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 (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 in advanced pancreatic cancer, and the improvement in response when 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 (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 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.
1. Herbst RS, Giaccone G, Schiller JH, et al: Gefitinib in combination with paclitaxel and carboplatin in advanced non-small-cell lung cancer: A phase III trial-INTACT 2. J Clin Oncol 22:785-794, 2004.
2. Giaccone G, Herbst RS, Manegold C, et al: Gefitinib in combination with gemcitabine and cisplatin in advanced non-small-cell lung cancer: A phase III trial-INTACT 1. J Clin Oncol 22:777-784, 2004.
3. Gatzemeier U, Pluzanska A, Szczesna A, et al: Results of a phase III trial of erlotinib (OSI-774) combined with cisplatin and gemcitabine (GC) chemotherapy in advanced non-small cell lung cancer (NSCLC) (abstract 7010). Proc Am Soc Clin Oncol 23:617, 2004.
4. Herbst RS, Prager D, Hermann R, et al: TRIBUTE: A phase III trial of erlotinib HCl (OSI-774) combined with carboplatin and paclitaxel chemotherapy in advanced non-small cell lung cancer. J Clin Oncol 23:5892-5899, 2005.
5. Miller VA, Herbst R, Prager D, et al: Long survival of never smoking non-small cell lung cancer (NSCLC) patients (pts) treated with erlotinib HCl (OSI-774) and chemotherapy: Sub-group analysis of TRIBUTE (abstract 7061). Proc Am Soc Clin Oncol 23:628, 2004.
6. Moore MJ, Goldstein D, Hamm J, et al: Erlotinib plus gemcitabine compared to gemcitabine alone in patients with advanced pancreatic cancer. A phase III trial of the National Cancer Institute of Canada Clinical Trials Group [NCIC-CTG] (abstract 1). J Clin Oncol 23(16S):1s, 2005.
7. Cunningham D, Humblet Y, Siena S, et al: Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 351:337-345, 2004.
8. Sandler AB, Gray R, BrahmerJ, et al: Randomized phase II/III trial of paclitaxel (P) plus carboplatin (C) with or without bevacizumab (NSC #704865) in patients with advanced non-squamous non-small cell lung cancer (NSCLC): An Eastern Cooperative Oncology Group (ECOG) trial-E4599 (abstract LBA4). J Clin Oncol 23(16S):2s, 2005.
9. Kris MG, Natale RB, Herbst RS, et al: Efficacy of gefitinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, in symptomatic patients with non-small cell lung cancer: A randomized trial. JAMA 290:2149-2158, 2003.
10. Shepherd FA, Pereira J, Ciuleanu TE, et al: Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med 353(pt 2):123-132, 2005.
11. Tarceva prescribing information. Available at www.Tarceva.com. Accessed April 5, 2006.
12. Thatcher N, Alex Chang A, Purvish Parikh P, et al: Results of a phase III placebo-controlled study (ISEL) of gefitinib (IRESSA) plus best supportive care (BSC) in patients with advanced non-small-cell lung cancer (NSCLC) who had received 1 or 2 prior chemotherapy regimens (abstract LB-6). Proc Am Assoc Cancer Res 46, 2005
13. Kelly K, Gaspar LE, Chansky K, et al: Low incidence of pneumonitis on SWOG 0023: A preliminary analysis of an ongoing phase III trial of concurrent chemoradiotherapy followed by consolidation docetaxel and gefitinib/placebo maintenance in patients with inoperable stage III non-small cell lung cancer (abstract 7058). J Clin Oncol 23(16S):634s, 2005.
14. Letter from AstraZeneca, December 17, 2004. Available at www.iressa-us.com/dr.pdf. Accessed April 5, 2006.
15. 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.
16. Alimta prescribing information. Available at www.Alimta.com. Accessed April 5, 2006.
17. Fukuoka M, Yano S, Giaccone G, et al: Multi-institutional randomized phase II trial of gefitinib for previously treated patients with advanced non-small-cell lung cancer. J Clin Oncol 21:2237-2246, 2003.
18. Miller VA, Kris MG, Shah N et al: Bronchioloalveolar pathologic subtype and smoking history predict sensitivity to gefitinib in advanced non-small-cell lung cancer. J Clin Oncol 22:1103-2103, 2004.
19. Lynch TJ, Bell DW, Sordella R, et al: Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 350:2129-2139, 2004.
20. Pao W, Miller V, Zakowski M, et al: EGF receptor gene mutations are common in lung cancers from "never smokers" and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc Natl Acad Sci 101:13306-133011, 2004.