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The novel oral tyrosine kinase inhibitor axitinib, in combination with docetaxel, improved the time to progression and nearly doubled the overall response rate compared with docetaxel alone in a phase II trial of patients with metastatic breast cancer.
The median time to progression by Response Evaluation Criteria in Solid Tumors (RECIST) was 8.2 months in 112 patients who received axitinib plus docetaxel, versus 7 months in 56 patients treated with docetaxel alone. The overall response rate (ORR) was 40% for the combination and 23% for docetaxel alone (P = .04), lead author Dr. Hope S. Rugo reported.
The ORR with axitinib was even more favorable in a preplanned subset analysis comparing patients who had prior adjuvant chemotherapy with those who were chemotherapy-naive. In that analysis, 28 of 62 patients (45%) in the combination therapy arm achieved an overall response, compared with 4 of 30 chemotherapy-naive patients (13%) in the docetaxel-alone arm.
"Further phase II testing of axitinib in breast cancer combined with other standard chemotherapies is warranted," said Dr. Rugo, professor of medicine and director of the breast oncology clinical trials program at the University of California, San Francisco.
Axitinib (AG-013736, Pfizer Inc.) is an investigational small molecule that selectively inhibits vascular endothelial growth factor receptor (VEGFR) 1, 2, and 3, thereby blocking tumor angiogenesis and halting the progression of the tumor. Other studies presented at this year's ASCO meeting showed that axitinib was active in thyroid cancer, non-small cell lung cancer, renal cell carcinoma, and other solid tumors.
Dr. Rugo conducted a lead-in phase I study in 6 patients, which determined that docetaxel 80 mg/m² three times per week in combination with axitinib 5 mg twice a day on an empty stomach would be the recommended phase II dosing regimen. In that phase I trial, there were two partial remissions and three patients with stable disease at week 24 or later. The study also found no changes in the plasma profiles or pharmacokinetics of either agent when given together.
In the current trial, 168 patients were randomized in a 2:1 ratio to axitinib plus docetaxel or docetaxel alone. They were stratified according to prior adjuvant chemotherapy or not, estrogen receptor status, and Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 versus 2. Patients whose disease progressed could choose to be unblinded and cross over to single-agent axitinib if they were on placebo. Thirteen patients did so, Dr. Rugo reported.
More than half of the patients had received prior adjuvant chemotherapy at least 12 months before entering the study; 56%, or 112 patients in the combination arm, and 54%, or 56 patients, in the docetaxel alone arm.
A median of seven cycles of both regimens were delivered. The addition of axitinib resulted in increased grade 3 and 4 diarrhea and fatigue, as well as an increase in all grades of stomatitis and grade 1 and 2 hypertension. Febrile neutropenia also was increased in the axitinib arm, Dr. Rugo reported.
In the question period after her presentation, Dr. Rugo hypothesized that the relative lack of efficacy of axitinib in patients who did not receive adjuvant chemotherapy may mean that the combination of axitinib and docetaxel has its greatest potency in reversing chemotherapy resistance.
"Even though these patients were more than a year out from their adjuvant chemotherapy, they would presumably already have some inherent resistance to treatment, so this therapy [axitinib] may add benefit in an advanced setting," she said. However, she cautioned that this was "an exploratory randomized phase II trial, so it is in no way definitive."
These results mandate a phase III trial, said discussant Dr. Francisco J. Esteva of the University of Texas M.D. Anderson Cancer Center, Houston.
"This was a phase II trial, and if we are going to move forward with this strategy of using small molecules to target the VEGF receptors, they will need to move to phase III," he said. Dr. Esteva also called for the investigators to assess biomarkers, in order to determine which patients are likely to benefit from these therapies, "either through biopsies or by assessing circulating tumor cells."
Dr. Rugo said her trial was funded by Pfizer Oncology.
Rugo H.S. A randomized, double-blind phase II study of the oral tyrosine kinase inhibitor (TKI) axitinib (AG-013736) in combination with docetaxel (DOC) compared to DOC plus placebo (PL) in metastatic breast cancer (MBC). Abstract 1003.
Commentary |
The use of randomized phase II trials to explore and confirm the activity of new agents has proven to be beneficial in a number of settings. This study of a novel tyrosine kinase inhibitor, axitinib (AG-013736), targeting the VEGFR pathway further employed a double-blind placebo design, adding credibility to the results. Both the greater than 15% improvement in response rate and 1-month increase in time to progression yielded statistically significant results. The benefit was even more substantial in patients previously treated with adjuvant chemotherapy, and the trade-off of moderately increased toxicity appears to be worthwhile. Certainly these results would suggest the need for further development of axitinib in breast cancer, including pivotal phase III trials. — Howard A. Burris, M.D.
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