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An experimental mTOR inhibitor produced partial remissions and disease stabilization in an open-label study enrolling chemotherapy-naive and previously treated patients with progressive, advanced endometrial cancer.
Dr. Nicoletta Colombo reported the mTOR (mammalian target of rapamycin) inhibitor AP23573 (Ariad Pharmaceuticals) was given to 45 women with advanced disease and documented progression in the 3 months before study entry.
The cohort included patients with mixed histologies. All but two had previous chemotherapy, and 30 women had previously received pelvic radiotherapy. Median age was 67 years. The women received 12.5 mg of AP23573 as an intravenous infusion for 5 days every 2 weeks, reported Dr. Colombo of the European Institute of Oncology, Milan.
Clinically beneficial responses were seen in 13 patients. "We observed 4 partial remissions, which represented 9% of the cohort, and 9 patients had stable disease lasting longer than 16 weeks, giving us a total clinical response of 29% in this heavily treated population," Dr. Colombo said at a poster session.
Of the four patients with partial responses, two had adenocarcinomas, one had an adeno-clear cell carcinoma, and one had a papillary serous carcinoma. Treatment was discontinued before four cycles in 18 patients because of progressive disease (14), consent withdrawal (1), or unrelated adverse events (3).
"This kind of drug activity in advanced endometrial cancer is very interesting, especially in view of how well the women tolerated the treatment," she said.
About one-third of patients developed fatigue, anemia, mucositis, or nausea and vomiting. Most adverse events were grades 1 or 2. There were 16 grade 3 or 4 events, mirroring rates in previous AP23573 trials, Dr. Colombo said.
Discussant Dr. Martin Gore said "endometrial cancer is crying out for mTOR inhibition." He called the responses in chemotherapy-naive patients encouraging and said they indicate mTOR inhibition would be a reasonable approach for any patient with advanced endometrial cancer.
"Even though it's only two patients, two out of two responded, and I certainly would be very comfortable in giving this material to chemotherapy-naive patients if they have metastatic endometrial cancer. One can always give them chemotherapy down the line," said Dr. Gore of the Royal Marsden Hospital, London.
Colombo N. et al. A phase II trial of the mTOR inhibitor AP23573 as a single agent in advanced endometrial cancer. Abstract 5516.
Commentary |
This study by Colombo et al. identifies potentially interesting activity for a new mTOR inhibitor, AP23573. These data suggest that this agent should be evaluated further in combination with chemotherapy in patients not previously exposed to systemic agents. One cannot, however, draw the conclusion that the agent has a role in the management of endometrial carcinoma when the objective response rate is less than 10% and the agent has not been shown to affect progression-free survival or overall survival in a randomized trial. The mTOR inhibitors are an interesting category of targeted agents with potential usefulness in endometrial carcinoma. We should anxiously await the next studies of this agent in this disease. In the interim, the optimal systemic therapy remains chemotherapy that includes two or more of the following: anthracyclines, taxanes, and platinum agents. — J. Tate Thigpen, M.D.
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