This podcast episode is made possible, in part, by a grant from Lilly.
Jamie DePolo: Hello. Thanks for listening. I’m podcasting from the 2023 American Society of Clinical Oncology Annual Meeting. My guest today is Dr. Dennis Slamon, a medical oncologist who is professor of medicine and executive vice chair for research for the UCLA Department of Medicine. He has many, many awards for his scientific accomplishments and is probably best known to our audience for doing the lab and clinical research that led to the development of Herceptin.
At this meeting, he presented primary results from the NATALEE trial, which is comparing Kisqali plus hormonal therapy to hormonal therapy alone after surgery for early-stage, hormone receptor-positive HER2-negative breast cancer.
Dr. Slamon welcome to the podcast.
Dr. Dennis Slamon: Thank you.
Jamie DePolo: So, right now Kisqali, or ribociclib as you call it in the study, is approved to treat metastatic breast cancer. What made you think it could offer benefits to people with early stage disease?
Dr. Dennis Slamon: The drug has a mechanism that is a basic mechanism and that is inhibiting the enzymes that control cell division along a certain pathway. And it seems to have a significant effect in our early lab studies in the hormone receptor-positive, HER2-negative breast cancer cells, and so we took that into clinical testing in advanced breast cancers or metastatic and found that it improved progression-free survival and it improved overall survival.
That same mechanism is operational whenever the breast cancer first starts. So, it seemed logical that it might have an effect there, and that was the purpose of designing NATALEE and executing the trial.
Jamie DePolo: Okay, and could you describe the NATALEE study for us. Just give us a brief overview.
Dr. Dennis Slamon: The NATALEE study tested 5,101 patients and they were randomized through to receive best available standard hormonal blockade versus that same therapy plus this drug ribociclib. And the randomization of one-to-one was basically breaking the population almost in half. They were balanced for all their criteria and characteristics, and we treated them for rather than two years, three years with the drug, because of its mechanism of action. The longer you keep these cells in arrest the more likely they’re going to go into a senescence pathway or what’s a cell death pathway.
Jamie DePolo: Okay. And I don’t mean to interrupt, but the Kisqali was for three years, but then did people continue on hormonal therapy for either five or 10 years?
Dr. Dennis Slamon: So, absolutely. A patient by protocol will continue on their hormonal blockade for their standard currently recommended doses of hormonal therapy, between five and 10 years depending on the treating physician and the patient.
Jamie DePolo: Sure. And so, my understanding from your presentation was these were sort of early results because the results looked so good you were asked to report out. Could you tell us what those were?
Dr. Dennis Slamon: Exactly. When you set up studies like this, there are safety criteria put in place for the study, certainly to protect the patients. There’s something called a futility analysis, which is the first analysis that occurs and it’s all done in a blind way. There’s a data safety monitoring board that monitors. They are the ones that actually see the data. The investigators don’t. The sponsors don’t. If it doesn’t look like there’s enough events, it doesn’t look like there’s any kind of separation, the trial is stopped for futility. So, you don’t continue to enroll patients on something that is not working.
Similarly, there are efficacy analyses that are early before you hit the end of the study, where you are looking for 5,000 patients enrolled and event rate of 500 events to analyze.
There was analysis at 320 some events, and analysis at 425 events, and analysis at 500 events. The first analysis, there was a difference but it wasn’t big enough to stop the trial but there’s a safety thing put in place that if it gets to a statistically significant difference, that data safety monitoring committee declares this trial is stopped because it’s achieved efficacy. The reason being you don’t want to continue to randomize patients on the standard therapy if you have something that’s looking better.
Jamie DePolo: Sure. And then people who were randomized to just get hormonal therapy, did they get the option to switch arms or does that sort of mess up the study?
Dr. Dennis Slamon: That’s an excellent question. There was not an option on this study. Many patients would drop off the study and go on one of the CDK4/6 inhibitors that was approved, either abemaciclib or palbociclib despite the fact that palbociclib did not show us a survival advantage. Other patients stayed on hormonal blockade and then we’ll do the final analysis on almost 2,000 patients that are still under treatment on the experimental arm and about 1,850 patients on the control arm. So, there’s still plenty of power in the trial to see what the final results will be, and the patients who go on these trials are every bit as much a collaborator in these studies as any investigator or any scientist. They are every bit as much a part of the story.
Jamie DePolo: Absolutely. So, could you summarize the results for us? What did you find?
Dr. Dennis Slamon: So, the results show that when you added this drug to the standard hormonal therapy you improved the recurrence rate and stopped -- I should say the recurrence rate by 25%. So, there was an improvement of 25% in terms of these recurrences. In terms of the incidence of distant disease recurrences -- meaning metastatic disease -- it went up 1% to 26%. Both of those were statistically significant. The other important thing about the study is it treated earlier patients, meaning patients with stage II disease. We didn’t just treat the very highest risk. We said there are patients at intermediate risk and we know that they still can have recurrences. 30% will have recurrences out of two or three decades. Can we benefit those patients? And that’s why the study included them as well.
Jamie DePolo: Okay, and are you going to follow people for that long?
Dr. Dennis Slamon: Absolutely. The study is designed to follow to the 500-event end point and beyond. Obviously, we want to report all of the data as it unfolds.
Jamie DePolo: Okay. Now what about side effects because I know I’ve talked to a lot of people. Hormonal therapy is difficult. Side effects can be very troubling. Some of the CDK4/6 inhibitors have other troubling side effects. How did that play out? Did the people who were on Kisqali have more side effects?
Dr. Dennis Slamon: So, clearly the patients on Kisqali have more side effects, the question is did they have significant side effects? And that’s determined by the patients. So, we have patient-reported outcomes. We also have objective measures like neutropenia. The drug does cause neutropenia but nowhere like the neutropenia you see with chemotherapy. The counts don’t go as low and they don’t stay down for as long. The cells recover very quickly. So, all that’s being monitored. The other thing that was unique to ribociclib was something in the EKG that I think concerned a lot of patients. It’s what’s called the prolongation of the QT interval.
Jamie DePolo: Okay. You’re going to have to explain that for us.
Dr. Dennis Slamon: Yeah. That’s just the electrical rhythm that’s going through the heart. There are certain periods of time between each part of that rhythm cycle and a prolongation, the initial space, could result in rhythm problems. So, we’re very careful about that. Even if you don’t see rhythm problems, even a little prolongation causes you to monitor and watch that very quickly. Both of those were seen at the dose that was set for metastatic disease. Patients who were on the metastatic disease trial who had any side effect went on a dose reduction to 400 milligrams. At the end of that metastatic disease trial, we were able to look at the outcomes for the patients that had a reduced dose, and it turns out their outcomes looked as good as the ones at 600-milligram dose.
So, the FDA is not going to go back and reverse the label for the metastatic trial, but we thought why not run the early breast cancer trial at a lower dose and see if we can improve safety. And that’s exactly what we found. We decreased the neutropenia rate significantly and we decreased this QTC prolongation to 0.2% of the populace from 1.2%. It was low to begin with. Now it’s a six-fold decrease lower. So, it’s really been very safe and very well tolerated. There were no new side effects.
Jamie DePolo: That’s great. And so, finally I want to ask if you could put these results in context because I know Verzenio is approved for adjuvant, or after surgery, for early-stage disease. Now we have Kisqali that looks very promising. If I’m diagnosed with this type of breast cancer, how do I decide? How do you decide which is right for you?
Dr. Dennis Slamon: So, obviously this is discussed with the patient and their treating physician. The critical thing is each of these drugs, they’re not all the same. They’re all different. Palbociclib hasn’t achieved a survival advantage or an improvement in recurrence rates in the early breast cancer setting so it’s not in play right now, but Verzenio, or abemaciclib, and Kisqali, or ribociclib, both have achieved that end point where they decrease these recurrence rates. So, how do you choose between the two? Well, they have different side effect profiles that we’ve talked about.
The Kisqali or ribociclib has a little bit more of the neutropenia, but again not the levels that we worry about like with chemotherapy and the patients all recover from it. Abemaciclib has less of that but abemaciclib has more diarrhea and the diarrhea can be challenging, especially in the early breast cancer setting. These patients are doing well. They’re working women. They go to their job and inducing grade II diarrhea is a challenge for a teacher.
Jamie DePolo: Absolutely. Absolutely. So, you take that into account.
Dr. Dennis Slamon: Those are the things that are taken into consideration.
Jamie DePolo: Okay. And discussion between a person and their doctor and ultimately what works best.
Dr. Dennis Slamon: Yeah. That’s exactly right. The other thing that’s taken into consideration is abemaciclib is approved for these high-risk patients, whereas ribociclib was tested in the lower-risk patients, not the lowest risk, but the lower-risk patients, the intermediate risk so to speak, and found that we have a benefit there. So, even in patients with stage II disease and node-negative disease, the drug appears to be having a benefit.
Jamie DePolo: Okay. Great. Thank you so much Dr. Slamon. I appreciate your time.
