Clin Cancer Res
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The molecular identification and characterization of antigenic epitopes recognized by T cells on human cancers has rapidly evolved since the cloning in 1991 of MAGEA1, the first gene reported to encode a CTL-defined human tumor antigen. In the expanding field of human tumor immunology, unique tumor antigens constitute a growing class of T cell-defined epitopes that exhibit strong immunogenicity. ⋯ Immunogenicity and constitutive expression of the unique tumor antigens provide a strong rationale for the design of novel, patient-tailored therapies that target such determinants. Here we discuss the immunologic relevance of unique tumor antigens in the light of the prospects for exploiting such epitopes as targets for patient-specific immune intervention strategies.
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Bevacizumab is a recombinant, humanized monoclonal antibody against vascular endothelial growth factor. Erlotinib HCl is a reversible, highly selective epidermal growth factor receptor tyrosine kinase inhibitor. Additionally, both agents have shown benefit in patients with previously treated non-small cell lung cancer (NSCLC). ⋯ The median overall survival for the 34 patients treated at the phase II dose was 12.6 months, with progression-free survival of 6.2 months. Encouraging antitumor activity and safety of erlotinib plus bevacizumab support further development of this combination for patients with advanced NSCLC. A randomized phase II trial has been completed, and a phase III trial is ongoing.
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Somatic mutations in the epidermal growth factor receptor (EGFR) have been identified in patients with advanced non-small cell lung cancer who achieve dramatic clinical and radiographic response to the EGFR tyrosine kinase inhibitors (TKI) gefitinib and erlotinib. These mutations in EGFR are found more frequently in patients with adenocarcinomas, nonsmokers, patients of Asian ethnicity, and in females: the same populations that are the most likely to have a clinical response when treated with EGFR TKIs. ⋯ These findings suggest that for patients with advanced non-small cell lung cancer bearing EGFR mutations, treatment with an EGFR TKI should be incorporated as at least part of their initial therapy. These approaches are being studied in ongoing clinical trials and will spur the development of additional technology for EGFR mutation detection.
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Given the increase in novel agents and difficulty with planning and completing many phase III studies, various phase II trial design options should be considered to more effectively guide phase III trial plans. The need for novel phase II trial designs has increased, given the number of novel molecular targeted therapies now available for testing, an abundance of cytostatic agents, and limited resources to conduct phase III studies for all interesting agents or combinations. ⋯ We review randomized phase II designs with placebo control, randomized selection designs, and randomized discontinuation designs. As agents become available for testing in the clinic, the strengths and weaknesses of different phase II trial designs should be considered to optimize a trial development plan that guides phase III trial decisions more effectively.
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Adjuvant chemotherapy is the standard of therapy for some patients with stages I, II, and III breast and colon cancer. The therapeutic efficacy of adjuvant chemotherapy following surgical resection of early stage non-small cell lung cancer (NSCLC) has been less clear. A meta-analysis was reported in 1995 of patients who underwent surgical resection for early stage NSCLC and were then randomized to either observation or chemotherapy. ⋯ The hazard ratio of death for the patients treated with chemotherapy ranged from 0.61 to 0.86 compared with patients on observation. Thus, the information available at the current time supports the administration of chemotherapy for patients with stages IB and II NSCLC. Further research will be needed to define the role of adjuvant chemotherapy and its use in conjunction with chest radiotherapy for the treatment of patients with resected stages IA and IIIA NSCLC.