Toremifene in Advanced Breast Cancer: Phase II Trials

January 1, 1997

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.

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

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

The studies include ER-unknown patients, he explained, because at thetime they were designed, some 10 years ago, many of the eastern Europeansites 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 froma number of small studies, ranging from 14 to 90 patients and using dosesof 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 trialsthat used 20 mg/day had approximately a 20% response rate versus about30% 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, theresponse rate was 8% among tamoxifen failures, and about 14% among thosewho had failed both tamoxifen and chemotherapy.

American Data

An American study by Dr. Charles Vogel, of South Florida ComprehensiveCancer Center, involved 102 tamoxifen-refractory patients, all perimenopausalor postmenopausal and ER or PR positive or unknown. The daily toremifenedose was 200 mg. Toxicity was as expected, primarily hot flashes, witha few patients complaining of nausea.

Dr. Vogel and his colleagues retrospectively divided the patients intothree categories: (1) those who failed to respond to tamoxifen after atleast 3 months of therapy (28 patients), (2) those who had progressivedisease after an initial partial or complete response to tamoxifen (43patients), and (3) those who were ER or PR positive and had failed whileon 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 rateoverall. 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 responseto toremifene was small (5 patients), the mean time to treatment failurefor these patients was almost 11 months. For the 23 patients who had diseasestabilization, time to treatment failure was almost 8 months. "That'sa respectable length of time," Dr. Hamm said.

In response to a question from the audience about a possible confusionbetween 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, butphysicians were hesitant to have patients with progressive disease offtherapy for that long a period.

Approval in Japan

In a phase II Japanese study of tamoxi-fen-refractory patients, responserates (CR and PR) were similar to those in the US trial--6% for patientswith progressive disease while on tamoxifen, 11% for those who failed aftera tamoxifen response, and 15% for adjuvant tamoxifen failures. The ratesfor stable disease (including only those who were stable for more than6 months on therapy) were 18%, 22%, and 11%, respectively.

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

A similar analysis of the US data (the only difference being that a6 month cut off point was not used in the definition of stable disease)produced a 27% combined rate of nonprogressors, he said, "so the dataare consistent between the United States and Japan."

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

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

Dr. Hamm summarized the phase II data on toremifene as follows: As first-linetherapy, response rates ranged from 21% to 54%, depending on the dose andthe group studied; the preferred dose appears to be 60 mg/day. There wereno responses in ER-negative patients.

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