Some interesting lectures from ASCO:
conference-cast.com
(but only a few have any internet-viewable lectures so far).
Also these two summary pieces:
Measured Progress Characterizes the Development of Angiogenesis Inhibitors and Endothelin Antagonists for Cancer Therapy
Each of six presentations comprising the Integrated Symposium II speaks for an expanding range of therapeutic and prognostic options arising from studies into host mechanisms that enable tumor growth. In today’s symposium, "Development of Angiogenesis Inhibitors and Endothelin Antagonists for Cancer Therapy," Robert S. Kerbel, PhD, University of Toronto, whose own work involves studies of the basis of metastasis, angiogenesis, and acquired drug resistance in cancer, will provide an overview of the scientific foundations that underlie these clinical milestones and a perspective on the future, arguing for reasonable expectations from an area of cancer medicine still in its infancy.
Endostatin and angiostatin are both potent, naturally occurring angiogenesis inhibitors that induce endothelial cell apoptosis and tumor regression in preclinical models. New results from two phase I clinical trials provide further evidence of safety, biologic activity, and efficacy of recombinant forms of endostatin (rHE) and angiostatin (rhA) in human subjects. In one study, Roy S. Herbst, MD, PhD, and colleagues at the University of Texas, M.D. Anderson Cancer Center analyzed the pharmacokinetics, safety, and efficacy of rHE in 22 patients with solid tumors, using tissue and radiologic response as surrogate endpoints. The results show that rHE appears to be safe, with no significant drug-related toxicities. The agent was found to possess biologic and antitumor activity according to multiple analytic criteria.
While disease was stabilized or a minor response occurred in only a few patients, O-15 PET scan analysis illustrated a significant decrease in blood flow with increasing doses of endostatin. In addition, tissue biopsy analysis of endothelial and tumor cell apoptosis showed a trend toward increased apoptotic rates after treatment with endostatin. These results suggest a biologic effect for this molecule, a finding that will be validated further in a subsequent study.
Presenting data from investigators involved in the first human trial with recombinant human angiostatin (rhA) will be Eduardo D. DeMoraes, MD, from Jefferson Medical College. Patients with diverse forms of metastatic cancer that had failed to respond to chemotherapy were enrolled in this phase I trial. Evidence relating to the safety of daily infused rhA established no dose-limiting toxicities or treatment-related hemorrhagic or thrombotic events. rhA was determined to have linear pharmacokinetics. The agent did not alter wound healing in 14 of 19 patients who underwent surgical procedures.
Vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) are two major targets of pharmacologic therapies that aim to block their expression and thereby control the growth of new blood vessels. In a phase I study being reported by Gordon C. Jayson, MD, PhD, for the European Organization for the Research and Treatment of Cancer (EORTC) Biological Therapeutic Development Group, the anti-VEGF antibody, HuMV833, was the subject of the first PET evaluation of an antiangiogenic agent. According to the endpoints of the study (maximal tolerated dose, dose-limiting toxicity, and optimum biologically active dose), HuMV833 is well tolerated, with biological activity and indications of future promise as an anticancer drug. Although the study was not designed to establish efficacy, HuMV833 produced a therapeutic response in one patient with ovarian cancer and stable disease in three other patients, including one patient in whom colon cancer has remained stable after 10 months of treatment.
Also presenting findings at the symposium is Barbro Kristina Linderholm, MD, from the Karolinska Institute and Hospital in Stockholm, who will report the results of a study involving VEGF. In the study, VEGF was found to be a statistically significant prognostic factor for overall survival in 1,307 patients with primary breast cancer. Data concerning recurrence-free survival and associations between VEGF and bFGF content with site of metastasis will also be presented. Overall, these results provide support for VEGF as a prognostic factor in primary breast cancer, regardless of the type of adjuvant therapy (tamoxifen or chemotherapy). Measurement of VEGF may also serve as a screen to select appropriate candidates for additional antiangiogenesis therapies, say the investigators.
Frances A. Shepherd, MD, will report results from a trial involving marimastat, an orally available, broad-spectrum matrix metallo- proteinase inhibitor that has shown preclinical activity in a number of solid tumors. The objectives of the randomized, double-blind, placebo-controlled trial study were to determine if adjuvant treatment with marimastat could prolong the duration of remission and overall survival in patients with small cell lung cancer in whom complete or partial response had been achieved by first-line chemotherapy. The preliminary results included a median survival for all enrolled patients of 9.5 months, a one-year survival of 38%, and a two-year survival of 20%. Survival rates according to treatment group will be presented at the symposium. Musculoskeletal syndrome was the primary toxicity and required dose modifications in 20% of patients; 23% of patients withdrew from the study primarily due to this toxicity.
According to Joel B. Nelson, MD, from the University of Pittsburgh, for the first time, a new agent has been shown to slow the progression of bone metastasis from prostate cancer. Dr. Nelson will report results from two multinational, randomized, double-blind, placebo-controlled trials to evaluate the effects on bone metabolism of the endothelin-A receptor antagonist atrasentan (ABT-627). The design of the trial was developed from earlier findings from Dr. Nelson’s laboratory showing that endothelin-1 (ET-1), a prostate protein that enhances osteoblastic activity and inhibits osteoclastic activity, is present in increased levels in men with advanced prostate cancer, and that blocking ET-1 can reduce osteoblastic bone formation. Dr. Nelson will provide evidence that oral atrasentan succeeds in reducing skeletal remodeling activity in men with advanced, hormone-refractory prostate cancer and is capable of inhibiting the progression of skeletal metastases.
New Evidence of Antineoplastic Activity Against Cancers Expressing the EGF Receptor
At today’s Integrated Symposium I, investigators will present new evidence that three investigational drugs have substantial activity against cancers that express the epidermal growth factor receptor (EGFR or HER1). Featured at the Symposium are data from two phase II trials that indicate improved response and/or survival rates for patients in whom colorectal and squamous cell head and neck tumors are refractory to traditional chemotherapy. In addition, the findings of an in vitro study of breast tumor cell lines demonstrate that blockade of the intracellular domain of HER1 may prevent transactivation of HER2 receptors that express EGFR.
"Integrated Symposium I: Targeting the EGF Receptor: A Clinical Reality," is the first of this year’s two Integrated Symposia, in which cutting-edge results from related abstracts are discussed and placed in the appropriate scientific and practice context by experts in the field. The findings from four abstracts will be presented after an introductory review of the scientific background, given by Carlos Arteaga, MD, of Vanderbilt University Medical Center. The Co-Chairs of the Symposium are Sandra J. Horning, MD, of Stanford University Medical Center, and Vice Chair of the ASCO Cancer Education Committee, and José Baselga, MD, of Vall d’Hebron General Hospital. Dr. Baselga will also lead a concluding discussion of the studies. The Integrated Symposium will be held today from 12:30 PM to 2:30 PM in the Esplanade Ballroom (Moscone South).
One study to be presented at the Symposium involves IMC-C225 (Cetuximab), a chimeric monoclonal antibody that binds selectively to the EGFR external domain, thereby preventing activation of signal transduction pathways initiated by ligand-induced receptor dimerization. Leonard Saltz, MD, from Memorial Sloan-Kettering Cancer Center, will report the results of a phase II trial in which 121 patients with colorectal cancer refractory to both fluorouracil (5-FU) and irinotecan (CPT-11) were treated with IMC-C225 plus CPT-11. The dose and scheduling of CPT-11 were the same as those that had been previously used for each patient (during which time disease progressed). The preliminary findings demonstrated a partial tumor response in 17% of patients for a median duration of 84 days. According to Dr. Saltz, "the updated analysis will show considerably better results than were reported in [the] abstract."
Another study featured at the Symposium involves the use of OSI-774, an oral small-molecule quinazoline that is a potent and selective inhibitor of EGFR tyrosine kinase at the internal domain of the EGFR. Neil N. Senzer, MD, from Texas Oncology, PA, Dallas, will present the results of a phase II single-agent trial involving patients with recurrent and advanced squamous cell carcinoma of the head and neck (SCCHN). Preliminary data from this study indicate that the overall objective response rate was 5.6%. Dr. Senzer remarked, however, that "objective response may be less significant as an endpoint in this type of trial than survival." In a revised data analysis prepared for the Symposium, he will show that one-year survival from treatment with OSI-774 "compares favorably with those of the two chemotherapeutic regimens used most commonly for treating SCCHN, but with considerably less toxicity," he says.
Although OSI-774 is being studied as a cytostatic, there is in vitro evidence that the inhibition of tyrosine kinase may also initiate cytotoxicity. Moreover, "because other malignancies such as lung and colorectal cancer express EGFR, it will be important to determine if response rates to radiotherapy will be improved by concurrent treatment with OSI-774," Dr. Senzer observes. Whether OSI-774 potentiates the effect of radiation on neoplastic cells or acts synergistically with it is unknown.
Eric Keith Rowinsky, MD, from the Institute for Drug Development, San Antonio, Texas, will report results of dose-schedule-efficacy trials of OSI-774. These results confirm that the dose used in the trial by Dr. Senzer and his colleagues is the maximum tolerable dose for uninterrupted, long-term daily therapy in humans. Dr. Rowinsky will also report results from a pilot investigation of serial 18FDG-positron emission tomographic studies and phosphorylated EGFR concentrations as surrogate measures of antitumor activity from OSI-774 therapy in cases of EGFR-expressing malignancies.
In the last abstract presentation, Stacy L. Moulder, MD, from Vanderbilt University, will report results from in vitro experiments involving exposure of multiple HER2-overexpressing human breast tumor cell lines to EGFR-specific tyrosine kinase inhibitors. Dr. Moulder and colleagues conducted the study to test the hypothesis that HER2, which lacks an activating ligand, is phosphorylated by transactivation via the co-receptor EGFR (HER1). The investigation involved ZD1839 (Iressa), a small-molecule adenosine triphosphate (ATP) mimetic that inhibits purified EGFR and HER2 tyrosine kinases in vitro. Treatment of three cell lines expressing EGFR with ZD1839 almost eliminated HER2 phosphorylation, whereas one tumor cell line devoid of EGFR expression was unaffected. This suggests that ZD1839-mediated inhibition of EGFR tyrosine kinase may explain the inhibition of HER2 phosphorylation in vivo. In some EGFR-expressing cell lines, ZD1839 exhibited a greater growth inhibitory effect than Herceptin, a monoclonal antibody specific to the HER2 ectodomain. At high concentrations, ZD1839 was effective against a Herceptin-resistant cell line expressing EGFR. In some tumor cell lines, both agents had cytostatic activity. In one tumor cell line, neither agent alone was cytotoxic but in combination they were.
These findings indicate that by inhibiting EGFR tyrosine kinase, ZD1839 blocks the transactivation of HER2. They also suggest that Herceptin plus ZD1839 may be effective for the treatment of breast tumors that overexpress HER2 and express EGFR. Dr. Moulder will present promising new data on subsequent experiments in addition to the findings in the abstract.
EGF receptors are also the topic of the Scientific Symposium, "Targeting Receptors in the EGF Receptor Family for Therapy," which is offered today, 7:45 AM – 9:00 AM and again on Tuesday, 11:15 AM – 12:30 PM (both in the Hilton, Grand Ballroom, Salon B).
Peter |
