Human Genome Sciences, Inc. said it initiated dosing of patients in a phase II clinical trial of HGS-ETR1 (mapatumumab) in combination with the chemotherapy agents paclitaxel and carboplatin as first-line therapy in patients with advanced non-small cell lung cancer.
"The majority of patients who are newly diagnosed with non-small cell lung cancer have locally advanced or metastatic disease that is currently incurable," said Philip D. Bonomi, M.D., a principal investigator in the study, and section director, Medical Oncology, Rush University Medical Center, Chicago. "Fewer than half of these patients are candidates for surgery. There is an urgent medical need for effective treatment options for non-small cell lung cancer because current treatment strategies have only a minimal impact on survival. We look forward to evaluating the potential of HGS-ETR1 plus chemotherapy to offer a new approach to the first-line treatment of this deadly disease."
HGS-ETR1 is a human monoclonal antibody to TRAIL receptor 1, a protein involved in programmed cell death (apoptosis). The first randomised phase II trial of HGS-ETR1 is currently underway in combination with bortezomib (Velcade) in patients with advanced multiple myeloma. HGS expects to have data available from the multiple myeloma study by mid-2008. Preclinical studies have demonstrated that AEG40826 and the HGS TRAIL receptor antibodies exhibit dramatic synergistic activity in a broad range of cancers. HGS plans to develop the TRAIL receptor antibodies and IAP inhibitors in combination with one another and in combination with other therapies.
"The TRAIL-mediated apoptosis pathway is an exciting area of cancer research, and agonistic antibodies to this target offer great promise to patients with a wide variety of cancers. HGS-ETR1 is the most advanced of these antibodies, now with two randomised phase I chemotherapy combination trials ongoing," said David C. Stump, M.D., executive vice president, Research and Development, HGS. "In addition, with the licensing and collaboration agreement we announced today, we have strengthened our oncology franchise by adding small-molecule drugs known as IAP inhibitors, which also enhance apoptosis in cancer cells. We look forward to developing our TRAIL receptor antibodies and IAP inhibitors in combination with one another and in combination with other therapeutic agents."
This randomised, multi-centre, open-label phase II study is designed to evaluate the efficacy and safety of HGS-ETR1 in combination with carboplatin and paclitaxel as first-line therapy in the treatment of advanced non-small cell lung cancer (Stage IIIB or IV). Approximately 105 patients will be randomly assigned among three treatment groups and treated with either the two-agent combination of carboplatin and paclitaxel or the three-agent combination of carboplatin, paclitaxel and HGS-ETR1 at either 10 mg/kg or 30 mg/kg.
TRAIL receptor 1 is differentially expressed on non-small cell lung cancer (NSCLC) cells compared with normal cells while HGS-ETR1 specifically binds TRAIL receptor 1 and triggers NSCLC cell death through apoptosis; and HGS-ETR1 inhibits NSCLC tumour growth in xenograft models of NSCLC, and can induce significant tumour regression in certain xenograft models of the disease. HGS preclinical studies also show that the activity of HGS-ETR1 in NSCLC models may be increased by co-treatment with chemotherapeutic agents including carboplatin and taxanes such as paclitaxel. The results of preclinical studies in a number of NSCLC cell lines showed that combining HGS-ETR1 with these chemotherapeutic agents resulted in increased cancer cell-killing ability despite resistance to mapatumumab alone, indicating a synergistic interaction. The combination of carboplatin, a taxane and HGS-ETR1 resulted in tumour regression and sustained reduction in tumour growth in a xenograft model of NSCLC that was significantly greater than any of the agents alone or the combination of carboplatin and a taxane.
The results of an earlier phase II clinical trial of HGS-ETR1 to evaluate its safety as a single agent in patients with advanced non-small cell lung cancer showed that the drug was generally well tolerated and could be administered safely and repetitively, with no patients discontinuing therapy due to drug-related toxicity. Patients participating in the earlier study previously had received up to seven different cancer treatment regimens (median of three). Stable disease was observed in 29 per cent (nine out of 32) of the patients treated, with eight patients receiving at least four cycles of therapy. The results, along with the results of other clinical and preclinical studies, support further evaluation of HGS-ETR1 in combination with chemotherapy agents.
Non-small cell lung cancer accounts for approximately 75-80 per cent of all lung cancers. It is estimated that more than 170,000 new cases and more than 160,000 deaths occur annually in the United States alone. It is currently the leading cause of cancer death in the US in both men and women.
HGS-ETR1 (mapatumumab) is an agonistic human monoclonal antibody that directly induces cancer-cell death by specifically binding to and activating the protein known as TRAIL receptor 1. Using genomic techniques, HGS originally identified the TRAIL receptor-1 protein. The HGS-ETR1 antibody was generated by HGS through collaboration with Cambridge Antibody Technology. HGS is developing HGS-ETR1 as a potential treatment for a broad range of cancers. GlaxoSmithKline (GSK) has exercised its option under a June 1996 agreement to develop and commercialise HGS- ETR 1 jointly with HGS. Under the terms of the agreement, GSK and HGS will share equally in Phase 3/4 development costs, and will share equally in sales and marketing expenses and profits of any product commercialised.