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The promise of blocking the epidermal growth factor receptor (EGFR) pathway of tumor cell proliferation has been sufficiently encouraging such that clinical studies may have outpaced basic research. The disappointing results with ZD-1839 in 2 large phase III trials in non-small cell lung cancer (NSCLC) were unexpected, and they have posed more questions than they have answered. Many of the explanations for why the tyrosine kinase inhibitor failed in INTACT-1 and INTACT-2 (Iressa Non-small cell lung cancer Trial Assessing Combination Therapy, 1 and 2) do not preclude benefit in a clinical trial with a different design.

"Why did this drug fail? Was it an inability to block EGFR? Did the reason have to do with patient selection? Is there a problem with blocking EGFR in combination with chemotherapy?" asked Roy Herbst, MD, during a session at the 20^th annual meeting of the Chemotherapy Foundation. "There are a lot of questions we can ask about what went wrong."

Trial Data Review
In the INTACT trials, ZD-1839 was evaluated for chemotherapy-naīve patients. Each trial randomized approximately 1,000 patients to standard chemotherapy regimens (cisplatin and gemcitabine in INTACT-1 and carboplatin and paclitaxel in INTACT-2) with ZD-1839 or placebo. The primary objective was to demonstrate at least a 25% improvement in overall survival. This end point was an ambitious goal in a challenging cancer, and unfortunately, it was not met. In fact, there was no added benefit from ZD-1839, despite encouraging rates of clinical activity when this drug was evaluated as a second-line therapy.

However, these results have not discouraged other studies evaluating ZD-1839 or OSI-774 as front-line therapy for NSCLC and/or other solid tumors. In fact, a study called TRIBUTE, which is very similar to the INTACT trials, is underway with a different small molecule inhibitor OSI-774. Trials of ZD-1839 with other chemotherapy regimens, radiation, or other targeted therapies, such as agents that inhibit vascular endothelial growth factor (VEGF), are proceeding in early-stage NSCLC. The substantial evidence of activity in earlier trials encourages the continued pursuit of clinical benefits with tyrosine kinase inhibitors.

In NSCLC specifically, ZD-1839 achieved tumor response rates of up to 20% in the IDEAL-1 and IDEAL-2 trials (Iressa Dose Evaluation in Advanced Lung cancer, 1 and 2), in which each trial enrolled slightly more than 200 highly treatment-experienced patients (Fukuoka M et al. Proc Am Soc Clin Oncol. 2002;21(suppl 1):298a. Abstract 1188; Kris MG et al. Proc Am Soc Clin Oncol. 2002;21(suppl 1):292a. Abstract 1166). In IDEAL-1, ZD-1839 was associated with disease control rates (which combined objective response and stable disease) of approximately 50%. In IDEAL-2, control rates were approximately 40%, but in both studies, symptoms improved in 35% to 40% of patients.

"Quality of life improvement generally accompanied disease control and disease-related symptom improvement and was seen in one-fourth to one-third of patients in both trials. That is, improvements at 250 mg/day of ZD-1839 in IDEAL-1 and IDEAL-2 were 24% and 34% and at 500 mg/day were 22% and 23%, respectively," Dr. Herbst reported. He noted that due to similar efficacy but greater tolerability, the 250-mg dose of ZD-1839, which is a once-daily oral drug, is the dose that is now being most widely tested.

In a more recent study, the 250-mg/day dose of ZD-1839 was combined with a weekly intravenous dose of 30 mg/m² docetaxel, a drug that is approved for second-line therapy in NSCLC. The results of this trial were encouraging, with an objective response rate of 27.7% in 18 patients who had progressive disease during or within 6 months of chemotherapy. Although the combined objective response and disease stabilization rate of 38.8% was lower than the 53.2% rate observed in a similar trial with cetuximab plus docetaxel, the results were sufficiently encouraging to warrant further studies.

"One of the questions that is still unclear is how best to combine biologicals, such as ZD-1839, with chemotherapy. Should there be sequencing? Are we looking for additive effects or synergy? Do we need to screen for the target to use these agents?" asked Edward S. Kim, MD, Department of Thoracic/Head and Neck Medical Oncology, M. D. Anderson Cancer Center, Houston, Texas. However, noting that "EGFR expression clearly appears to contribute to the growth and survival of tumor cells," he expects extensive trials program in this area to be pursued.

This includes studies with OSI-774, which achieved a 12.3% response rate in 57 patients with treatment-refractory NSCLC in a phase II setting. This rate of response rose to 21% in the subgroup previously treated with a platinum-based regimen, according to Philip Bonomi, MD, Rush Medical College, Chicago, Illinois. Dr. Bonomi noted that although OSI-774 was well tolerated in this study, 75% of patients developed the characteristic acneiform rash including all of those who responded.

A phase III study now underway in Canada is randomizing 750 patients with refractory NSCLC to 150 mg/day of OSI-774 or placebo. This trial should directly address the role of OSI-774 as a salvage regimen.

Potential Efficacy Against Other Solid Tumors?
Much of the initial work with tyrosine kinase inhibitors was conducted in NSCLC, but patients with other solid tumors associated with overexpression of EGFR are being entered into clinical trials with these agents. These include cancers of the prostate, breast, head and neck, ovaries, and gastrointestinal tract, according to Dr. Herbst. The molecular activity of EGFR and promising early results in clinical trials are fueling interest in continued research.

"Agents that act on EGFR have been developed in order to inhibit a signal transduction pathway that has been correlated with cell-cycle progression, inhibition of apoptosis, angiogenesis, tumor cell motility and metastasis," Dr. Kim observed. This pathway seems to provide an important opportunity "to inhibit tumor proliferation and improve overall clinical outcome".

Key Points In Focus:

Disappointing results with ZD-1839 as front-line therapy in NSCLC have not discouraged efforts to further examine the potential of this agent or OSI-774, another tyrosine kinase inhibitor. Encouraging rates of activity in late-stage disease suggest the need for further studies to determine the best clinical use for these agents.
As a second-line agent, ZD-1839 has been associated with a substantial objective response rate, reduced symptoms, and improved quality of life in treatment-refractory NSCLC patients.
The importance of EGFR signal transduction to tumor growth, including promotion of apoptosis and inhibition of angiogenesis, has made this an important target in NSCLC and a number of other solid tumors that overexpress EGFR.

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