Evolving Treatment Patterns in Breast Cancer - Episode 5
Transcript:Joyce O’Shaughnessy, MD: Let’s transition then to ER [estrogen receptor]-positive disease, but now we’ll go into the metastatic setting. Because we have really interesting survival data with the CDK4/6 [cyclin-dependent kinases 4 and 6] inhibitor palbociclib that hit the New England Journal of Medicine in October and is coming out at ESMO [European Society of Medical Oncology]. We have our very first survival data. So, Ruth, why don’t you give us a feel. Where are we with CDK4/6 inhibitors in ER-positive metastatic disease?
Ruth O'Regan, MD: Obviously the results are very dramatic. It’s so interesting across all the trials that have been done that the hazard ratios are always about 0.55 no matter where you go to look at them. So I think the question really is, does everybody need them in the first-line or can some people get them in the second-line? Despite very elegant work by multiple investigators, the only biomarker we have right now is estrogen receptor. And there’s an attempt in the neoadjuvant setting to use these drugs to see if you can actually find a biomarker of benefit. But again, we’ve come up with nothing so far. So I think for most of us we’re going to use them first-line because it’s very hard to ignore the almost doubling of progression-free survival we have seen in these patients.
The survival data from the first-line trials will be very interesting when we see that, because if they don’t have a survival advantage, then we’re really going to have to rethink what we’re doing a little bit. But again, disease control is also very important to patients.
Joyce O’Shaughnessy, MD: These are very impressive data. Tell us about the PALOMA-3 data in the New England Journal of Medicine.
Ruth O'Regan, MD: That was basically a hormone refractory group of patients. So if you look at the progression-free survival in the control arm, it was consistent with hormone refractory settings and obviously we already knew that the addition of palbociclib to fulvestrant markedly improved progression-free survival. We’re now seeing a significant survival advantage, which is really very encouraging.
Joyce O’Shaughnessy, MD: This is very interesting, getting the right things.
Adam M. Brufsky, MD, PhD: But you had to have prior sensitivity to hormone therapy. What does that mean?
Joyce O’Shaughnessy, MD: Right, to get that survival advantage.
Adam M. Brufsky, MD, PhD: Well, what does that mean?
Ruth O'Regan, MD: They haven’t defined that.
Joyce O’Shaughnessy, MD: They did, they did.
Adam M. Brufsky, MD, PhD: They kind of did. I think it was that you had to be on hormone therapy for 6 months or something.
Joyce O’Shaughnessy, MD: Six months in metastatic disease, and they were very stringent with a primary refractory diagnosis. So there could be no benefits from endocrine therapy in the metastatic studies or clinical benefits, not more than 6 months. And neither of these could be present. If you had adjuvant endocrine therapy you could not have been on it for 2 years. You had to recur within 2 years. So, super resistant disease. That was 20% of the PALOMA 3 population. And in that population, interestingly, there wasn’t any benefit from palbociclib on survival. But in those who were hormone therapy sensitive, which means just getting past 2 years of your adjuvant endocrine therapy or having 6 months on any endocrine therapy in the metastatic setting, there was this 10-month improvement in overall survival, which is really interesting.
The overall survival just missed statistical significance. It was definitely in the right direction, but it just missed the statistical significance. It’s really interesting what it says to us about palbociclib in that primary endocrine therapy, refractory patient population and also what it says to us in the more endocrine therapy-sensitive population, you know?
Adam M. Brufsky, MD, PhD: The question is if you’re primarily refractory. Think about the genomics of what this is, because I know you love to think about genomics, Joyce. The thing is that these are probably people who are FGF [fibroblast growth factor] mutated from the beginning or PB3 mutated from the beginning. Nothing we give them is going to work. So why do you think the patient who’s sensitive to an AI [aromatase inhibitor] up front becomes resistant? Why? Why do they become resistant? ESR mutation? 30% of ESR mutation? We don’t know the rest of it. Let’s say it’s 30% of ESR mutation, then they’ll respond to fulvestrant, and then you’re boosting whatever response you get. I view these agents as boosters, right? Are they really resistance overcomers, or are they boosters of the existing hormone response you’re going to get?
So when we talk about this being hormone refractory, are they truly hormone refractory to all hormones in PALOMA-3 or not? I’m trying to get a sense of this. Do you know what I’m trying to say here?
Ruth O'Regan, MD: Yes. I don’t think that they were all refractory, but I think the progression-free survival in the control arm of PALOMA-3 was shorter than the other second-line studies. So I think it was probably a slightly more refractory population than the other second-line studies. But as you say, we don’t obviously know it.
Adam M. Brufsky, MD, PhD: We don’t know why they’re resistant, because they clearly respond to another hormone therapy, right?
Ruth O'Regan, MD: I think ER is still a very good target in these cancers.
Adam M. Brufsky, MD, PhD: Right.
Ruth O'Regan, MD: If you look at the mTOR inhibitors and now the PI3-kinase inhibitors, they appear to be more effective in the resistant population compared to the sensitive population, which I think makes sense. Because I think those pathways become more important as the cancers become resistant.
Adam M. Brufsky, MD, PhD: So you think that’s going to give us a way to figure that out? Because I don’t know if we’re going to talk about it, but the decision point is going to be PI3-kinase inhibitor, obviously with a mutation, mTOR inhibitor, or CDK4 inhibitor in someone who’s second- or third-line. So which do you use?
Joyce O’Shaughnessy, MD: That’s a really interesting question. One comment about fulvestrant after progression on CDK4/6 inhibitor. We just haven’t really had any data to look at, except in the SOLAR-1 trial that was updated at San Antonio, of course. The SOLAR-1 trial is for a group of wild-type PIK3CA or mutant PIK3CA patients who had already progressed on an aromatase inhibitor and were randomized to fulvestrant/placebo versus fulvestrant plus alpelisib, the alpha-specific targeted inhibitor of PIK3CA mutation. And there were just 6%, small numbers.
Adam M. Brufsky, MD, PhD: 10 per arm.
Joyce O’Shaughnessy, MD: The fulvestrant arm after CDK came down very steeply, but there was a very small tail on that curve. It was interesting to see that, but we certainly need more data on that.
Adam M. Brufsky, MD, PhD: There was benefit with alpelisib in the people who were CDK4 positive.
Joyce O’Shaughnessy, MD: Oh, clearly.
Adam M. Brufsky, MD, PhD: But it was only 10 patients per arm. What can you make of it? That’s the thing.
Joyce O’Shaughnessy, MD: Yes, but the curves were separated.
Adam M. Brufsky, MD, PhD: They separated, but it was only 10 patients per arm.
Joyce O’Shaughnessy, MD: Yes, it was very small, but it was quite reassuring,
Transcript edited for clarity.