PALM SPRINGS, Calif--A large body of research on toremifene (Fareston) has been accumulated in research carried out over more than a decade in Europe, the United States, and the former Soviet Union, John T. Hamm, MD, of the University of Louisville and Alliant Health Systems, said in his presentation on the phase II trials of the agent.

"There are 500 patients in phase I studies and 1,000 in phase II studies and beyond," Dr. Hamm said. Phase II studies have been done in two main areas--as first-line therapy in breast cancer patients with estrogen-receptor (ER)-positive or ER-unknown disease, and as second- and third-line therapy in patients who have failed chemotherapy or tamoxifen (Nolvadex).

The studies include ER-unknown patients, he explained, because at the time they were designed, some 10 years ago, many of the eastern European sites were not testing patients for estrogen or progesterone receptors.

European Phase II Trials

The European phase II data on the primary use of toremifene comes from a number of small studies, ranging from 14 to 90 patients and using doses of 20 to 240 mg/day. Response rates ranged from 21% up to a high of 54%, and the time to progression "was very reasonable," Dr. Hamm said, ranging from about 5 months to 1 year.

There was some correlation of response rate to dose. The two trials that used 20 mg/day had approximately a 20% response rate versus about 30% to 40% for 40 to 60 mg/day, with similar responses at 240 mg/day.

In phase II European trials of toremifene as second-line therapy, the response rate was 8% among tamoxifen failures, and about 14% among those who had failed both tamoxifen and chemotherapy.

American Data

An American study by Dr. Charles Vogel, of South Florida Comprehensive Cancer Center, involved 102 tamoxifen-refractory patients, all perimenopausal or postmenopausal and ER or PR positive or unknown. The daily toremifene dose was 200 mg. Toxicity was as expected, primarily hot flashes, with a few patients complaining of nausea.

Dr. Vogel and his colleagues retrospectively divided the patients into three categories: (1) those who failed to respond to tamoxifen after at least 3 months of therapy (28 patients), (2) those who had progressive disease after an initial partial or complete response to tamoxifen (43 patients), and (3) those who were ER or PR positive and had failed while on adjuvant tamoxifen (31 patients).

Complete and partial response rates were not high in any of these groups, he said--4%, 7%, and 3%, respectively, with a 5% objective response rate overall. Rates of stable disease ranged from 16% to 26% (23% overall); and the majority of patients (63%) had progressive disease.

Although the number of patients who had a complete or partial response to toremifene was small (5 patients), the mean time to treatment failure for these patients was almost 11 months. For the 23 patients who had disease stabilization, time to treatment failure was almost 8 months. "That's a respectable length of time," Dr. Hamm said.

In response to a question from the audience about a possible confusion between responses to toremifene and responses to tamoxifen withdrawal, Dr. Hamm said that the US study included a 4-week time interval off tamoxifen. Two months off tamoxifen might have been a better protocol, he said, but physicians were hesitant to have patients with progressive disease off therapy for that long a period.

Approval in Japan

In a phase II Japanese study of tamoxi-fen-refractory patients, response rates (CR and PR) were similar to those in the US trial--6% for patients with progressive disease while on tamoxifen, 11% for those who failed after a tamoxifen response, and 15% for adjuvant tamoxifen failures. The rates for stable disease (including only those who were stable for more than 6 months on therapy) were 18%, 22%, and 11%, respectively.

"If you add up the CRs, PRs, and those who were stable for more than 6 months on toremifene, you come up with response or prolonged stabilization rates for the three groups of 25%, 33%, and 27%," Dr. Hamm said. Toremifene was licensed for use in tamoxifen-refractory patients in Japan, based partially on these data.

A similar analysis of the US data (the only difference being that a 6 month cut off point was not used in the definition of stable disease) produced a 27% combined rate of nonprogressors, he said, "so the data are consistent between the United States and Japan."

Dr. Hamm noted that in the United States, there is a bias against viewing stable disease as a drug benefit. Indeed, he said, patients with stable disease after treatment may simple have fairly indolent disease that progresses slowly.

Finally, a CALGB (Cancer and Leukemia Group B) study explored the use of toremifene, 400 mg/day, in 20 patients with ER- and PR-negative disease. There were no objective responses. "They did have six patients with stable disease briefly," he said, "but by 8 weeks, five of those six patients had progressed, so really they had no responses, no benefit in this ER-PR negative group, even at these high doses."

Dr. Hamm summarized the phase II data on toremifene as follows: As first-line therapy, response rates ranged from 21% to 54%, depending on the dose and the group studied; the preferred dose appears to be 60 mg/day. There were no responses in ER-negative patients.

Finally, Dr. Hamm commented, there was a prolonged stabilization of disease in some tamoxifen-failure patients with use of toremifene, which could indicate a need to look further at this aspect, or could simply be due to slow progression of disease.