Introduction

Thomas J. Lynch, Jr., MD
Massachusetts General Hospital Cancer Center
Boston, Massachusetts

Advanced non–small cell lung cancer (NSCLC) remains a devastating illness. In clinical trials evaluating standard platinum based doublets, median survival has remained relatively constant at 8 to 11 months, leading some investigators to believe that a plateau has been reached using cytotoxic chemotherapy. In contrast, the use of novel targeted therapies may offer significant benefit for patients with advanced disease.¹ Over the past decade, several significant advances in targeted therapies have improved our ability to treat certain tumors. These have all involved 1) the discovery of a key biologic lesion vital to survival of the tumor, coupled with 2) the availability of a drug targeted to that key lesion, which blocks signaling and leads to clinical responses. The most notable early successes were achieved by targeting the Bcr-Abl fusion protein in chronic myelogenous leukemia (CML) with imatinib (Gleevec®, Novartis),² HER2 expression in breast cancer with trastuzumab (Herceptin®, Genentech),^3,4 and C-Kit mutations with imatinib or sunitinib (Sutent®, Pfizer) in gastrointestinal stromal tumors.^5,6

The discovery and clinical application of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) such as gefitinib (Iressa®, AstraZeneca) and erlotinib (Tarceva®, Genentech/ Roche) have similarly revolutionized treatment for a subset of patients with advanced NSCLC. This is particularly true for patients with somatic activating EGFR mutations that are associated with EGFR-TKI sensitivity, which occur at a frequency of approximately 10% in North American NSCLC patients and at least 30% in Asian patients.^7-9 In-frame deletions in exon 19, or substitution of arginine for leucine at position 858 (L858R) in exon 21, account for about 85% of mutations in this receptor.9When patients harboring one of these mutations are treated with EGFR- TKIs, aggregate responses rates of 75% and favorable progression free survival (PFS) and overall survival (OS) have been seen in prospective phase II trials. Recently, preliminary results of IPASS, a randomized phase III trial, suggested the superiority of first-line gefitinib to cytotoxic chemotherapy in a clinically enriched population of 1200 patients.¹⁰ Subset analysis revealed that patients harboring an EGFR mutation had improved progression-free survival with gefitinib compared to chemotherapy, while those who were EGFR wild-type had a greater progression-free survival with chemotherapy compared to gefitinib. The identification of EGFR TK domain mutations in NSCLC and their association with sensitivity to EGFR-TKIs has thus been a landmark event in the treatment of this lethal cancer. Therapy may now be selected in some patients on a truly individual basis rather than on empiricism.

Although responses to EGFR-TKIs may extend for months or even years, the disease ultimately progresses due to the development of "acquired resistance." In many cases, following initial response to a targeted agent, the emergence of resistance coincides with the acquisition of new mutations in the target receptor. For example, the acquisition of the secondary T315I mutation in Bcr-Abl is implicated in imatinib resistance in patients with CML.¹¹ Similarly, in EGFR-mutated NSCLC, the T790M EGFR mutation is responsible for about 50% of gefitinib or erlotinib resistance.^12,13 In other cases, resistance follows the activation of a parallel or alternate signaling pathway that abrogates the one inhibited by the effective targeted therapy. Thus, in patients without T790M mutations, amplification of the MET tyrosine kinase gene accounts for an additional 20% of cases of EGFR-TKI resistance.¹⁴

New drugs have been developed that may be effective in lung cancers resistant to EGFR-TKIs. Several new small-molecule EGFR inhibitors can covalently bind to this receptor, potentially leading to more effective and durable antitumor activity. These can effectively inhibit growth of tumors harboring T790M and induce regression of established tumors in mice bearing mutations such as L858R/T790M. In preclinical studies and clinical trials, some of these inhibitors have demonstrated activity in tumors with acquired resistance.^15-17 Careful examination of rebiopsy specimens or circulating tumor cells obtained at treatment failure can help identify and more fully understand the basis of acquired resistance, facilitating the development of these and other effective treatment strategies for patients with resistant lung cancer. As the era of molecularly targeted therapies for cancer comes into its own, understanding, preventing, and treating resistance to targeted agents such as EGFR-TKIs is becoming an area of intense interest both in basic research and clinical development.

This educational monograph presents recent data on the optimal use of targeted therapy for patients with advanced NSCLC, particularly those agents that inhibit the EGFR. Guidelines on patient selection for EGFR inhibitor therapy in NSCLC, the mechanisms underlying acquisition of EGFR-TKI resistance, and novel agents that may be effective for treatment of resistant disease are highlighted.

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