This podcast is made possible by the generous support of Lilly Oncology.
Jamie DePolo: Hello, and welcome to the Breastcancer.org podcast. I'm your host Jamie DePolo, senior editor at Breastcancer.org. We're podcasting live from the European Society for Medical Oncology 2019 Congress in Barcelona, Spain.
My guest is Dr. Dennis Slamon, professor of medicine and executive vice-chair for research for the UCLA Department of Medicine. He also serves as director of clinical and translational research and director of the Revlon UCLA Women's Cancer Center Research Program at the Jonsson Comprehensive Cancer Center at UCLA. He is probably best known for doing the laboratory and clinical research that led to the development of Herceptin, the first medicine to specifically treat HER2-positive breast cancer. Dr. Slamon has won numerous awards for his research. Earlier this month, he received the 2019 Lasker Award for clinical medical research for his groundbreaking work on Herceptin.
At this conference, he presented overall survival results from the MONALEESA-3 study, looking at using Kisqali plus Faslodex to treat advanced-stage hormone-receptor-positive, HER2-negative breast cancer in postmenopausal women. Dr. Slamon, welcome to the podcast.
Dr. Dennis Slamon: Thank you.
Jamie DePolo: So, can you give us a brief summary of the MONALEESA-3 study, just in case anybody isn't familiar?
Dr. Dennis Slamon: The MONALEESA-3 trial’s designed to look at a CDK4/6 inhibitor, in this case ribociclib, in combination with hormonal therapy, a very effective hormonal therapy, fulvestrant, versus fulvestrant plus a placebo, to ask a couple of questions. One would be, what was the progression-free survival and now the overall survival, but also whether or not this combination would be particularly effective if it was given in the first line versus what we see in the second line. It was clear from earlier data that the drug was approved based on its improvement in progression-free survival, but the hardest endpoint and the most important to reach for patients is overall survival. And so, we are presenting among the first data in this setting on overall survival and that is what the MONALEESA trial was designed to look at.
Jamie DePolo: And it was, you touched on this, but this was unique because this was the first treatment for the advanced-stage disease, and that was kind of unique. And can you talk about that a little bit? Why did you decide to do it that way?
Dr. Dennis Slamon: It was an important question to ask and answer because there's been an ongoing debate in a lot of areas that held that perhaps we should save the CDK4/6 inhibitors until the second line. Since there are a number of different hormonal therapies that, if a patient were to have a reccurrence after receiving their initial therapy, it might be right to just treat with another hormonal therapy and get the benefit of that, and then add the CDK4/6 inhibitor in the second line in metastatic disease.
What MONALEESA-3 looked at was, it compared a large number of patients, essentially half of the patient population studied, were in the first line and addressed that question, would there be a better survival advantage if the combination were used right up front in metastatic disease? And the answer is unequivocally yes. There's a highly statistically significant difference, but more importantly, it's a clinically meaningful difference. We know that the median overall survival hasn't even been reached yet in the whole population. So, the true magnitude is yet to be seen, but it's clear that it's a significant benefit that will be meaningful for patients.
Jamie DePolo: Can you talk a little bit about the overall survival results? What were the differences?
Dr. Dennis Slamon: There's a lot of... It's a 28% relative risk reduction at this point, but again, we need to follow the trial further because the median has not yet even been reached in the combination arm for overall survival, whereas it has been reached in the control arm.
Jamie DePolo: Okay, and what was the follow up time? How much time are we talking?
Dr. Dennis Slamon: We're now at about 40 months follow-up, and there will be a third analysis that’ll be done. These are all event-driven analyses, so when a certain number of events have occurred, we then look at the data and see what the difference is. At the first analysis, there was a trend, but there wasn't a statistically significant difference. The second analysis, which is what we're reporting now, has shown this big difference and has already crossed the boundary indicating that this can only get bigger, I believe the same or bigger, likely to get bigger. And so, we'll see when we do this third analysis. But all the data show that there’s this clinically meaningful impact and something that's significant.
Jamie Depolo: Now what about side effects? Did you see any different, more within this...?
Dr. Dennis Slamon: So, the class side effects of the CDK4/6 inhibitors is bone marrow neutropenia, and that's been known since the drugs have been introduced. It's a different kind of neutropenia than you see with chemotherapy in the sense that the white counts in general do not go down as low as you see with chemotherapy. Nor do they stay down as long. They recover much more quickly, and that's because the drugs are not cytotoxic. They don't kill cells. They're cytostatic. They, for the normal cells, they stop their growth, and when the patient goes off for the one week on the treatment cycle — you have 3 weeks of drug, 1 week off — the bone marrow recovers quite quickly. There's no need so far for growth factors or anything like that. It's just the normal marrow that's recovering quite quickly.
So, in that sense, that is a side effect that we know about with the class. Both palbociclib and ribociclib have that effect, more than abemaciclib. Abemaciclib has less of the neutropenia, but abemaciclib has more GI toxicity, in particular, diarrhea.
We also watch for pneumonitis, which is an inflammation in the lung. In Japan, there have been some reported cases of severe pneumonitis, but in the MONALEESA trial, we did not see anything above a grade 1, 2 pneumonitis.
There's occasionally liver disfunction, again, nothing that indicates a true hepatitis, just some abnormality in the liver enzymes, that again, recovers when the drug is held for a brief period of time.
And finally, with ribociclib there appears to be an electrocardiogram, as Dr. Sledge said this morning, sort of a paper observation that hasn't resulted in any significant problems with regards to impact on the patient, but it's something we watch for very closely.
Jamie DePolo: Okay, and you mentioned a lung inflammation. The FDA just asked the companies to put the extra warning on the labelling about lung inflammation with the CDK4/6 inhibitors…
Dr. Dennis Slamon: Yes.
Jamie DePolo: …but it sounds like you did not see a lot of that. It's very rare.
Dr. Dennis Slamon: We did not with the MONALEESA trial. I think the alarm bell went off when they saw it with abemaciclib in the Japanese study. There may be something unique about the Asian population, but we don't know that yet, it still needs to be studied further. However, when we, because of that finding, the agencies, both the FDA, and I think the EMA, have asked that people look at all the data. And MONALEESA had been looked at carefully, and there's nothing that's beyond a grade 1, 2, either lung respiratory issue or pneumonitis, none of them have gone on to any kind of serious problem.
Jamie DePolo: Excellent. That's good to hear. And finally, to wrap up, what do these results mean for people who are diagnosed with advanced-stage hormone-receptor-positive, HER2-negative breast cancer? Is this practice-changing? I mean, I know it's talked about in the second line, do you think it's going to become the standard of care?
Dr. Dennis Slamon: So, you've asked the essential question and the whole reason MONALEESA-3 is, I think, a study that's being looked at. It's the first study that shows that this should be a new standard of care in the first-line setting of metastatic disease. If the differences were statistically significant but not clinically meaningful, you could make the debate that, yeah, the numbers improved some, but it's not a big improvement. We've seen a big improvement.
So, I think there's no longer a question of whether or not we should hold these drugs. And for women who have metastatic disease that is hormone-receptor-positive and HER2-negative, this drug should be used in combination right up front.
Jamie Depolo: Thank you so much for your time. I appreciate it.
Dr. Dennis Slamon: You're welcome.
