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Ribociclib plus letrozole extends PFS in hormone receptor–positive, HER-2–negative advanced breast cancer
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COPENHAGEN, Denmark — The addition of ribociclib to letrozole significantly extended PFS in postmenopausal women with hormone receptor–positive, HER-2–negative advanced breast cancer, according to an interim analysis of the double blind, randomized phase 3 MONALEESA-2 trial presented at the European Society for Medical Oncology Congress.
“About two-thirds of breast cancers are hormone dependent. For these patients, endocrine treatments represent the treatment of choice, both in the primary and metastatic setting,” Gabriel N. Hortobagyi, MD, FACP, professor of medicine in the department of breast medical oncology in the division of cancer medicine at The University of Texas MD Anderson Cancer Center, said during a press conference. “Especially in the metastatic setting, after several months of exposure, the tumors become resistant of such treatment. There has been a rich area of research in breast cancer trying to develop strategies to overcome, prevent or reverse resistance to endocrine or hormonal therapy.”
One such line of research has been the development of cyclin-dependent kinase (CDK) 4/6 inhibitors, such as ribociclib (LEE011, Novartis).
“This line of research has been going on for 50 years, but only recently have the selective CDK 4/6 inhibitors become available,” Hortobagyi said.
Hortobagyi and colleagues evaluated whether the addition of ribociclib to first-line treatment with letrozole would extend PFS among women with hormone receptor–positive, HER-2–negative advanced breast cancer.
The analysis included data from 668 postmenopausal women previously untreated for their advanced disease. Researchers randomly assigned patients 1:1 to receive 2.5 mg daily letrozole with placebo or 600 mg daily ribociclib.
PFS served as the study’s primary endpoint. Secondary endpoints included OS, overall response rate, clinical benefit rate and safety.
The first analysis was planned to occur when approximately 70% of 302 PFS events had been reached.
Median follow-up was 15.3 months.
At the time of the interim analysis, median PFS was not reached in the ribociclib arm (95% CI, 19.3-not reached) and was 14.7 months (95% CI, 13-16.5) in the placebo arm. This equated to about a 44% reduction in risk for progression (HR = 0.556; 95% CI, 0.42-0.72).
OS data were not yet mature at the time of the analysis.
“There was such a significant difference in the two curves in terms of PFS that it was declared that, statistically, the study had met its primary endpoint,” Hortobagyi said. “The curves start to separate very early and the separation continues and expands.”
Ribociclib also was associated with a greater overall response rate (53% vs. 37%; P = .00028) and clinical benefit rate (80% vs. 72%; P = .02) among patients with measurable disease at baseline.
The treatment benefit appeared consistent across patient subgroups, such as those for age, performance status, and extent or location of metastases.
Adverse events occurred frequently but were mostly uncomplicated and asymptomatic, Hortobagyi said. The most common grade 3 and grade 4 adverse events included neutropenia (59% vs. 1%), leukopenia (21% vs. 1%), hypertension (10% vs. 11%), elevated alanine aminotransferase (9% vs. 1%) lymphopenia (7% vs. 1%) and elevated aspartate aminotransferase (6% vs. 1%).
“This study is paradigm changing in the sense that, historically, there have not been studies in metastatic breast cancer with this magnitude of benefit,” Hortobagyi said. “The problem is we do not have biomarkers. We do not know whether 100% of patients benefit, 50% or 30%. So, we cannot select a patient population to enrich, although we are working on developing such biomarkers.
“There is room today for women with asymptomatic, hormone receptor–positive metastatic breast cancer to be treated with endocrine therapy alone, but that is not an evidence-based recommendation,” Hortobagyi added. “If you want the maximum benefit for metastatic hormone receptor–positive breast cancer, you are going to select the combination with a CDK 4/6 inhibitor as your first choice.”– by Alexandra Todak
Reference:
Hortobagyi GN, et al. Abstract LBA1_PR. Presented at: European Society for Medical Oncology Congress; Oct. 7-11, 2016; Copenhagen, Denmark.
Disclosure: Hortobagyi reports grants and personal fees from Novartis during the conduct of the study, as well was personal fees from Eli Lilly and Pfizer outside the submitted work. Please see the abstract for a list of all other researchers’ relevant financial disclosures.