ATLANTA - The potential to treat cancer by inhibiting mammalian target of rapamycin (mTOR) gained support at this year's American Society of Clinical Oncology meeting at the Georgia World Congress Center in Atlanta, with two companies presenting positive clinical data.
Late Monday afternoon, Ariad Pharmaceuticals Inc. reported Phase II data here showing that treatment with AP23573, an intravenously administered, small-molecule mTOR inhibitor, more than doubled progression-free survival rates in patients with metastatic and/or unresectable soft-tissue and bone sarcomas when compared to control data compiled by the European Organization for Research and Treatment of Cancer.
A day earlier, Wyeth Pharmaceuticals, a division of Madison, N.J.-based Wyeth, revealed preliminary interim data from its ongoing Phase III study of temsirolimus, which indicate increased overall survival in advanced renal-cell carcinoma patients.
A protein kinase, mTOR is a central player in cell growth, acting as a "master switch," in cancer cells, said Harvey Berger, chairman and CEO of Cambridge, Mass.-based Ariad.
Blocking mTOR starves the cancer cell in three ways: It prevents nutrients from entering the cell, blocks the VEGF pathway to stop the flow of blood and halts the cell's growth stimulation.
In short, they inhibit "growth, cell division, metabolism and angiogenesis," he told BioWorld Today.
In Ariad's 212-patient Phase II study, sarcoma patients in each of four subgroups - bone sarcomas, and three soft-tissue sarcoma groups, including leiomyosarcoma, liposarcoma and any other soft-tissue sarcoma - received daily doses of 12.5 mg of AP23573 on a cycle that gave treatment for five days and then withheld it for nine. Efficacy was determined using clinical-benefit response and progression-free survival.
The clinical-benefit response for the total trial population was 29 percent, exceeding the primary endpoint of 25 percent. Breaking down the data from subgroups showed rates of 30 percent for bone sarcomas, 33 percent for leiomyosarcoma, 30 percent for liposarcoma and 23 percent for other soft-tissue sarcomas.
The progression-free survival rate was 24 percent at six months for the overall study, and averaged 25 percent in bone sarcomas and 23 percent in soft-tissue sarcomas. Median progression-free survival was 15 weeks. The figures were significantly higher than the historic patient data provided by the EORTC showing an 8 percent progression-free survival rate at six months, and median progression-free survival of seven weeks.
"This is the first time a new agent has shown activity across the whole sarcoma spectrum," Berger said. "A third of the 212 patients showed sustained clinical benefit."
Based on those data, Ariad intends to initiate a Phase III trial of AP23573 in sarcoma before the end of the year. Upon successful results, the company hopes to launch the drug, which received fast-track and orphan designation, in late 2008.
The most advanced mTOR inhibitor in development is Wyeth's temsirolimus, in a 626-patient Phase III trial in kidney cancer. Preliminary data from an interim analysis showed that the drug increased survival as a first-line treatment in patients with advanced disease and poor risk features compared to interferon-alpha. Patients in the temsirolimus group experienced a 3.6 month, or 49 percent, increase in median overall survival to 10.9 months vs. 7.3 months for the interferon-alpha group.
For Ariad, Wyeth's data were "great validation of mTOR as an important cancer target," Berger said, though it's too early to tell whether the AP23573 and temsirolimus would ever go head to head in the same market.
"They're both inhibiting mTOR, but they have different properties and different dosages," he said.
Beyond sarcoma, Ariad has 11 recently completed or ongoing trials of AP23573 in solid tumors and hematological cancers, including three studies testing AP23573 in combination with chemotherapeutic agents.
The decision to start with sarcoma stemmed from the company's earliest Phase I trials, which suggested a strong clinical benefit with AP23573. In fact, the very first patient to receive the drug had uterine sarcoma, and demonstrated a "remarkable, almost immediate response," Berger said, adding that three years later the patient still is taking AP23573.
At this time, Ariad retains all rights to AP23573, though it anticipates signing a partner later this year to commercialize AP23573 outside of the U.S. The company expects to handle U.S. sales itself. Shares of Ariad (NASDAQ:ARIA) closed at $5.08 Tuesday, down 15 cents.
The conference, which featured more than 4,000 abstracts in 27 disease-specific subject and oncology areas, ended Tuesday. By the afternoon, attendees had packed up their presentations and exhibits and were headed out the door, many of them to Hartsfield-Jackson International airport, with ASCO tote bags slung over their shoulders.
Next year's annual meeting will be in Chicago.