NEW YORK (Reuters Health) Jul 15 - About a third of women with trastuzumab-resistant HER2-overexpressing metastatic breast cancer get clinical benefit from the combination of trastuzumab (Herceptin) and everolimus (Afinitor), according to new results.
The 34% clinical benefit rate seen in the two small, pooled phase I/II studies consisted of 15% partial responses plus 19% persistent stable disease (six months or longer) in 47 study participants, as reported online July 5 in the Journal of Clinical Oncology.
Participants' median age was 50 years. All had biopsy-proven HER2-overexpressing breast cancer and radiographic evidence of metastasis. All had an Eastern Cooperative Oncology Group performance status of 2 or lower, at least one measurable lesion according to Response Evaluation Criteria in Solid Tumors, and progressive disease after at least one trastuzumab-based therapy.
They received either 5 mg or 10 mg of everolimus daily. The typical maintenance dose of trastuzumab was 6 mg/kg every three weeks.
The benefit rate of 34%, the researchers wrote, "is clinically important in this population because many patients demonstrated a high burden of visceral disease and had received two chemotherapy regimens" for metastatic breast cancer.
Toxicity was considered to be acceptable, with fatigue, infection and mucositis the predominant nonhematologic toxicities. There were no treatment-related deaths.
"One of the interesting aspects of our study is that it did not include chemotherapy, which makes for a more tolerable treatment in patients with advanced metastatic disease," senior author Dr. Francisco J. Esteva told Reuters Health in an email.
He added that the only FDA-approved regimen for HER2-positive metastatic breast cancer after trastuzumab-based therapy is a combination of capecitabine and lapatinib. But, he pointed out, other combinations have shown clinical activity in this setting, such as capecitabine plus trastuzumab and vinorelbine plus trastuzumab.
Dr. Esteva, of the M.D. Anderson Cancer Center in Houston, Texas, explained that the HER2 protein activates phosphoinositol 3-kinase (PI3K), which in turns activates mammalian target of rapamycin (mTOR), resulting in cancer cell survival.
But everolimus, when it binds to a protein called FKBP12, blocks mTOR.
In an editorial, Drs. Sarat Chandarlapaty and Shanu Modi of Memorial Sloan-Kettering Cancer Center in New York noted the growing number of HER2 targeting agents in development - and their similar efficacies.
They say Dr. Esteva's findings "push everolimus onto the list of promising therapies for HER2-positive breast cancer and highlights mTOR as a relevant target, but all the more, it focuses a spotlight on our need for robust biomarkers to rationalize an otherwise uninterpretable menu of options."
The study was supported by the U.S. National Cancer Institute and Novartis, maker of Afinitor (everolimus).
The 34% clinical benefit rate seen in the two small, pooled phase I/II studies consisted of 15% partial responses plus 19% persistent stable disease (six months or longer) in 47 study participants, as reported online July 5 in the Journal of Clinical Oncology.
Participants' median age was 50 years. All had biopsy-proven HER2-overexpressing breast cancer and radiographic evidence of metastasis. All had an Eastern Cooperative Oncology Group performance status of 2 or lower, at least one measurable lesion according to Response Evaluation Criteria in Solid Tumors, and progressive disease after at least one trastuzumab-based therapy.
They received either 5 mg or 10 mg of everolimus daily. The typical maintenance dose of trastuzumab was 6 mg/kg every three weeks.
The benefit rate of 34%, the researchers wrote, "is clinically important in this population because many patients demonstrated a high burden of visceral disease and had received two chemotherapy regimens" for metastatic breast cancer.
Toxicity was considered to be acceptable, with fatigue, infection and mucositis the predominant nonhematologic toxicities. There were no treatment-related deaths.
"One of the interesting aspects of our study is that it did not include chemotherapy, which makes for a more tolerable treatment in patients with advanced metastatic disease," senior author Dr. Francisco J. Esteva told Reuters Health in an email.
He added that the only FDA-approved regimen for HER2-positive metastatic breast cancer after trastuzumab-based therapy is a combination of capecitabine and lapatinib. But, he pointed out, other combinations have shown clinical activity in this setting, such as capecitabine plus trastuzumab and vinorelbine plus trastuzumab.
Dr. Esteva, of the M.D. Anderson Cancer Center in Houston, Texas, explained that the HER2 protein activates phosphoinositol 3-kinase (PI3K), which in turns activates mammalian target of rapamycin (mTOR), resulting in cancer cell survival.
But everolimus, when it binds to a protein called FKBP12, blocks mTOR.
In an editorial, Drs. Sarat Chandarlapaty and Shanu Modi of Memorial Sloan-Kettering Cancer Center in New York noted the growing number of HER2 targeting agents in development - and their similar efficacies.
They say Dr. Esteva's findings "push everolimus onto the list of promising therapies for HER2-positive breast cancer and highlights mTOR as a relevant target, but all the more, it focuses a spotlight on our need for robust biomarkers to rationalize an otherwise uninterpretable menu of options."
The study was supported by the U.S. National Cancer Institute and Novartis, maker of Afinitor (everolimus).
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