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ZD1839 (Iressa) With Standard Chemotherapy Does Not Improve Outcome in Advanced NSCLC: Presented at ESMO

By Adrian Burton

NICE, FRANCE -- October 23, 2002 -- Adding ZD 1839 (Iressa) to standard chemotherapy regimens offers no clinical benefit in patients with advanced non-small cell lung cancer (NSCLC), according to the combined results of two randomized, double-blind, placebo-controlled, multicentre trials reported here October 21^st at the 27^th Congress of the European Society for Medical Oncology.

Earlier studies (the IDEAL trials) had shown that ZD 1839 (an inhibitor of epidermal growth factor receptor tyrosine kinase) has an extremely promising activity profile when used as monotherapy.

"It was clear to all of us in the field that we had reached a plateau in the therapy of metastatic lung cancer," said Dr. David Johnson, Deputy Director of the Vanderbilt-Ingram Cancer Center, Nashville, Tennessee, United States. "When four of the most popular chemotherapy regimens in the world were recently compared, none emerged as superior. We thought that adding a third drug [Iressa] to some of these doublets might be a useful strategy. We hoped we might see an improvement."

The 2130 patients enrolled in the trials had grade ¾ NSCLC, were chemotherapy-naive, and had a European Cooperative Oncology Group performance status of 0-2. Median patient age was 61 years in the INTACT I trial and 62 years in INTACT II.

Patients in Europe were randomly assigned to one of three treatment groups: (1) six cycles of chemotherapy (CT) with gemcitabine 1250 mg/m² on days 1 and 8 +cisplatin 80 mg/m² on day 1 + a placebo, (2) six cycles of CT + ZD 1839 250 mg/d, or (3) six cycles of CT + ZD 1839 500 mg/d. North American patients received one of the following regimens: (1) carboplatin area under the curve 6 + paclitaxel 250 mg/m² + placebo every 3 weeks, (2) the same + 250 mg/d ZD1839, or (3) the same + 500 mg/d ZD1839. All treatment groups were well balanced with regard to disease stage and demography.

The primary end point was overall survival. Secondary end points included progression-free survival, time to worsening of symptoms, quality of life, and safety.

Toxicity profiles of the ZD1839 arms were acceptable, although some cases of dose-dependent diarrhoea and skin rash were observed. No significant differences were seen with respect to overall survival -- which was approximately 9 months -- on any of the regimens. There were no differences in progression-free survival or time to worsening of symptoms. Comparative hazard ratios were also very similar for all treatments (between 9.0 and 1.0).

"The bottom line is that there is no difference in outcome. Survival in the three arms, though numerically different, is statistically identical," explained Dr. Johnson. "Of course we are disappointed about the way these results turned out. We are now in the process of trying to find out what happened."

Some data presented at the meeting suggest that the triplet may have some effect in the subset of adenocarcinoma patients.

Though disappointing, there is more research to be done. "Sequential use of these agents rather than concomitant use might be a superior strategy," concluded Dr. Johnson. "The IDEAL data would seem to suggest that this might be the case."

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