New SERM Promising in Advanced Breast Cancer

BARCELONA—Preliminary results of a trial of a new selective estrogen-receptor modulator (SERM), known as LY353381, show a 32% response rate in patients with previously untreated locally advanced or metastatic breast cancer, José Baselga, MD, of Vall d’Hebron University Hospital, Barcelona, Spain, said at the San Antonio Breast Cancer Symposium.

“LY353381 acts as a potent estrogen antagonist in the breast and in the uterus,” Dr. Baselga said, “while acting as an estrogen agonist to maintain bone density and lower cholesterol levels.”

A phase I trial examining four dose levels (10, 20, 50, and 100 mg per day) found no dose-limiting toxicities, he said. The primary objective of the phase II trial, Dr. Baselga said, “was to select whether 20 mg or 50 mg was the best daily dose of LY353381, as reflected by tumor response rate or clinical benefit rate.”

The Phase II Trial

The phase II trial, conducted at several facilities in Spain, France, Belgium, and the Czech Republic, included 92 patients randomized to receive, in a double-blind fashion, 20 mg or 50 mg daily of LY353381. Dr. Baselga noted that patients initially placed on 20 mg could be elevated to 50 mg upon progression at the discretion of the investigator. Interim data were available on 87 patients, with a median age of 70 (range, 37 to 94).

The time from diagnosis to inclusion in the study was fairly rapid, he noted, at about 1 month. A significant proportion of patients had either skin/soft tissue sites of metastasis or node-only disease (40 patients) as opposed to visceral and bone metastases (47 patients).

Eligibility criteria included pathologic confirmation of locally advanced breast cancer (31 patients) or metastatic breast cancer (56 patients); ER- positive and/or PR-positive disease (although patients older than 50 were admitted with unknown ER or PR status); and no prior systemic therapy for locally advanced or metastatic breast cancer.

Patients who had received adjuvant therapy were admitted if they had completed chemotherapy 6 months or more prior to metastatic disease, or had received tamoxifen (Nolvadex) 12 months or more prior to admission to the study. He noted that the majority of patients had not received prior tamoxifen.

Response Rates

The overall response rate in all patients with a median time on therapy of 3 months was 32%. At the 20 mg level, there was 1 complete response and 13 partial responses. With the 50 mg dose, there were no complete responses and 14 partial responses.

The clinical benefit rate (complete and partial responses plus stable disease for at least 6 months) was 50% in the patients receiving 20 mg and 52% in those receiving 50 mg. The clinical benefit rate was 58% in patients with locally advanced disease and 47% in patients with metastatic disease.

Minimal Toxicity

Toxicities were generally minimal, with no differences between the dose levels. Overall, the most common side effect was hot flashes. “It is important to mention that of these almost 90 patients, only one case of endometrial hyperplasia was observed, and it was benign,” he said.

Dr. Baselga concluded that LY353381 “demonstrated tumor activity and clinical benefit at both the 20 mg and 50 mg dose level, with no significant differences in either efficacy or toxicity observed between the two dose levels.” In light of this, Dr. Baselga said, multinational, randomized, phase III trials of LY353381 vs tamoxifen are planned in the metastatic and adjuvant settings.