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American Society of Clinical Oncology 35th Annual
Meeting
Day 1 - May 15,
1999
Marshall Posner, MD
Listen to a 
Audio interview with Dr. Posner. Duration: 5 min 16
secs.
(To download a free copy of the Real Player, click here.)
Phase I trials of a new therapeutic "target" for cancer therapy, studied initially in squamous cell cancer of the head and neck (SCCHN), suggest that treatment approaches focusing on this factor may hold clinical promise.
The epidermal growth factor receptor (EGFr) inhibitors are among the newer agents directed at specific receptors that may play critical roles in cancer cell growth. They are being tested as single agents and as radiation sensitizers. Preliminary studies are promising and demonstrate biological effects and biologically relevant dosing. But additional studies are being pursued to determine how effective these agents are as direct anticancer agents, combination agents, or radiation sensitizers.
John Mendelsohn first recognized EGFr as a potential therapeutic target in 1983.[1] The EGFr is an important regulator of normal cell growth and is necessary for the initial growth of many SCCHN cell lines cultured in vitro. Critical features that made it an attractive target for therapy are: (1) EGFr is overexpressed on many epithelial cancers, including more then 95% of SCCHN; (2) it is activated in these tumors by both autocrine and paracrine growth factors; and (3) murine monoclonal antibodies that blocked EGF and TGF-alpha binding to EGFr also inhibited cell growth.
EGFr signaling occurs when EGF or TGF bind and cause 2 EGF molecules to form a dimer. The molecules phosphorylate one another on several tyrosines. Subsequently, a number of molecules complex with EGFr and mediate signaling through RAS and the MAP kinase system. Interventions that block receptor dimerization or phosphorylation inhibit EGFr signaling and inhibit cell growth. Inhibition occurs through a block in cell cycling.
Early studies in animal models indicated that anti-EGFr antibodies were more effective when combined with chemotherapy agents such as cisplatin or doxorubicin or radiation than when used alone.
Using biopsies and specialized tissue testing the group showed that, after a loading dose and 2 of 6 subsequent weekly injections, tumor EGFr was 75-95% inhibited by antibody. Optimum dose was felt to be 400 mg/m2 as a loading dose and 250 mg/m2 weekly, based on a biological end point rather than dose-limiting toxicity. The only significant toxicity was a follicular rash, which never exceeded grade 3 in this trial. Twelve patients have been treated and 9 are evaluable for response, with 5 partial responses (PRs) and 1 complete response (CR). These results were thought to be more remarkable because several patients had received prior therapy with platinum-based regimens. A phase II trial in platinum-resistant recurrent SCCHN is planned.
A companion trial was presented by Ezekial et al and was an integral part of an educational session presented by Bonner (ES8) on novel agents for chemoradiation.[3,4] This phase I trial entered 16 previously untreated patients with unresectable SCCHN. Patients were treated with a loading dose of CH225 and then weekly intravenous CH225 for 7 additional doses during QD (13 patients) or BID (3 patients) curative radiation therapy. Radiation doses were 70 Gy for the QD and 76.8 Gy for the BID treatments. One patient experienced an anaphylactic reaction to a test dose and was not evaluable for response or further toxicity.
No dose-limiting toxicity was encountered, but on the basis of the biological findings reported above a loading dose of 400 mg/m2 and 250 mg/m2 weekly was used in the BID patients and selected as the biologically maximal dose. Toxicity was a follicular rash, worse in and near the radiated fields. All patients experienced grade 3 mucositis. Surprisingly, no grade 4 mucositis was observed. At the end of "chemo"-radiotherapy, 13 of 15 evaluable patients were CR and 2 were PR, an unexpectedly high response rate in a small study. A randomized trial of CH225 and radiation therapy alone is planned.
CP-358, 774 was studied in a weekly schedule by Karp and coworkers.[5] Treatment was weekly for 3 out of 4 weeks. Toxicity was found to be diarrhea, which was controlled by medication, and skin rash. Dose-limiting toxicity was not observed at 1600mg weekly. Pharmacokinetics showed clinically relevant plasma levels at all doses. Skin biopsies showed epidermal thickening and increased proliferation. While no responses were seen, several patients had stable disease.
A second Phase I trial evaluated CP-358, 774 in a daily schedule. Siu and associates gave the agent daily for 28 days and then continuously.[6] Starting at 25 mg/day, dose-limiting toxicity was folliculitis and diarrhea; the latter was controlled with medication. The maximally tolerated dose was determined to be 150 mg/day. Pharmacokinetic studies revealed that biologically effective doses were reached at 50 mg/day. A multicenter phase II trial in SCCHN is planned with the daily dose.
Hammond and colleagues described a second small molecule, ZD 1839, and reported on its use in a 14-day schedule.[7] Dosage was being escalated above 525 mg/day with only minor rash and diarrhea reported. Clinically meaningful doses were achieved and maintained above 150 mg/day. Minor responses were reported with this agent. Dosage escalation continues.
A common toxicity of these agents is rash. Diarrhea is seen with the small, oral molecules but was not seen with CH225. This difference may reflect either different targeting or restricted access for the antibody in normal tissues, or it may be related to oral dosing of the agents. Diarrhea seems to be easily controlled by medication. Because the level of EGFr is frequently increased early in carcinogenesis in many tumors, these agents may have a role as chemopreventives.
If these agents prove to have limited toxicity and markedly enhance other anticancer agent activity, they may prove to be a valuable addition to current treatment options.
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