Reactions to new overall survival results from the MONALEESA-2 study in patients with HR+/HER2- advanced breast cancer in the first-line setting.
Joyce O’Shaughnessy, MD: Let’s turn to some of the key data sets that help us make the treatment decisions for patients. Gabe, your update of the MONALEESA-2 study is super important. Because it’s a first-line survival study, it might be the most important metastatic data set we have. It’s a really important trial. Could you tell us about where we were and then the new data that you’ve recently presented?
Gabriel Hortobagyi, MD, MACP, FASCO: First, over the past 4 decades, we’ve run hundreds of randomized trials. Many of them have shown progression survival benefit, but very few have shown an overall survival benefit—especially in first-line, as you pointed out. The MONALEESA-2 trial was designed specifically for first-line therapy of postmenopausal women with advanced breast cancer. It randomized patients to all receiving letrozole, half receiving the placebo, and the other half receiving ribociclib.
We reported the progression-free survival analysis in 2016 showing a 9-month prolongation of progression-free survival. That was highly significant. Then we had to wait another 5 years to reach maturity and analyze it for overall survival. The data I presented at ESMO [European Society for Medical Oncology Congress] were about overall survival. They showed that the control arm had a median overall survival of 51 months, and the ribociclib group had a median overall survival of 64 months. This prolongation of greater than 12 month was highly significant statistically but especially clinically. There are very few clinical trials we have run that have resulted in a 1-year prolongation of overall survival in any type of breast cancer. These are impactful results, and they should make us think of how we should move forward and what the clinical changes should be as we go back to the clinic.
Joyce O’Shaughnessy, MD: Is that the longest median survival in breast cancer in a first-line study?
Gabriel Hortobagyi, MD, MACP, FASCO: Prior to this study, we had made the greatest amount of progress in the HER2+ [human epidermal growth factor receptor 2–positive] phase, where the CLEOPATRA trial had almost reached 5 years of median survival. As an old man, I just want to go back to the 1970s, when I started. The median survival of breast cancer was about 2 years. Now, this is the first report that exceeds the 5-year median survival, which is wonderful for our patients. It delayed our report by 5 years, but it’s wonderful for our patients to see this manifestation of progress. It’s the longest median survival of any phase 3 study, in any type of breast cancer, that I’m aware of.
Joyce O’Shaughnessy, MD: That means half live longer than 5 years, which is really exciting. Gabe, what about subsets? Were there any subsets that didn’t get a survival advantage, or were there certain subsets that got the biggest survival advantage? Do we need that in the clinic, or is it across the board?
Gabriel Hortobagyi, MD, MACP, FASCO: We looked at a number of subsets, some built into the initial protocol and some later exploratory subsets. The study was not powered to look at the individual subsets for overall survival benefit. If you look at the forest plot, you see that every subset benefits to a similar degree. Although there are subsets that have a much smaller sample size ,and there are a couple of subsets that may have a difference. We’re still exploring that because not being a stratification criteria and the difference needs to be looked at more critically, because it could just be because of chance. The short answer is no, there’s no subset that has a significant difference in outcome.
Joyce O’Shaughnessy, MD: Awesome.
Sarah Sammons, MD: Another thing that I found very interesting about your presentation was that the overall survival benefit seemed to increase over time. I was trying to figure out why. At 6 years, 44% of the patients who got ribociclib in the first line were alive vs 32% who got placebo. That benefit seemed to increase as the years went on. Any thoughts on why that could be?
Gabriel Hortobagyi, MD, MACP, FASCO: You’re right on track, Sarah. In many of the clinical trials we’ve conducted in the past, the unfortunate reality was that the survival curve separated at the beginning and then came together later. Precisely because of that, it has been difficult to show an overall survival benefit in first-line metastatic breast cancer. These data are impressive because we started to show a significant difference at 4 years, and that difference increased to about 8% at 5 years, then to about 12% absolute difference at 6 years. Most of these patients have been off their first-line therapy for a number of years, although some are still receiving it. This is very impressive, and this indicates that some of these patients are exquisitely sensitive to the treatments we’re giving them, and they are tolerating it very well.
Joyce O’Shaughnessy, MD: That’s key, isn’t it? You can’t benefit from a treatment you can’t stay on. These survival advantages always seemed to be associated with well-tolerated therapy that people can actually take.
Transcript edited for clarity.