Update of Letrozole Pivotal Trials in Advanced Breast Cancer

SAN ANTONIO—The pivotal multinational phase III trials of the aromatase inhibitor letrozole (Femara) showed it to be clinically superior to both megestrol acetate and aminoglutethimide in the treatment of advanced breast cancer that relapses during or after therapy with tamoxifen (Nolvadex), said Ian Smith, MD, of the Royal Marsden Hospital, Sutton, UK.

He presented updated findings from both studies at a symposium sponsored by Schering Oncology/Biotech and Novartis Oncology at the San Antonio Breast Cancer Symposium.

A surprising finding in these studies was a dose-effect for letrozole 2.5 mg over 0.5 mg in terms of response and overall survival. “Previous data have shown no significant difference in plasma estrogen suppression between these two doses,” Dr. Smith said.

This finding raises the possibility that, with powerful third-generation aroma-tase inhibitors such as letrozole, intra-tumoral aromatase suppression may be a more important mechanism of action than plasma estrogen levels, with the higher letrozole dose achieving greater intratumoral aromatase inhibition.

“Further clinical development of aromatase inhibitors must take into account that plasma estrogen is probably not a surrogate marker for optimal response,” he said.

The trial of letrozole versus megestrol involved 551 postmenopausal patients with locally advanced or metastatic breast cancer who had failed previous antiestro-gen therapy. They were randomized to receive letrozole 2.5 mg, letrozole 0.5 mg, or megestrol 160 mg, once a day. All tumors were estrogen- or progestogen-receptor positive or status unknown.

Letrozole proved significantly better in terms of objective response rate and response duration, duration of overall clinical benefit (including patients with an objective response and those with stable disease), time to progression, and time to treatment failure, with a trend toward improved survival, Dr. Smith said.

In the higher-dose letrozole group, 24.1% of patients had an objective response, compared with 12.28% for the letrozole 0.5 mg group and 16.4% for the megestrol group. “This represented a significant dose effect in favor of letrozole 2.5 mg, compared with 0.5 mg, and a significant superiority of letrozole 2.5 mg over megestrol acetate,” he said.

Median duration of response was significantly longer with higher-dose letrozole: 33 months for letrozole 2.5 mg versus 18 months for megestrol and for letrozole 0.5 mg. Letrozole 2.5 mg was significantly superior to megestrol in overall time to treatment failure (5.1 months vs 3.9 months), and a significant dose-response effect was seen in favor of the higher letrozole dose.

Letrozole also had a lower incidence of adverse effects, including thromboem-bolic events and weight gain. Said Dr. Smith: “The percentage of patients discontinuing treatment due to poor tolerability was significantly higher with megestrol (9.5%) than with letrozole 2.5 mg (2.9%) or letrozole 0.5 mg (5.3%).”

The second study included 555 post-menopausal patients with advanced or metastatic breast cancer randomized to receive daily doses of letrozole 2.5 mg, letrozole 0.5 mg, or aminoglutethimide 500 mg, orally with hydrocortisone or cortisone acetate supplementation.

Although similar in design to the megestrol trial, this study was not double-blinded, and the data are less mature. Dr. Smith reported the most recent 45-month follow-up figures.

Patients on letrozole 2.5 mg achieved the highest objective response rate (19.5% vs 16.7% for letrozole 0.5 mg and 12.4% for aminoglutethimide). These differ-ences were not significant, although the difference between letrozole 2.5 mg and aminoglutethimide showed a trend toward superiority (P = .06), as did the difference between letrozole 0.5 mg and aminoglutethimide (P = .10). Similarly, there was a trend in favor of both letrozole dosages for greater response duration.

Letrozole 2.5 mg was significantly better than aminoglutethimide in duration of overall clinical benefit (CR, PR, and stable disease for 6 months or more) and survival. Median overall survival was 28 months for letrozole 2.5 mg, compared with 21 months for letrozole 0.5 mg, and 20 months for aminoglutethimide.

Letrozole had a lower incidence of rash and somnolence. Of patients on amino-glutethimide, 5% discontinued treatment because of adverse effects vs 3% on letro-zole 2.5 mg and 3% on letrozole 0.5 mg.