors had activating EGFR mutations derived the greatest PFS benefit from maintenance erlotinib treatment (n = 49; HR, 0.10; P < .0001).
- Patients whose tumors with wild-type EGFR also obtained significant PFS and OS improvements (HR, 0.78 and 0.77, respectively).
- In the subgroup of patients with stable disease whose tumors did not have activating EGFR mutations (n = 217), both PFS and OS were significantly prolonged with erlotinib (HR, 0.72; 95% CI, 0.54–0.96; P = .0231 and HR, 0.65; 95% CI, 0.48–0.87; P = .0041, respectively).
- In patients whose tumors had activating EGFR mutations (n = 30), OS was also improved with erlotinib (HR, 0.48; 95% CI, 0.14–1.62) but was not statistically significant in this analysis.
- EGFR IHC [immunohistochemistry], EGFR FISH [fluorescence in situ hybridization], KRAS mutation, and EGFR CA-SSR1 [simple sequence repeat 1] repeat length status were not predictive for erlotinib efficacy.KRAS mutation status was a significant, negative prognostic factor for PFS.[Level of evidence: 1iDiii]