New Antifolate Shows Activity in Advanced Breast Cancer Patients

SAN FRANCISCO—As a salvage therapy in advanced breast cancer patients who have failed prior therapy with anthracyclines or anthracenediones, taxanes, and capecitabine (Xeloda), the investigational antifolate pemetrexed disodium (Alimta) shows promising activity, according to clinical trial results presented at the American Society of Clinical Oncology annual meeting (abstract 194).

Currently, there are no data to guide oncologists in choosing chemotherapy for metastatic breast cancer patients whose disease has progressed in spite of treatment with the above-named agents, said Joyce O’Shaughnessy, MD, co-director, breast cancer research, US Oncology, Dallas.

Pemetrexed disodium, Dr. O’Shaughnessy noted, is a cytotoxic compound that inhibits three enzymes in folate-dependent pathways (pyrimidine and purine biosynthesis). It has shown activity in non-small-cell lung cancer, breast, pancreas, colorectal, and head and neck cancers in phase I/II studies, and, she speculated, its activity may not be affected by mechanisms of capecitabine resistance because of its several mechanisms of action.

In this study, metastatic breast cancer patients received pemetrexed disodium (500 mg/m² as a 10-minute IV infusion) every 21 days with prophylactic dexamethasone to prevent skin rash.

To date, 42 of 80 patients enrolled are evaluable for safety and efficacy. The median age was 52 years (range, 33 to 75), and patients had a mean of four prior chemotherapy regimens. Patients had metastases in soft tissue (48%), lung (41%), liver (45%), and bone (30%).

Folic acid (350 to 600 µg orally) and vitamin B12 (1,000 µg IM) were administered to 19 of 42 patients (45%) beginning after the 23rd patient. They were added after it was observed that their administration substantially reduced neutropenia and GI toxicity (see also article below). No dose reductions or omissions were necessary in a total of 169 cycles administered (median 2; range, 1 to 18).

Dr. O’Shaughnessy reported an objective response rate of 10%, with 5% complete responses and 5% partial responses. Responses were observed in skin, lymph nodes, and liver. Durations of the two complete responses were 3.6 and 3.0 months and of the two partial responses, 3.2 and 2.8 months.

"If you can get a 10% to 15% response rate in very late line therapy, that means when you move into earlier stage disease, you probably are going to be in the 30% to 40% response rate range," she said.

In patients not receiving vitamins or receiving them after cycle 0 (n = 23), grade 3 and 4 neutropenia (without fever) occurred in 22% and 61% of patients, respectively, whereas with those receiving vitamin supplementation from the outset (n = 19), grade 3 and 4 neutropenia was reported in 5% and 11% of patients. Other toxicities, Dr. O’Shaughnessy said, were manageable, predictable, and tolerable.

"There is very little toxicity with no hair loss, no mouth sores, no diarrhea, and it is mild on the bone marrow. There is a bit of fatigue, though," she said. She added that all studies with pemetrexed disodium are currently including folic acid and vitamin B12 supplementation.

She concluded: "The early results of two complete and two partial responses out of 42 patients are encouraging in this hard-to-treat population."