R-1549

Gene amplification, over-expression, and mutation of growth factors, or the receptors themselves, causes increased signaling through receptor kinases, which has been implicated in many human cancers and is associated with poor prognosis. Tumor growth has been shown to be decreased by interrupting this process of extensive growth factor-mediated signaling by directly targeting either the surface receptor or the ligand and thereby preventing cell survival and promoting apoptosis. Monoclonal antibodies have long been eyed as a potential new class of therapeutics targeting cancer and other diseases. Antibody-based therapy initially entered clinical practice when trastuzumab/Herceptin became the first clinically approved drug against an oncogene product as a well-established blocking reagent for tumors with hyperactivity of epidermal growth factor signaling pathways. In the first part of this review we explain basic terms related to the development of antibody-based drugs, give a brief historic perspective of the field, and also touch on topics such as the "humanization of antibodie" or creation of hybrid antibodies. The second part of the review gives an overview of the clinical usage of bispecific antibodies and antibodies "armed" with cytotoxic agents or enzymes. Further within this section, cancer-specific, site-specific, or signaling pathway-specific therapies are discussed in detail. Among other antibody-based therapeutic products, we discuss: Avastin (bevacizumab), CG76030, Theragyn (pemtumomab), daclizumab (Zenapax), TriAb, MDX-210, Herceptin (trastuzumab), panitumumab (ABX-EGF), mastuzimab (EMD-72000), Erbitux (certuximab, IMC225), Panorex (edrecolomab), STI571, CeaVac, Campath (alemtuizumab), Mylotarg (gemtuzumab, ozogamicin), and many others. The end of the review deliberates upon potential problems associated with cancer immunotherapy.

The treatment course for advanced ovarian cancer is marked both by chemotherapy sensitivity at the outset and by eventual death from resistant disease in patients who relapse. Aggressive surgical debulking and platinum plus taxane therapy have improved median survival from 1 year in 1975 to approximately 5 years in 2005, but the long-term cure rate continues to languish in the 20% to 30% range. Approximately 50% of patients will enter a pathologic first complete clinical remission, yet 90% of suboptimally debulked patients and 70% of optimally debulked patients relapse in 18 to 24 months. Subsequent and repeated chemotherapy responses are often seen with ever shortening intervals until broad chemotherapy resistance develops. Opportunities to improve the outcome for patients exist by making primary therapy more effective, or by applying consolidation or maintenance approaches to patients in a complete primary or subsequent remission. Well-designed randomized studies such as the SMART study by Verheijen et al in complete clinical remission patients represent a new opportunity for progress. The SMART study, evaluating intraperitoneal therapy with yttrium-90-labeled HMFG1 murine monoclonal antibody (Y-muHMFG1), described in this issue of the Journal of Clinical Oncology, was logically based and appropriately designed. Ovarian cancer patients usually have disease localized to the peritoneal cavity at the time of progression, thus providing a rationale for intraperitoneal (IP) therapy. The small volume of disease during remission is appropriate to consider an immune mechanism. The MUC 1 antigen that Y-muHMFG1 is directed towards is well established as an attractive immunotherapy target since it is overexpressed on 90% of adenocarcinomas, including ovarian cancer. The phase II data supporting the use of Y-muHMFG1 administered intraperitoneally in patients in first remission was promising, with a Cox model estimate of 10-year survival at 70% compared to 32% of case matched controls (P .003). Patients were stratified using a second surgical assessment where disease status at second look remains a powerful predictor of ultimate progression free and overall survival. Finally, the study was adequately powered to answer the question as to whether a single intraperitoneal administration of Y-muHMFG1 for patients in remission impacted outcome. While the negative therapeutic results are disappointing and one can speculate whether changing frequency or dose could affect efficacy, the trial serves as the largest prospective randomized study of patients in a surgically defined remission population with overall survival as the outcome. The outcome of this trial reminds us all that randomized trials are the only reasonable way to move cancer therapy forward. The value of treatment in clinical complete remission was first established in acute leukemia and additional consolidation or maintenance chemotherapy dramatically improved the outcome for some of these patients. These concepts have not found a place in solid tumor therapy. Even the nomenclature is confusing. Strictly speaking, consolidation should be best applied to those strategies that are of limited duration such as high-dose chemotherapy or whole abdominal radiotherapy, and maintenance is best used to describe interventions that continue for years (or until progression). As treatment options move beyond classic cytotoxic chemotherapy to hormones, immune interventions, and targeted therapy, the consolidation strategy is regaining interest in solid tumors. A recent study, for example, showed the benefit of consolidation trastuzumab for one year in patients with breast cancer. In ovarian cancer, no randomized consolidation study has provided a statistically significant improvement in overall survival, although many attempts have been made. Negative randomized consolidation approaches include both subcutaneous and IP interferon-alfa, high-dose chemotherapy, continued intravenous carboplatin versus whole abdominal radiotherapy (WART), chemotherapy versus observation versus WART, IP radioactive phosphorus (32P), noncross resistant chemotherapy in the form of cisplatin and fluorouracil for three cyclesor topotecan for four cycles, and the monoclonal antibody orgovomab which targets CA125. With regards to IP cytotoxic chemotherapy as consolidation, no adequately powered randomized study versus observation has been completed. The only randomized study to show evidence of clinical benefit was the Southwest Oncology Group/Gynecologic Oncology Group study of ovarian cancer patients receiving three versus 12 additional cycles of intravenous paclitaxel following a complete response to platinum and paclitaxel therapy. This study showed a progression free survival advantage of 28 months versus 21 months in favor of the 12 cycle arm (hazard ratio [HR], 2.31; 99% CI, 1.08 to 4.94). Survival data is not available due to its early termination by the data safety monitoring committee. With the important exception of the paclitaxel consolidation study, the extended chemotherapy trials and radiotherapy treatments have been disappointing. A variety of clinical observations have supported the role of the immune system in determining the outcome of patients with ovarian cancer. In a study by Zhang et al with 74 patients in complete clinical remission (ie, the consolidation population), 5-year overall survival was 73.9% in those whose tumors were found to have infiltrating T lymphocytes present versus 11.9% in those that did not (P .001). The characterization of surface antigens and the JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 24 NUMBER 4 FEBRUARY 1 2006