What is the optimal third-line therapy in unselected patients with stage IV inoperable NSCLC?

From Cancer Guidelines Wiki


The majority of patients treated with NSCLC have stage IV disease, with common sites of metastases including lymph nodes, the pleura, liver, adrenal glands, bone and brain. Consequently, systemic therapy has been the mainstay of treatment attempting to control overall disease. A historical summary of the evolution of systemic drug treatment for stage IV NSCLC can be found here. The focus of the following question is based on the evidence in support of the old and new practice paradigms for stage IV NSCLC. Empirical therapy refers to therapy given to all fit patients deemed suitable without any particular restrictions.

Third-line therapy

Few randomised controlled trials (RCTs) have evaluated third line therapy in unselected patients with advanced NSCLC. The aforementioned negative RCT (ISEL) of gefitinib versus placebo in 1692 patients included 847 patients (50%) that had received two previous lines of therapy.[1] The positive RCT (BR21) of erlotinib versus placebo in 731 patients included approximately 50% of patients having received two previous lines of therapy. Univariate analysis of OS by number of prior regimens found OS remained in favour of erlotinib (compared with placebo) by similar magnitude to the overall study population results (HR 0.80, p = 0.02).[2] The study by Kim et al, comparing gefitinib to docetaxel in previously treated advanced NSCLC, only included 235 (16%) patients that had received two previous lines of therapy. Analysis of OS number of prior regimens found OS more in favour of docetaxel. But as this is a post hoc analysis with small patient numbers, it is not appropriate to draw conclusions.[3]

Evidence summary and recommendations

Evidence summary Level References
In unselected previously treated patients with advanced NSCLC who have received two lines of therapy, single agent erlotinib 150 mg per day orally as third-line therapy improves survival compared with placebo.

Last reviewed December 2015

II [2]
Evidence-based recommendationQuestion mark transparent.png Grade
In unselected patients having previously received two lines of treatment for advanced NSCLC, erlotinib 150 mg per day orally can be used as third-line therapy.

Last reviewed December 2015


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  1. Thatcher N, Chang A, Parikh P, Rodrigues Pereira J, Ciuleanu T, von Pawel J, et al. Gefitinib plus best supportive care in previously treated patients with refractory advanced non-small-cell lung cancer: results from a randomised, placebo-controlled, multicentre study (Iressa Survival Evaluation in Lung Cancer). Lancet 2005 Oct;366(9496):1527-37 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/16257339.
  2. 2.0 2.1 Shepherd FA, Rodrigues Pereira J, Ciuleanu T, Tan EH, Hirsh V, Thongprasert S, et al. Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med 2005 Jul 14;353(2):123-32 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/16014882.
  3. Kim ES, Hirsh V, Mok T, Socinski MA, Gervais R, Wu YL, et al. Gefitinib versus docetaxel in previously treated non-small-cell lung cancer (INTEREST): a randomised phase III trial. Lancet 2008 Nov 22;372(9652):1809-18 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/19027483.

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Further resources

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