Will we ever have personalized medicine for non-small cell lung cancer?

As we approached a new millennium in the year 2000, 6 years ago, the hope and expectation was that we would enter a new era of medical discovery and treatment. Lung cancer remains the most common cause of cancer death in the United States and in most other countries around the world. The anticipation, as we complete the first decade of this new millennium, is that we will have personalized medicine for lung cancer. Instead of patients being treated based on their diagnosis, stage of disease, and perhaps some clinical characteristic such as performance status, with the use of proteomics, DNA microarray, and pharmacogenomics, we will truly be able to have individualized medicine for patients with lung cancer. To a certain degree, this paradigm already exists in breast cancer, gastrointestinal stromal tumor, myelodysplasia, and even glioblastoma. Breast cancer genes such as Her-2neu and the estrogen receptor were already known and established as independent prognostic variables and therapeutic targets that can be exploited before this new century and millennium. Gastrointestinal stromal tumors, such as chronic myelogenous leukemia, represent somewhat of an aberration in malignant diseases because there appears to be only a single molecular abnormality. Drugs such as lenalidomide provide significant benefit in patients with myelodysplasia with deletion 5q. In high-grade glioblastoma, the addition of temozolomide to central nervous system radiotherapy produced survival benefit, especially in patients with alterations in the MGMT gene. Thus, there are already examples in malignant diseases where personalized medicine has dictated appropriate and novel therapies. For the purpose of this article, I will discuss lung cancer in two different areas, metastatic disease and adjuvant therapy, in terms of whether individualized medicine will make a difference in directing therapy in the near and distant future. Treatment results of wet stage IIIB and stage IV disease remain dismal. During the past 5 years, the modest advances have primarily been achieved with second-, third-, and even fourth-line therapy rather than any significant improvement in first-line therapy. Platinum doublets are superior to best supportive care and also to single-agent therapy. However, survival benefit is usually, at most, 2 to 3 months. All platinum doublets seem comparable. Until recently, there was no substantive evidence that adding a third drug to a platinum doublet made a difference in survival. However, a recent European study suggested a survival benefit to the three-drug combination of carboplatin plus paclitaxel plus gemcitabine compared with carboplatin plus paclitaxel alone. With the sobering data of such minimal benefit, attention instead has turned to nonchemotherapy molecular targeted agents. Agents such as bexarotene, matrix metalloproteinase inhibitors, erlotinib, gefitinib, protein kinase C inhibitors, and farnesyl transferase inhibitors have all been subjected to well-designed phase III studies comparing a platinum doublet to a platinum triplet in which the third drug was a molecular targeted agent. Almost 9000 patients entered these phase III studies, all of which were negative (Table 1). When the Eastern Cooperative Oncology Group 4599 study opened comparing carboplatin plus paclitaxel versus carboplatin plus paclitaxel plus bevacizumab, my opinion at the time was that this would be yet another negative study similar to those depicted in Table 1. Furthermore, there were no data of clinical activity of bevacizumab as a single agent in non-small cell lung cancer. However, this study, unlike its predecessors in Table 1, was a positive study. The results are depicted in Table 2. We know much more about bevacizumab than we did several years ago. Phase III studies with this agent have been positive in colorectal cancer, breast cancer, and renal cell carcinoma, and the drug appears to have significant activity in ovarian cancer and probably malignant mesothelioma. In a study of second-line chemotherapy for breast cancer, in which survival was the primary endpoint, the comparison of capecitabine with or without bevacizumab demonstrated twice the objective response rate but no difference in overall survival. Bevacizumab is a vascular endothelial growth factor inhibitor but probably has other known and unknown activities above and beyond angiogenesis. Despite the positive results of the Eastern Cooperative Oncology Group 4599 study, this still just represents a 2.3month improvement in median survival. This is somewhat similar to the survival benefit of a platinum doublet compared Division of Hematology-Oncology, Indiana University School of Medicine and Walther Cancer Institute, Indianapolis, Indiana. Address for correspondence: Lawrence H. Einhorn, M.D., 535 Barnhill, Room 473, Indianapolis, IN 46202-5289. E-mail: leinhorn@iupui.edu Copyright © 2006 by the International Association for the Study of Lung Cancer ISSN: 1556-0864/06/0107-0737