Updated February 2008

Patients who fail to respond to a standard first line regimen or progress within less than 3 months after chemotherapy completion have resistant tumours that are unlikely to respond to second line therapy. Patients with good performance status that obtained a good response or stable disease for at least 3-6 months after first-line chemotherapy completion may benefit from additional chemotherapy.

Three agents have been approved for second line therapy in metastatic NSCLC; docetaxel, pemetrexed and erlotinib. TAX317 compared docetaxel at two different doses to best supportive care in patients previously treated with a platinum based doublet.¹ The median survival was improved from 4.6 months to 7 months with docetaxel. A second phase III trial of docetaxel versus vinorelbine/ifosfamide as the control arm did not demonstrate a benefit in overall survival although the 1 year survival trended towards improvement with docetaxel.² Based on these trials, the FDA approved docetaxel for second line treatment.

Pemetrexed was compared to docetaxel in a large randomized phase III study conducted by Hanna et al.³ While the trial did not meet its endpoint of non-inferiority, treatment with pemetrexed resulted in clinically equivalent outcomes with a response rate of 9.1% versus 8.9% and median survival of 8.3 versus 7.9 months. Pemetrexed also resulted in less toxicity and hospitalizations than docetaxel. Pemetrexed is an alternate, well-tolerated chemotherapeutic option for second line therapy.

Targeted therapy has also been evaluated in patients who previously failed one or two chemotherapy regimens for NSCLC.⁴ In BR21, patients were randomized to erlotinib versus placebo. Erlotinib is an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI). The response rate was 8.9% with erlotinib (<1% placebo) and the median survival was improved from 4.7 to 6.7 months. Erlotinib has been approved in the second and third line setting.

Gefitinib, also an EGFR TKI, was initially approved by the FDA for treatment of patients after two lines of chemotherapy. Approval was withdrawn after the ISEL trial which demonstrated no improvement in survival with gefitinib over placebo.⁵ This trial may have been flawed in that patients had to have progressive disease within 3 months of enrollment, thereby selecting for patients with poor prognosis. A subsequent trial conducted in Japan compared gefitinib and docetaxel.⁶ While the endpoint of non inferiority was not met, there was no difference in overall survival. This failure to meet the designated endpoint may have been influenced by the fact that more patients in the docetaxel arm went on to have further systemic therapy. A second phase III study, INTEREST, also compared gefitinib to docetaxel and the results demonstrated non-inferiority.⁷ At this time access to gefitinib is limited, but based on this data wider availability is anticipated.

Ultimately, the choice of second line therapy should be tailored to the individual patient.

References: 

1. Shepherd FA, Dancey J, Ramlau R, et al: Prospective randomized trial of docetaxel versus best supportive care in patients with non-small-cell lung cancer previously treated with platinum-based chemotherapy.[comment]. Journal of Clinical Oncology. 18:2095-103, 2000

2. Fossella FV, DeVore R, Kerr RN, et al: Randomized Phase III Trial of Docetaxel Versus Vinorelbine or Ifosfamide in Patients With Advanced Non-Small-Cell Lung Cancer Previously Treated With Platinum-Containing Chemotherapy Regimens. J Clin Oncol 18:2354-2362, 2000

3. Hanna N, Shepherd FA, Fossella FV, et al: Randomized Phase III Trial of Pemetrexed Versus Docetaxel in Patients With Non-Small-Cell Lung Cancer Previously Treated With Chemotherapy. J Clin Oncol 22:1589-1597, 2004

4. Shepherd FA, Rodrigues Pereira J, Ciuleanu T, et al: Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med 353:123-32, 2005

5. Thatcher N, Chang A, Parikh P, et al: ISEL: A phase III survival study comparing gefitinib (Iressa) plus best supportive care (BSC) with placebo plus BSC in patients with advanced non small cell lung cancer (NSCLC) who had received one or two prior chemotherapy regimens. Lung Cancer 49:S4, 2005

6. Niho S, Ichinose Y, Tamura T, et al: Results of a randomized phase III study to compare the overall survival of gefitinib (IRESSA) versus docetaxel in Japanese patients with non-small cell lung cancer who failed one or two chemotherapy regimens. ASCO Meeting Abstracts 25:LBA7509-, 2007

7. Douillard JY, Kim E, Hirsh V, Mok T, Socinski M et al: Gefitinib (IRESSA) versus docetaxel in patients with locally advanced or metastatic non-small-cell lung cancer pre-treated with platinum-based chemotherapy: a randomized, open-label Phase III study (INTEREST): PRS-02. . Journal of Thoracic Oncology. 12th World Conference on Lung Cancer, Seoul, Korea, September 2-6, 2007 2:S305-306, 2007