Adam M. Brufsky, MD, PhD: Let’s go on to the San Antonio [Breast Cancer Symposium 2020] and what’s exciting. We’ve got a hint of a few things, specifically in terms of CDK4/6 [cyclin-dependent kinases 4/6] inhibitors in the adjuvant setting. Do you have any comments about what you want to see, or what you think you’re going to see in San Antonio?
Erika P. Hamilton, MD: We’re seeing a bit more data on CDK4/6. You mentioned that we’ve written the story as a metastatic disease, so these are early data. We saw the monarchE trial results. That was a positive trial of course, and all those patients were node positive with very high risk. That trial was a higher-risk population than the patients who were in the PALLAS trial.
You had to have at least 4 positive nodes. If you had 1 to 3 positive nodes, then you had to have an additional high-risk factor: either grade 3, a tumor size of at least 5 cm, or Ki-67 over 20%. This is our ultra-high risk of ER-positive adjuvant breast cancer.
We saw invasive disease-free status improved from 88.7% to 92.2% with the addition of abemaciclib; that was a benefit of about 3.5%. What one could argue is, is that some in-breast recurrence or distant recurrence? It did appear to be distant recurrence as that was a 3.3% difference.
We’re going to see an update of this, the final invasive disease-free survival. I’m eager to see that because the monarchE study was a bit of an early snapshot, so we’ll see how those data have matured over time.
Adam M. Brufsky, MD, PhD: Yes. With the monarchE trial, we were all excited about the presentation at ESMO [the European Society for Medical Oncology annual meeting]. Something that struck me was that the median time on trial was something like 16 or 18 months, and you have to be on abemaciclib for 2 years. Therefore, you’ve got to know that the problem with these CDK4/6 inhibitors is that, once you stop them in the neoadjuvant setting, suddenly the Ki-67 goes right back up. The question is going to be this: what happens when you stop the drug?
You’re really going to need some long-term follow-up. We’re all excited because we think the FDA is potentially going to approve these drugs based on these registration trials. But on the other hand, they may say, “We don’t know. We want to see a little more follow-up in the EFS [event-free survival] to be sure that the stuff we’re seeing is true.” I don’t know. It’s going to be an interesting dilemma here.
That’s why Joyce O’Shaughnessy, MD, is presenting these data. I think it’s the first presentation: it’s GS101 [general session 101], so it’s the prime spot on Wednesday morning, December 9, at the San Antonio [Breast Cancer Symposium]. I’ll be interested to see what happens with that. I don’t know if you have any more thoughts before we go on to the other trial, which is the more disappointing study, which is the palbociclib trial. What do you think about the monarchE study before we go on?
Erika P. Hamilton, MD: I completely agree with you. It could theoretically go either way. You certainly bring up that if we stop the CDK4/6 inhibitor, are those patients going to relapse, albeit a little bit later? Or are we going to see that separation grow? It may be that we are curing some of these patients.
We have to follow it. It’s an interesting time in breast cancer research in general because we have a lot of different end points to look at. With each of these trials, we have to think about what that end point means, and how it is going to mature over time, whether that’s pCR [pathologic complete response] for triple negative breast cancer with immunotherapy translating to disease-free recurrence, or whether it’s endocrine therapy here.
Adam M. Brufsky, MD, PhD: You’re right. I’ll go even further. It’s interesting. What intrigued me is that, when you do those neoMONARCH trials and give people abemaciclib for a long time, like 4 or 5 months, you start to see T-cell infiltration where you didn’t see it.
There’s going to be something to that. It may be that there’s something about being on a CDK4/6 inhibitor—with abemaciclib in particular, but who knows—that somehow leads to some sort of immune response that’s allowing you to have a PFS [progression-free survival] or an event-free survival. That’s where we may be going with this. It’s a crazy idea, but you need some crazy ideas in this business every so often.
Erika P. Hamilton, MD: Right. People who have been successful in history have been thought of as crazy at one point, right?
Adam M. Brufsky, MD, PhD: Exactly. The thing is that I’ve always been intrigued by that factor, you saw the serial biopsies, if you remember that trial. You do the ones at the end, and they start to see T-cell infiltration in a number of tumors.
Let’s move on to the other trial. I was shocked, I’ve got to tell you. We all looked, when the PALLAS trial was presented, I was looking with a microscope trying to see anything at all. I understand that 45% of the people in PALLAS came off trial because of typical neutropenia issues, which we don’t usually do in practice. Erica, what do you think? That is a totally negative trial.
Erika P. Hamilton, MD: Yes. It’s completely negative. There are a variety of things we could attribute to why it’s negative now. Speaking to what you were talking about with the neoadjuvant setting and the T-cell infiltration, we also see that same thing in Ki-67. In the neoadjuvant trials, you knock down Ki-67 considerably, but they stop the CDK4/6 inhibitor a couple of weeks before you go to surgery. Then in the surgical specimens, it’s back up where it was.
Adam M. Brufsky, MD, PhD: Right.
Erika P. Hamilton, MD: Right. That raises the possibility that we could be seeing some type of difference between continuous and intermittent dosing.
Adam M. Brufsky, MD, PhD: Yes. That’s a great question.
Erika P. Hamilton, MD: That hasn’t been borne out in the metastatic literature, but that doesn’t mean that it’s not different in the early literature. Immunotherapy benefit across early and late disease settings is certainly different. Then you bring up the discontinuation rate. That’s a shame. We have to be careful about the way we design our clinical trials now. We certainly see neutropenia, and yes, that neutropenia can be significant. However, we’ve proven, even across many metastatic patients, that it does not translate to clinical infections. Our febrile neutropenia rate is less than 1%.
If we’re saying that these patients are high enough risk that they need the potential addition of this agent, we need to be more liberal with the neutrophil criteria to allow them to get it. That was probably a bit of a mistake in the trial design.
The other thing is, if I had to put my eggs in a basket, this would be the basket I’d pick. It’s the risk. In the PALLAS trial, the patients with N2/3 [2 or 3 positive lymph nodes] were 37%, whereas in the monarchE study, the N2/3 patients were 59%, so a 22% difference. We’ve already talked about the fact that those N1 patients in the monarchE trial had an additional quite significant high-risk factor of a tumor size over 5 cm or a high Ki-67.
It may come back to the fact that, if we’re taking a population in which very few people are going to relapse anyway, you’re not going to see a big difference by adding another drug.
Adam M. Brufsky, MD, PhD: I agree. I was even trying to look at the subgroup analysis, but I didn’t see anything there. This is getting to the PENELOPE-B study: importantly, they had people who got neoadjuvant therapy up front and then chemotherapy, and then in the adjuvant setting got either hormonal therapy or hormonal therapy plus palbociclib. They didn’t see any difference.
That’s predictive of PENELOPE-B, and then a couple of weeks later, the PENELOPE-B study announces. We only have the top line data in the press release, but it announces that it’s negative. I am now curious to see it. This is going to be the No. 2 presentation: it’s GS102, so it’s right after the monarchE trial. I don’t know who’s discussing it; it would be cool to see who is discussing it. The bottom line is this: I want to know if there is any piece of information that we can take from PENELOPE-B to learn about why it didn’t work because it would be interesting for us to figure that out.
Erika P. Hamilton, MD: Absolutely. The PENELOPE-B study was from the German Breast Group, and it was a pretty large study: it was 1250 patients. It was looking at the addition of palbociclib to endocrine therapy in patients with residual disease after neoadjuvant chemotherapy and surgery. You could almost think of it as the KATHERINE trial, but this time with ER+ disease. It started a long time ago in November of 2013, and we’re just now getting the readout of it.
I also found that a bit surprising. It goes back to clinical trial design too. I would have thought that it had been positive, but we have to ask ourselves—pCR and residual disease is a big deal for us in triple negative cancer and in patients with HER2-positive disease. But is this the right end point for the high-risk patient for ER+ disease? I’d argue that it probably isn’t.
Adam M. Brufsky, MD, PhD: I agree with you: no way. I don’t think it is going to be right. But I’m just looking for a biomarker. I’m trying to put all these data together. I like your continuous vs intermittent dosing concept here, and that may be it. It may be something else: some off-target effect. These things are tyrosine kinase inhibitors of a lot of different ones, so there may be one that we don’t know. The question is, this would have normally come out in the metastatic setting, and it didn’t.
Erika P. Hamilton, MD: Right.
Adam M. Brufsky, MD, PhD: The adjuvant setting is teaching us about the metastatic setting. It’s like vice versa.
Erika P. Hamilton, MD: Right, and it’s not only that. In the metastatic setting, those hazard ratios were all 0.55. They were identical.
Adam M. Brufsky, MD, PhD: It’s crazy. We’ll figure that one out.
Transcript edited for clarity.