It's been an interesting time for those of us who treat patients with lung cancer. Over the past few years, non-small-cell lung cancer (NSCLC) has been a target for the numerous companies developing agents that inhibit receptors, growth factors, signaling molecules, and genes involved in tumor growth and development. The "biologic-targeted" approach to treatment is still in its infancy, but it has already given us great expectations, some surprises, some disappointments, and, ultimately, satisfaction that we now have a nonchemotherapeutic option.
There has been much focus on agents targeting the human epidermal growth factor receptor (HER1/EGFR). Promising preclinical data for erlotinib (Tarceva) and gefitinib(Drug information on gefitinib) (Iressa) led us to expect that we would have an effective addition to first-line platinum-based chemotherapy. The negative results from the INTACT 1 and 2 studies with gefitinib and chemotherapy,[1,2] and later TALENT and TRIBUTE studies with erlotinib and chemotherapy,[3,4] were both surprising and disappointing. Numerous hypotheses have been proposed, but it remains unclear why these trials failed.
Nevertheless, further analysis suggests that combining these agents with chemotherapy may still be beneficial in certain patients (ie, "never-smokers") or with specific regimens. Adding to the puzzle are recent data showing a survival benefit with erlotinib in combination with gemcitabine(Drug information on gemcitabine) in advanced pancreatic cancer, and the improvement in response when cetuximab(Drug information on cetuximab) (Erbitux), an anti-HER1/EGFR monoclonal antibody, is combined with irinotecan (Camptosar) for patients with metastatic colorectal cancer. Recently, exciting data show that adding bevacizumab(Drug information on bevacizumab) (Avastin), an anti-vascular endothelial growth factor monoclonal antibody, to first-line chemotherapy significantly improved survival for patients with nonsquamous NSCLC.
Despite disappointing results with HER1/EGFR-targeted agents and chemotherapy in NSCLC, monotherapy data in patients with refractory or relapsed disease have been more encouraging. In May 2003, the US Food and Drug Administration (FDA) approved gefitinib at 250 mg/d for patients with advanced NSCLC after failure of both platinum-based and docetaxel(Drug information on docetaxel) chemotherapy. The study (IDEAL 2) was not placebo-controlled, but showed a response rate of 12% with symptom improvement in 44% of patients. Gefitinib was the first biologic-targeted agent approved for NSCLC, and the first for third-line treatment. US oncologists were quick to use gefitinib for these previously poorly served patients.
Research and development efforts were further encouraged by positive data from the phase III trial of erlotinib vs placebo in patients with advanced NSCLC who had failed one or two prior chemotherapy regimens (the National Cancer Institute of Canada [NCIC] trial BR.21). Erlotinib recipients had a significant improvement in median and progression-free survival (42.5% and 25.3% improvement, respectively), and 31.2% of these patients were alive after 1 year.[10,11] The survival benefit was evident in all patient subgroups evaluated. Based on these data, in November 2004, the FDA approved erlotinib at 150 mg/d for patients with advanced NSCLC after failure of at least one prior chemotherapy, giving us another third-line option and an alternative to second-line chemotherapy.
The FDA approved gefitinib on the condition that AstraZeneca run the following confirmatory studies of its benefit in NSCLC:
•Iressa Survival Evaluation in Lung cancer (ISEL) trial, which compared gefitinib with best supportive care in a randomized, double-blind, placebo-controlled setting
•Iressa NSCLC Trial Evaluating Response and Survival against Taxotere (INTEREST)
•Iressa vs Best Supportive Care Randomized Evaluation of Effect on Symptom Endpoint (IBREESE) trial.
The INTEREST and IBREESE studies have not reported at the time of writing, but, surprisingly, results from ISEL showed that gefitinib does not significantly prolong survival compared with placebo in patients with locally advanced or metastatic NSCLC who have failed at least one prior chemotherapy regimen.
The FDA also requested two phase IV postmarketing studies with gefitinib. Southwest Oncology Group (SWOG) 0023 was designed to assess overall survival with maintenance gefitinib compared with placebo in patients with stage III NSCLC who have successfully completed chemoradiation and chemotherapy consolidation therapy. In April 2005, the study was stopped because the end point was considered impossible to reach; 2 years after randomization, overall survival was 29 months on placebo vs 19 months on gefitinib. The second trial, BR.19designed to assess survival with gefitinib vs placebo in the adjuvant NSCLC setting after definitive surgeryhas also been stopped because of the negative results of the ISEL and SWOG trials.
Based on the lack of survival benefit in ISEL, AstraZeneca suspended promotion of gefitinib and advised physicians to consider other treatment options for patients who were previously treated with two prior chemotherapy regimens. Recently, the FDA approved changes to the product label, limiting use to patients who are currently benefiting or have previously benefited from gefitinib. To implement this change, AstraZeneca is starting the Iressa Access Program. Patients who began taking gefitinib prior to September 15, 2005, fill prescription refills through this program. Since that date, new patients do not have access to gefitinib unless they are part of a clinical study approved by an Institutional Review Board (and, if such a trial was approved after June 17, 2005, it must be conducted under an investigational new drug application). So, although gefitinib and erlotinib target the same receptor, their clinical results appear to be different.