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my personal edition > lung cancer > news
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DGDispatch
Studies Show Preferential Effect of Paclitaxel Poliglumex in Chemonaive Women With Advanced NSCLC and Poor Performance Status: Presented at AACR-NCI-EORTC
By Chris Berrie
PRAGUE, CZECH REPUBLIC -- November 15, 2006 -- Paclitaxel poliglumex (Xyotax(R)) promotes the delivery of the taxane paclitaxel to tumour tissue and provides a significant survival benefit for chemonaive women with advanced non-small-cell lung cancer (NSCLC) and poor performance status, the researchers report, and are most pronounced in women younger than 55 years or with premenopausal oestrogen levels.
Lung cancer is the leading cause of cancer-related deaths in women, and as women are also overrepresented among the younger lung cancer patients, this suggests that oestrogen exposure has a role in lung cancer development in this population.
These findings, from a composite analysis of 2 randomised phase 3 trials, were presented by Jack Singer, MD, chief medical officer and executive vice-president, Cell Therapeutics Inc., Seattle, Washington, on behalf of the Selective Targeting for Efficacy in Lung Cancer, Lower Adverse Reaction (STELLAR) Steering Committee and Investigators.
"We performed two large phase 3 trials in front-line therapy of non-small-cell lung cancer to test whether [paclitaxel poliglumex] was more effective than standard therapy in patients with performance status 2," he said in a presentation on November 10th at the American Association for Cancer Research 18th Symposium on Molecular Targets and Cancer Therapeutics - National Cancer Institute - 18th European Organisation for Research and Treatment of Cancer (AACR-NCI-EORTC).
The 2 studies enrolled women who were chemonaïve and had advanced-stage NSCLC. The subjects were stratified by disease stage, sex, brain metastases and geography.
In STELLAR 3, the women received 1 of 2 treatment regimens: paclitaxel poliglumex 210 mg/m2 plus carboplatin AUC 6, every 3 weeks; paclitaxel 225 mg/m2 plus carboplatin AUC 6, every 3 weeks. In STELLAR 4, women were randomised as follows: paclitaxel poliglumex 175 mg/m2, every 3 weeks; or gemcitabine 1,000 mg/m2 on days 1, 8, 15, every 4 weeks; or vinorelbine 30 mg/m2 on days 1, 8, 15, every 3 weeks.
These efficacy studies showed equivalence for patient survival, but no superiority of paclitaxel poliglumex over standard therapies. However, within the pre-specified demographic and stratification factors there were indications of better than expected results for women treated with paclitaxel poliglumex.
These individual exploratory analyses for effects of sex within STELLAR 3 and STELLAR 4 compared the paclitaxel poliglumex arms with the comparator arms as controls.
Results of this analysis of STELLAR 3 data showed a non-significant trend towards selective benefit for women for 1-year overall survival (paclitaxel poliglumex vs control): male (n = 151 vs 156), 29% versus 33% (hazard ratio [HR], 1.04; P = .780); female (n = 48 vs 45), 37% versus 25% (HR, 0.76; P = .239).
Similarly for STELLAR 4 the data showed: male (n = 142 vs 134), 20% versus 25% (HR, 1.08; P = .579); female (n = 49 vs 56), 43% versus 26% (HR, 0.65; P = .069).
This finding led to the present composite analysis, based on identical inclusion and exclusion criteria and stratification in these 2 concurrent trials of patients with similar demographics, Dr. Singer noted.
This composite analysis confirmed a selective significant survival benefit for women receiving paclitaxel poliglumex compared with those in the control arm. One-year overall survival was as follows: male, n = 283 vs 290), 26% versus 30% (HR, 1.05; P = .585); female (n = 97 vs 101), 40% versus 25% (HR, 0.70; P = .03).
These data were also analysed for oestrogen effects on overall survival in women treated with paclitaxel poliglumex. This retrospective analysis determined the presumed menopausal status of the women according to age (<55 years old; serum oestrogen >30 pg/mL).
The composite analysis demonstrated significantly improved median overall survival for the 28 women younger than 55 years treated with on paclitaxel poliglumex compared with the 22 controls (304 vs 158 days, hazard ratio [HR], 0.51; P = .030). This effect was largely lost for the 69 women age 55 years or more compared with controls (271 vs 262 days; HR, 0.75; P = .134).
When the researchers analysed the data according to oestrogen levels that were available from 86 women on STELLAR 3, there was again a significantly improved median overall survival for the 29 women with >30 pg/mL oestrogen on paclitaxel poliglumex over the 25 controls (286 vs 154 days; HR, 0.54; P = .039). Treatment did not affect median overall survival in patients with post-menopausal oestrogen levels (HR, 1.20; P = .676).
Dr. Singer noted that these particularly beneficial effects of paclitaxel poliglumex on treatment of chemonaïve women will be investigated in a confirmatory phase 3 study with a direct comparison of paclitaxel poliglumex and paclitaxel at equal dosing schedules.
Of further particular interest, Dr Singer detailed: "What was unknown to us at the time we did these studies was that the metabolism [of paclitaxel poliglumex] is heavily controlled by oestrogen through an enzyme known as cathepsin B, which allows more drug to get into the tumour and more to be released, enhancing the efficacy. At the same time, oestradiol works in a negative way in patients who are not treated with this drug, in that it shortens survival."
Therefore, these preferential effects of paclitaxel poliglumex appear to arise from oestrogen acting as a negative factor for outcome in control therapy, and as a positive factor with paclitaxel poliglumex.
Finally, Dr Singer noted that this finding raises the issue of whether this provides a way of pre-targeting and making this very standard agent (paclitaxel) more effective in other oestrogen-response situations.
This study was supported by Cell Therapeutics Inc.
[Presentation title: Effect of Sex on Outcome in Two Randomised Phase 3 Trials of Paclitaxel Poliglumex (paclitaxel poliglumex) in Chemonaive Patients With Advanced NSCLC and Poor Performance Status (PS 2). Abstract 645]
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