Gabriel N. Hortobagyi, MD
An interim analysis of data from the randomized, double-blind MONALEESA-2 trial has shown that the addition of the CDK4/6 inhibitor ribociclib to letrozole significantly improved progression-free survival (PFS) in postmenopausal women with hormone receptor (HR)–positive advanced breast cancer.
Patients in the ribociclib arm had a 44% reduction in the risk of progression or death compared with patients who placebo plus received hormone therapy (HR, 0.556; 95% CI, 0.43-0.72; P
= .00000329). This difference satisfied prespecified statistical requirements for superiority.“
It is clear that these are practice-changing findings,” said Gabriel N. Hortobagyi, MD. “Going forward, the treatment of choice for these same postmenopausal women with HR-positive breast cancer, will be a combination of a drug like letrozole with a CDK4/6 inhibitor such as ribociclib.”
In an interview with OncLive
, Hortobagyi, professor of Medicine at the University of Texas MD Anderson Cancer Center, discusses the design of the MONALEESA-2 trial, the impact that these findings stand to have in this setting, and the integral role of hormonal therapy in the treatment of patients with HR-positive breast cancer.OncLive: Could you provide an overview of the MONALEESA-2 trial?Hortobagyi:
The MONALEESA-2 trial was designed as a phase III randomized placebo-controlled trial for postmenopausal women with HR-positive metastatic breast cancer who had not received prior treatment for advanced disease. The study recruited 668 patients from about 29 countries, 223 centers.
After stratifying them by the presence or absence of liver or lung metastases, patients were randomized in a 1:1 ratio to receive either letrozole plus ribociclib or letrozole plus placebo. Letrozole was administered daily at the standard dose of 2.5 mg daily, while ribociclib was administered at 600 mg daily for 21 days in a row followed by a 1-week interruption. Treatment was continued until disease got worse or progression.
The primary efficacy variable was progression-free survival. The study was designed so that, every 8 weeks, we repeated the staging workup to determine whether the disease was stable, responding, or had progressed. That was done for the first 18 months of the study, and after that, it was done somewhat less frequently. But the data I’m talking about today really focused on the first 15 months or so, because the median follow-up at the time of this analysis, which is based on data up until January 29, 2016, was a follow-up of 15.3 months.
At the time of that analysis, which was an interim analysis by the way, and interim analyses are designed to reject a study because of futility, which was not the case, or because we want to determine a favorable therapeutic effect early, which was the case here. So under normal circumstances, you wait until a definitive analysis to determine whether the treatment is good or not. In this case, well before that, with only about 70% of the expected PFS events, we found such a significant difference between the 2 treatment arms that the study was declared as having reached its primary efficacy variable.
So, at that time, the 2 treatments were so different that the hazard ratio showed a 44% reduction in PFS events, with a highly significant P
value, and with curves that started to diverge at the first evaluation at 8 weeks, and continued to diverge as time went on.
So this is a very stable and powerful observation that exceeds the power of the study as designed. Because of that, we reached our objective several months earlier than we had planned, which is a wonderful surprise when running a clinical trial.What is the significance of these results in the general treatment landscape of HR-positive breast cancer?
Up until the development of the CDK4/6 inhibitors, the standard of care for managing patients with HR-positive metastatic breast cancer was an aromatase inhibitor such as letrozole or anastrozole. Since the development of these very favorable results, it is clear that these are practice-changing findings. And, going forward, the treatment of choice for these same postmenopausal women with HR-positive breast cancer will be a combination of a drug like letrozole with a CDK4/6 inhibitor such as ribociclib.
And that’s a major change, because with letrozole alone, the best data—which incidentally come from the MONALEESA-2 trial—is about a 14-month PFS. And with the addition of ribociclib, we are adding a significant number of months, to be determined by more mature data from the MONALEESA-2 trial. And that is likely to impact the overall survival of these patients, though we still await a more mature analysis of this study.Are there plans to combine ribociclib with other agents in the future?