Targeting the HER1/EGFR Receptor to Improve Outcomes in Non–Small-Cell Lung Cancer

Non-small-cell lung cancer is a growing global burden and an ongoing therapeutic challenge. Despite attempts to optimize disease management and treatment, there have been only limited advances with new variations on standard chemotherapeutic regimens, and overall progress in this regard has been poor. There has been no substantial improvement in patient survival over the past 20 years. The advent of targeted cancer therapies such as those targeting the HER1/epidermal growth factor receptor (EGFR) offers the promise of improved treatment of non-small-cell lung cancer. Current Status of Standard Chemotherapy Lung cancer is almost uniformly fatal, and accounts for approximately 20% of all cancer deaths (excluding those due to skin cancers) according to World Health Organization estimates for 2000.[1] In the United States, lung cancer continues to be the leading cause of cancer-related mortality.[ 2] Approximately 75% to 80% of lung cancers exhibit non-small-cell lung cancer histology, and the major- ity of these patients present with either locally advanced (stage III) or metastatic (stage IV) disease.[3] Patients undergoing successful surgical resection for early (stage I/II) localized non-small-cell lung cancer have survival rates of 50% to 80%. However, chemotherapy is required in the majority of non-small-cell lung cancer patients, because the majority present at advanced stages of disease and because many patients require chemotherapy for relapse after surgery.[ 3] Chemotherapy for advanced non- small-cell lung cancer appears to have reached a plateau in terms of improving survival, with slight improvements over the past 10 years still leaving median survival at less than 1 year. As demonstrated by the recent trial by Schiller et al comparing combinations of cisplatin(Drug information on cisplatin) with paclitaxel(Drug information on paclitaxel), docetaxel (Taxotere), or gemcitabine(Drug information on gemcitabine) (Gemzar) and carboplatin(Drug information on carboplatin) (Paraplatin)/ paclitaxel, there are no survival differences among standard regimens, with 1-year survival rates being 35% to 40%.[4] Apart from the limited survival benefit with traditional chemotherapy, such treatment often is associated with toxicity that cannot be tolerated by patients already debilitated from major surgery, concomitant morbidities in older age, prior chemotherapy, or symptoms of late-stage disease. In brief, therapeutic needs in non-small-cell lung cancer include improved survival and prolonged time to disease progression, improvement in disease-related symptoms and other aspects of quality of life, and better tolerated regimens for patients who are not candidates for standard combinations. Targeted Treatment: HER1/EGFR Inhibitors Newer, molecular-targeted approaches to treatment offer the potential for improving tumor responses and reducing treatment-associated toxicities. A variety of classes of these new biologic agents that target cell signaling pathways may find roles in treatment of non-small-cell lung cancer (Table 1): HER1/EGFR targeted agents, including EGFR tyrosine kinase inhibitors and monoclonal anti- antibodies; angiogenesis inhibitors; signal transduction inhibitors, cyclooxygenase- 2 inhibitors, and other inhibitors of cell survival pathways. HER1/EGFR inhibition is an attractive target in non-small-cell lung cancer; exploitation of this approach has produced a number of novel agents that are well along in clinical development and investigation. HER1/ EGFR is pivotal in regulating a number of functions that determine tumor cell proliferation and survival and appears to have no critical function in healthy tissue. Overexpression/ dysregulation of the receptor is common in non-smal-cell lung cancer, having been identified in 76% of squamous cell carcinomas, 47% of adenocarcinomas, and 43% of large cell carcinomas, and there is evidence that overexpression/dysregulation is associated with poor prognosis[5-8]; there is also evidence that the EGFRvIII mutant is associated with progression of non-small-cell lung cancer.[9] Early investigation of this target showed no evidence of severe toxicity with its inhibition in vivo and demonstrated that inhibition in vitro resulted in blocking of downstream cell activation. A wide range of uses of HER1/ EGFR inhibitors can be conceived in non-small-cell lung cancer, including in the settings of neoadjuvant or adjuvant therapy, as first- or second-line therapy in combination with standard chemotherapeutic agents in patients with advanced disease or as first-line treatment in those who are not suitable candidates for standard chemotherapy, and as palliative therapy aimed at maintaining/improving quality of life. In addition, such agents may eventually be targeted to specific subgroups of patients based on molecular profiling of disease. Erlotinib (Tarceva) is a promising HER1/EGFR-targeting agent. This agent exhibits highly selective, potent, and reversible inhibition of HER1/ EGFR tyrosine kinase phosphorylation, resulting in inhibition of tumor cell proliferation and induction of cell apoptosis, and has been found to inhibit the EGFR mutant EGFRvIII. In tumor models, erlotinib has been shown to have at least additive antitu- mor effects when combined with cytotoxic agents with no increase in cellular toxicity and to result in stasis or regression of tumor growth in non- small-cell lung cancer and other human tumor xenografts. The agent is orally available, and is well tolerated in human subjects. Erlotinib is currently being evaluated in a number of phase III and phase II trials in advanced non-small-cell lung cancer (Table 2). These include the phase III TRIBUTE trial evaluating the effects of adding erlotinib to carboplatin/paclitaxel in first-line therapy and the phase III TALENT trial evaluating the addition of erlotinib to cisplatin/gemcitabine in first-line therapy. Recent final results have shown that these trials did not meet their primary end points of improving overall survival. Further studies will attempt to detect a survival advantage for erlotinib use as a single agent in second- and third-line treatment. In addition, the phase III BR.21 trial will provide important information on the effects of erlotinib alone in advanced disease. Ongoing phase II trials include an evaluation of the combination of erlotinib with the angiogenesis inhibitor bevacizumab(Drug information on bevacizumab) (Avastin), a humanized monoclonal antibody directed against vascular endothelial growth factor (VEGF); VEGF plays a central role in tumor angiogenesis and maintenance of established blood vessels. Bevacizumab has been shown to improve survival in colorectal cancer by 30% as first-line therapy, and is currently being investigated in non- small-cell lung cancer and small-cell lung cancer. The prospect of combining HER1/EGFR-inhibitory and antiangiogenesis effects with the erlotinib/bevacizumab combination is highly attractive. Select pivotal studies with other agents targeting HER1/EGFR in advanced non-small-cell lung cancer are shown in Table 3. These include the phase III INTACT 1 and 2 trials of the HER1/EGFR tyrosine kinase inhibitor gefitinib(Drug information on gefitinib) (Iressa) in combination with standard chemotherapy as firstline treatment; results of these trials showed no benefit of adding gefitinib to chemotherapy in this setting. How ever, positive results of the IDEAL 1 and 2 trials[10,11] resulted in US Food and Drug Administration approval of use of this agent for treatment of advanced, refractory non-small-cell lung cancer. The anti-HER1/EGFR monoclonal antibody cetuximab(Drug information on cetuximab) (Erbitux) is being evaluated in combination with chemotherapy as first-or second-line treatment in a number of phase II trials; the phase II randomized trial of cisplatin/vinorelbine (Navelbine) with or without cetuximab has shown a markedly higher response rate with the cetuximab-including regimen. In addition, a phase II trial of the monoclonal antibody ABX-EGF combined with chemotherapy in patients with tumors shown to overexpress HER1/ EGFR is under way. Conclusion Figure 1 provides some idea of the current status of attempting to improve treatment and outcomes in advanced non-small-cell lung cancer. As noted, gefitinib is now available for treatment of advanced, refractory disease. The antifolate agent pemetrexed(Drug information on pemetrexed) was shown to be as effective as docetaxel(Drug information on docetaxel) therapy in recurrent lung cancer. The hypoxic cell cytotoxin tirapazamine showed no additional benefits when added to chemotherapy in two large randomized trials. The outcomes of the phase III TRIBUTE, TALENT, and BR.21 trials of erlotinib are eagerly awaited. There are a number of challenges to be met in defining the role and optimizing the benefits of HER1/EGFRtargeted therapy in non-small-cell lung cancer. It should be determined whether HER1/EGFR overexpression/ activation is predictive of response to inhibitors and whether there are other predictive markers that could permit effective patient targeting. Surrogate markers of activity may be useful in assessing whether subpopulations of patients respond to these treatments. Optimal doses of these agents for effective inhibition of their target and for inhibition of downstream pathways remain to be elucidated. Likewise, optimal doses and schedules of these agents when used alone or in combination with chemotherapy remain to be determined, and optimal combinations with chemotherapeutic agents and/or other biologic agents remain to be identified. Evaluation of use of these therapies at each stage of non-small-cell lung cancer is ongoing. It is hoped that in the near future, the classical options of surgery, radiation therapy, and cytotoxic chemotherapy in non-smallcell lung cancer will be joined by HER1/EGFR inhibition and angiogenesis inhibition as modalities that improve overall patient management and outcomes of treatment in this disease.