HOUSTON‘‘We appear to be approaching a ceiling for benefits of cytotoxic chemotherapy in advanced non-small-cell lung cancer (NSCLC). All recent randomized studies have had similar results, and there has been no clear efficacy benefit from nonplatinum combinations or triplets. Certainly for advanced disease and even for early disease, where metastases kill most patients, a paradigm shift is needed, and that shift will probably be to targeted therapy that works against specific biologic pathways," said Roy S. Herbst, MD, PhD. Dr. Herbst is assistant professor of medicine and chief of the Section of Thoracic Oncology at the University of Texas M.D. Anderson Cancer Center in Houston, Texas.
"Initially, these agents were classified as cytostatic agents, as opposed to the current cytotoxic drugs and were thought not to produce single-agent responses. Recent data suggest a low but real single-agent response for some of them," Dr. Herbst said. The main categories now under active study are signal transduction or cell-cycle inhibitors, angiogenesis inhibitors, gene therapy, vaccines, and receptor-targeted therapy.
Perhaps More Specific
Dr. Herbst said that the hope is that agents aimed at biological pathways will be even more specific for the tumor cell than for normal cells and therefore less toxic. "The hope is that these agents could be used for longer periods, used for maintenance therapy, and used to prevent or keep in check metastatic disease," he said. "In lung cancer, we can think about integrating these agents with current therapy at all stages of disease. In the earliest premalignancy stage, they may be useful as preventive agents. In localized disease, where there is still 40% recurrence in stage I disease, we might think about surgery, radiotherapy, then a biological as maintenance therapy. In locally or regionally advanced disease, after the best response we might try to prevent recurrence with a biologic agent. In the advanced setting, where we do not cure anyone, perhaps we could prolong survival by using a biological agent."
Dr. Herbst suggested that the new paradigm for lung cancer treatment will involve surgery and radiation combined with chemotherapy and biologic therapy for distant metastases. "In almost all cases they are synergistic," he said. "This will be directed at preventing recurrence and keeping metastases in check."
Major issues regarding new molecular therapies include identification of the target and determining whether the target is important in NSCLC and whether screening for overexpression of the target is necessary. "It also helps to know the mechanism of action and whether there are surrogate markers for drug response that can be used in phase I trials," Dr. Herbst said.
New trial designs are also needed. "You don’t want to dose these biologic agents to the maximum tolerated dose but to the biologically effective dose," Dr. Herbst said.