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Stage IV NSCLC Treatment


    Evidence (first-line platinum-based combination chemotherapy followed by pemetrexed):

    1. 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]
      1. 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.[47]
        • 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.[48] 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.
      2. In the second trial, 539 patients with NSCLC with nonprogression following treatment with pemetrexed and cisplatin were randomly assigned to continued pemetrexed or placebo.[44]
        • 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.[44][Level of evidence: 1iDiii]

    Evidence (maintenance erlotinib following platinum-based doublet chemotherapy):

    1. One trial (NCT00556712) reported favorable outcomes with maintenance erlotinib after four cycles of platinum-based doublet chemotherapy in patients with stable disease.[49]
      1. 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.[49]
        • 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.[50]
        • 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.[51]KRAS mutation status was a significant, negative prognostic factor for PFS.[51][Level of evidence: 1iDiii]

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