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.
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.
‘Exciting’ New Therapies
Dr. Herbst described anti-epithelial growth factor receptor (EGFR) therapies as "the most exciting ones in NSCLC." EGFR comprises a family of four receptors, one of which is HER-2 or C-erbB2. The monoclonal antibody trastuzumab (Herceptin) is highly effective against HER-2, but Dr. Herbst said that unfortunately only 10% to 15% of NSCLCs overexpress the HER-2 receptor. "It is very hard to find lung cancer patients who overexpress HER-2," he said.
The investigational drugs OSI-774 (Tarceva) and ZD 1839 (Iressa), are EGFR-specific tyrosine kinase inhibitors, that are orally bioavailable and have shown preclinical activity in multiple tumor xenografts, Dr. Herbst said.
The major toxicity is an acneiform rash, the extent of which is related to frequency and dose. Unfortunately this makes blinded trials difficult. "If patients had the rash, they knew they were getting the drug, but clearly not every patient gets a rash" Dr. Herbst said.
Multiple responses were noted in all phase I NSCLC studies of ZD 1839, and about one third of treated patients have had stable disease lasting for 3 months are more. "Multiple patients with significant pretreatment had stable disease for more than 1 year after ZD 1839, and preclinical studies have demonstrated a synergy with cytotoxic chemotherapy," Dr. Herbst said.
OSI-774 was tested in 50 patients with NSCLC positive for EGFR expression (over 10% of cells by immunohistochemistry) who had progression or relapse after platinum-based therapy. All patients had at least one prior chemotherapy, and none had active brain metastasis. Patients were treated with OSI-774 at 150 mg/d. Dr. Herbst said that the overall response rate was 14.3%, which included 1 (1.8%) complete response, 7 (12.5%) partial responses, and 15 (26.8%) stable disease. Median survival was 257 days, and 1-year survival was 48%. "This almost looks too good to be true and needs to confirmed, but it is an exciting result," Dr. Herbst said. Randomized trials of ZD 1839 with chemotherapy in advanced NSCLC quickly completed enrollment.
The anti-EGFR antibody cetuximab (C-225) is currently in phase II pilot studies as first-line therapy for NSCLC in combination with carboplatin (Paraplatin)/gemcitabine (Gemzar) and with carboplatin/paclitaxel (Taxol). Cetuximab is also in trials as second-line therapy in combination with docetaxel (Taxotere).
MMP Inhibitors Promising
Matrix metalloproteinase (MMP) inhibitors, which interfere with the development of invasive carcinoma, were seen as promising, but Dr. Herbst said that the failure to develop "proof of principal" in early trials has resulted in costly and negative or harmful trials.
Drugs that target vascular endothelial growth factor (VEGF) or its receptor are in clinical trials in NSCLC and a number of other advanced malignancies. "Anti-VEGF is the most advanced angiogenesis inhibitor in lung cancer therapy," Dr. Herbst said. Recombinant human anti-VEGF (rhuMab-VEGF) produced a 7.4-month time to progression but also caused life-threatening hemorrhage in 6 of 67 patients, 4 of whom died. The risk of hemorrhage appears to be less in patients with nonsquamous-cell cancers, perhaps because patients with squamous-cell cancers are more likely to have centrally located tumors that are more prone to bleeding.
RhuMab-VEGF is under study in Eastern Cooperative Oncology Group (ECOG) randomized trial E-4599, which will compare carboplatin/paclitaxel to carboplatin/paclitaxel/rhuMAb-VEGF in previously untreated patients with stage IIIB or IV nonsquamous cell lung cancer.
"These new agents will be used with chemotherapy in most situations," Dr. Herbst said. "Where possible, we must explore preclinical models and surrogate markers of activity to evaluate and choose which agents to pursue. The molecular diversity of tumors may ultimately necessitate use of a cocktail of agents to maximize therapeutic effect. The specific makeup of this cocktail will be determined based on the molecular phenotype of any given tumor to most specifically block its growth."