Higlights Of the American Society Of Clinical Oncology conference, Day 1 6/1/2003
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Reported by Melissa Stoller
This year's ASCO meeting began with an Education Session entitled "Update on Therapeutic Approaches to Brain Tumors." Much of the material presented in this session was review, but some new information was included. Paul Kleihues began the session with a review of the molecular transformations that characterizes gliomas, and presented some data that indicate the truncated EGF receptor is more common in primary GBMs than in those that have progressed from lower grade tumors. He cautioned that the receptor mutation is not common, even in the primary tumors (13%), and that the majority of GBMs usually evidence overexpression without evident EGFR mutations. In the question period, he mentioned that he has a study in press on low grade juvenile pilocytic astrocytomas that supports a surgery-only approach; he is concerned that some children with this diagnosis are overtreated.
The next presenter, Roger Stupp, summarized a concurrent RT, low dose TZ study he published in JCO last year. In this trial, Temodar was given at 75mg/m2 every day for seven weeks, concurrent with radiation, then followed by the standard 5-on 28 day TZ courses. After some sobering statistics about the lack of effect of chemotherapy in GBM, he reviewed his study's results: Median survival 14.3 mos. Time to progression 6.8 mos. He noted, however, that though the overall result was disappointing, there was 28% survival at 2 years, indicating that some subset of patients may have benefited.
The final presentation was on low-grade gliomas by Edward Shaw. He cautioned that prognostic factors for high grade gliomas are often not significant in low grade tumors, though patient age, size of tumor, and possibly extent of resection are predictive in both. He reported that the RTOG plans a COX-2 study in low grade gliomas, and a narrow margin radiation study in pediatric low-grade gliomas. RTOG 9802, comparing RT alone with RT +PCV is running, but the final data are not expected for several years.
The afternoon's CNS session featured five presentations that were especially interesting. Three were Phase I studies, however, so the data are limited. All of the abstracts will be available at ASCO.org after June 2. Prados (Abstract 394 ) presented the results of the UCSF study comparing the maximum tolerated dose of TZ + OSI-774 with OSI-774 alone. This was an interpatient dose escalation trial, which means that patients were allowed to dose escalate if appropriate. 66 patients were entered with stable or recurrent malignant gliomas; 55 of these with GBM. Four groups were followed: OSI-774 with and without EIAEDs [enzyme-inducing antiepileptic drugs],and OSI-774 +TZ with and without EIAIDs. The use of enzyme-inducing antiepileptic drugs clearly affected bioavailibilty of Tarceva with maximum tolerated dose approximately double in this group. Though the study is still enrolling, and no survival or progression data were presented, 8 of 49 evaluable patients had partial or complete responses, 3 with minor responses, 11 stable and 27 progressed quickly. Interestingly 6 of the 8 major responses were in the OSI-774 alone cohort. 7 of the 8 major responders had a GBM diagnosis. Future plans are for a Phase II trial and analysis of the EGFR status of responders vs. nonresponders.
Data on another drug targeting EGFR, the transforming growth factor alpha/ mutated pseudomonas endotoxin TP-38 protein were presented by JH Sampson (Abstract 397). Here, the first domain of pseudomonas exotoxin was replaced with TGF alpha so that the protein would bind with the EGFR. 53 patients, 80% of whom had GBM, were treated with 2 20ml infusions of 25 ng/ml, 50ng/ml and 100ng/ml of the fusion protein. The MTD has not yet been reached. Interestingly, later patients had the protein labeled with I-123 and imaging revealed that only 19% of the infusions had no evidence of pooling or leakage. Logistic issues, such as catheter design and placement still need to be optimized. At this time, three patients are alive without progression, 47, 61 and 110 weeks out, 2 patients are alive with progression 50 and 54 weeks out and 15 patients have died. The two longest survivors were both treated at the lowest dose level.
Al Yung (Abstract 395) presented results of a phase I study of PTK/ZK an oral VEGF receptors inhibitor. This study was notable for the use of dynamic contrast MRI to document reduction in tumor microvascularity, a technique that might be applied to optimize dosing of anti-angiogenic agents in the future. The MTD was established at 1200 mg for the phase II trial. Of the 43 patients, 1 had a partial response, 20 were stable disease and 10 progressed. Additional data on this agent will be presented tomorrow, and I will report the findings.
DA Reardon presented the Peery et al study (Abstract 396), which won an ASCO merit award. This was a Phase II study of Iressa in GBM at first relapse. Dose was 500mg in patients not on EIAEDs and up to 1000mg in those taking EIAEDs. The median age was 54 and the drug was well tolerated, with rash and diarrhea being the main toxicities. There was one partial response, 19 stable disease ( stable for 2 or more 4-week courses) and 32 progressions. 17% of the patient completed 6 cycles ; all of these were near-total or gross total resections. During the question and answer period, it was suggested that the study may be underdosing those on EIAEDs. It was questioned whether drugs such as Tarceva and Iressa, which mainly affect non-mutated EGFR can produce continued responses in gliomas.
Linassier ( Abstract 399) reported that accrual in a study comparing high-dose BCNU with autologous blood stem cell support vs. standard dose BCNU in supratentorial GBM was stopped due to toxicity and lack of efficacy in the high-dose BCNU arm. This was a disappointing but important study, as Phase II results had looked promising. In contrast, Colombat (Abstract 400 which I read but did not attend), reports preliminary but promising results with high-dose chemotherapy in CNS lymphoma.
Finally, in a Therapeutics session, Sparreboon (abstract 504) presented a poster suggesting that flat-dosing may be more appropriate that dosing based on body-surface area for irinotecan, following the results of Mathijssen et al, J Clin Oncol 2002.