FDA Approves mTOR Inhibitor Everolimus for Breast Cancer
该项批准是基于随机、双盲、安慰剂对照Ⅲ期BOLERO-2试验的结果，该试验纳入了724例上述新适应证的绝经后女性患者。结果显示，接受依维莫司(10 mg/d)+依西美坦(25 mg/d)治疗者的中位无进展生存期(主要终点指标)为7.8个月，而依西美坦(25 mg/d)+安慰剂组为3.2个月，前者中位无进展生存期延长1倍多，差异非常显著。联合治疗组客观应答率为12.6%，而对照组为1.7%；依维莫司治疗组3例完全应答(0.6%)，58例部分应答(12%)，而安慰剂组无1例完全应答，4例部分应答(1.7%)。根据药品说明书有关信息，总生存率结果“在中期分析时还不成熟，未见与治疗相关的显著差异”。
By: ELIZABETH MECHCATIE, Internal Medicine News Digital Network
The approval of everolimus has been expanded to include a group of postmenopausal women with advanced hormone receptor–positive, HER2-negative breast cancer, the Food and Drug Administration announced on July 20.
A mammalian target of rapamycin (mTOR) inhibitor marketed as Afinitor, everolimus is indicated in combination with exemestane (Aromasin) for this group of women when they have had recurrence or progression of disease after treatment with letrozole (Femara) or anastrozole (Arimidex).
The drug becomes the first mTOR inhibitor approved for advanced hormone receptor–positive breast cancer. Exemestane, letrozole, and anastrazole are aromatase inhibitors, a class of drugs that has become an alternative to tamoxifen for adjuvant treatment of women with estrogen receptor– and/or progesterone receptor–positive breast cancer.
The new approval is based on the phase III BOLERO-2 trial, a randomized, double-blind, placebo-controlled study of 724 postmenopausal women who matched the population in the new indication.
Median progression-free survival, the primary end point, more than doubled among those treated with everolimus (the approved tablet dose of 10 mg per day) plus exemestane (25 mg per day). The median reached 7.8 months in this group, vs. 3.2 months among those treated with exemestane (25 mg per day) and placebo, a difference that was highly significant statistically.
The objective response rate was 12.6% among those on the combination, compared with 1.7% in the control group. There were 3 complete responses (0.6%) and 58 partial responses (12%) in women who received everolimus, compared with no complete responses and 4 partial responses (1.7%) among those given placebo.
Overall survival results "were not mature at the time of the interim analysis, and no statistically significant treatment-related difference in OS was noted," according to the prescribing information.
The most common adverse effects reported in patients treated with everolimus included stomatitis, infections, rash, fatigue, diarrhea, and decreased appetite. Adverse events are more common among patients aged 65 years and older, who should be monitored closely, according to the FDA statement announcing the approval.
Everolimus was first approved in 2009 as a treatment for advanced renal cell carcinoma that has progressed after treatment with other cancer therapies. This was followed by approvals for adults with progressive advanced neuroendocrine tumors of pancreatic origin, patients with renal angiomyolipoma and tuberous sclerosis complex (TSC) not requiring immediate surgery, and adults and children with subependymal giant cell astrocytoma associated with TSC who require treatment but are not candidates for curative surgery.
"This approval redefines the treatment and management of advanced hormone receptor–positive breast cancer, offering a critical new option for physicians and patients," Dr. Gabriel Hortobagyi, chair of Breast Medical Oncology, at the University of Texas M.D. Anderson Cancer Center, said in a statement released by Novartis Pharmaceuticals Corp., which markets everolimus. The company noted that two ongoing phase III trials are studying everolimus in HER2-positive breast cancer.