Targeted Therapy in the Multimodality Treatment of Lung Cancer

Lung cancer is the leading cause of cancer death throughout the world. The majority of new cases, over 80%, are non-small cell lung cancer (NSCLC), and more than one third of patients have advanced disease at the time of diagnosis. The median 5-year survival rate for patients with NSCLC is 10% in most parts of the world and ∼15% for patients in the United States. Although the use of third-generation chemotherapeutic agents in combination has resulted in improved 1-year survival and quality of life in patients with stage IV NSCLC, many oncologists believe that we have reached a therapeutic plateau with cytotoxic chemotherapy. Evolving knowledge and understanding of cancer biology over the past decade have allowed for the development of targeted cancer therapy. Therapeutic agents directed against the epidermal growth factor receptor (EGFR) have demonstrated efficacy with limited toxicity in advanced clinical trials in NSCLC and are reviewed in this supplement.

Rivera discusses the role of new chemotherapeutic agents in the treatment of stage IV NSCLC; the use of multimodality therapy in patients with locally advanced disease (chemotherapy offers the potential of treating micrometastatic disease and decreasing the chance of systemic recurrences, whereas surgery and radiation therapy optimize the chance for local control); and the rationale, given recent data, for the role of adjuvant and neoadjuvant chemotherapy in the treatment of early-stage NSCLC. Although slight increases in survival have been seen with these approaches, improvement of symptoms and quality of life remain the primary goals for many patients. Thus, novel therapies with mechanisms of action distinct from chemotherapeutics are needed to achieve therapeutic advances.

Efforts to further develop effective anticancer therapy have included targeting growth factors and receptors that play a role in tumor development and are differentially expressed in tumor cells. Schiller identifies the EGFR as a key target in lung cancer because it is overexpressed in 40 to 80% of NSCLC cases and is critical to tumor cell proliferation, survival, and invasiveness. Thus, agents that target the EGFR may have clinical benefit in tumors with high EGFR expression such as NSCLC.

Laskin and Sandler review the rationale, utility, toxicity profile, and therapeutic strategy of EGFR-targeted therapy. The two approaches that have been most extensively studied in clinical trials involve the use of small-molecular-weight tyrosine kinase inhibitors and monoclonal antibodies directed against the EGFR. Tyrosine kinase inhibitors bind to the cytoplasmic tyrosine kinase component of the EGFR, thus blocking its activity. ZD1839 (gefitinib, Iressa; AstraZeneca Pharmaceuticals, LP, Wilmington, DE) and OSI-774 are the furthest along in their development and testing; phase I, II, and III clinical trials have been completed or are underway. EGFR-targeted monoclonal antibodies have been developed to specifically target the extracellular component of the EGF receptor and include IMC-C225, ABX-EGF, and EMD 72000. These agents have been generally well tolerated, with limited host toxicity (usually low-grade diarrhea and skin rash).

Natale describes two phase II trials of patients with heavily pretreated, locally advanced or metastatic NSCLC randomized to receive ZD1839 monotherapy. The Iressa Dose Evaluation in Advanced Lung cancer (IDEAL-1 and -2) trials measured not only tumor response and safety but also symptom improvement and quality of life. In both trials, response rates were between 10 and 20%. Symptom improvement was rapid, similar at both dose levels, and correlated with both objective disease response and survival. Improvements in quality of life paralleled symptom improvement; both were long lasting and sustained while patients were receiving ZD1839.

In the last article, Choy and Kim review the potential role for EGFR inhibitors as an adjunct to the current combined-modality approach (chemotherapy/radiation therapy ± surgery) for treatment of NSCLC and head and neck cancer. Both preclinical and clinical data have supported the use of these combinations. Synergistic and nonoverlapping toxicities allow concomitant administration of EGFR inhibitors with cytotoxic therapy. Several well-designed clinical studies using EGFR-directed therapy in combination with other standard therapies are ongoing or will soon be initiated. Challenges of evaluating EGFR-targeted agents exist in selecting optimal doses, determining long-term toxicity, and understanding the molecular mechanisms of disease response.