INTACT Trial Analyses Fail to Find Prognostic Factors for Gefitinib in Non–Small-CellLung Cancer

CHICAGO-Multivariate and subset analyses of the two INTACT (Iressa NSCLC Trial Assessing Combination Treatment) trials have so far failed to identify any new prognostic factors for improved survival of advanced non-small-cell lung cancer (NSCLC) patients treated with gefitinib(Drug information on gefitinib) (ZD1839, Iressa) and platinumbased chemotherapy (ASCO abstracts 2522 and 2523). Investigators are intrigued, however, by a trend toward improved survival in a subset of adenocarcinoma patients who were on chemotherapy for 90 days or more. Patients given 250 mg of gefitinib daily in INTACT 2 had a median survival of 17.1 months compared to 16.1 months for patients on a 500-mg dose and 13.6 months for patients on placebo. The trend suggests that giving gefitinib as a maintenance drug might benefit some patients who do well on chemotherapy, according to investigator Roy S. Herbst, MD, chief of thoracic oncology at the University of Texas M. D. Anderson Cancer Center. "There's a hint that there might be an effective maintenance therapy following chemotherapy. And that should hopefully lead to future trials," he told ONI. "This is only hypothesis generating," Dr. Herbst cautioned. "It's only a hypothesis-a subset analysis to a trial. New trials are concurrently being designed to follow-up on this finding," he said. No Consistent Effects
Although gefitinib produced significant antitumor activity in singleagent phase I and II trials in patients with advanced or metastatic NSCLC, it failed to improve survival when combined with standard chemotherapy in the phase III INTACT trials. Patients received a gemcitabine(Drug information on gemcitabine) (Gemzar)/cisplatin doublet in INTACT 1 or a carboplatin(Drug information on carboplatin)/paclitaxel doublet in INTACT 2. They were also randomized to receive either 250 mg or 500 mg of gefitinib daily or a placebo (Figure 1). Median survival in INTACT 1 was 9.9 months for both gefitinib groups vs 10.9 months for patients on placebo. In INTACT 2, median survival was 9.8 months with 250 mg of gefi- tinib, 8.7 months with 500 mg, and 9.9 months with placebo. Despite findings linking survival to gender and histology in the smaller single-therapy trials with gefitinib, the new analyses did not turn up a relationship in INTACT 1 or 2. Multivariate analysis with eight prognostic factors also failed to show any consistent able effects. Tissue samples are still being analyzed for expression of the HER1/epidermal growth factor receptor (HER1/ EGFR) tyrosine kinase targeted by gefitinib, as investigators are interested in whether positive status could be a prognostic factor. They speculated that patients might not have benefited because they were chemotherapy-naive, the dose and scheduling were not op- timal, or patients were insensitive to gefitinib. "In both trials we didn't see a benefit from giving the drug up front. Possibly the sequencing was not ideal. These were good trials," Dr. Herbst said, adding that benefit might be greater if the investigators knew how to select patients who would respond to the agent. He plans to collect tissue samples in future trials to look at HER1/EGFR status and other potential biomarkers. In a discussion of NSCLC trials, Alex Adjei, MD, PhD, of the Mayo Clinic in Rochester, Minnesota, sup- opported further investigation, possibly using proteomics, to identify subsets of patients who might benefit from gefitinib and other novel agents. He warned the investigators to "beware of spurious associations," however. Dr. Adjei explained that "correlation does not equate to causation" and "the fact that tumors express EGFR does not mean EGFR has a causal and critical role in cancer cell growth." Nonetheless, he agreed that in the absence of prognostic factors, giving a novel agent to patients who did well on chemotherapy might be an approach worth trying.