Refining Treatment Approaches for HER2+ Breast Cancer - Episode 3
Joyce O’Shaughnessy, MD: Let’s turn to Claudine. Maybe you could refresh and update for us about APHINITY, ExteNET, and KATHERINE. I think we all know what the data are, but is there anything new around those 3 particular topics?
Claudine Isaacs, MD: Absolutely. For APHINITY we’ve already alluded that the differences were pretty modest. There were groups where we saw the differences on the patients with hormone receptor negative or node positive disease were where the differences emerged, but they weren’t huge. They were a few percentage points in terms of evasive disease-free survival.
There was a presentation at San Antonio Breast Cancer Symposium. There was a poster that tried to look at which populations were the ones that derived the greatest benefit and tried to get estimates based on treatment or patient subpopulations. What came out was very much in keeping with what we thought that the group that derived the greatest benefit were the patients who had higher clinical risk. Then they also looked at other parameters. They looked at TILs [tumor-infiltrating lymphocytes] and HER2 [human epidermal growth factor receptor 2] fluorescence in situ hybridization copy number. They found that the patients with the highest TILs were also the group that seemed to derive the greatest benefit from pertuzumab. Something else to put in there, not that we’re necessarily getting TIL numbers when we’re getting path specimens on patients who are getting core biopsies on patients, but the concept that the patient was at higher risk, and still incorporating what we’ve been incorporating like the node-positive or the hormone receptor–negative patients.
I know I’ve heard others say that they started with TCH [docetaxel, carboplatin, trastuzumab]. I’d say in that the neoadjuvant setting, if I’m treating somebody, I do tend to give TCHP [docetaxel, trastuzumab, pertuzumab, carboplatin] except in an older patient or somebody where there would be a reason for me not to. But I realize I’m probably a little more conservative on that than I need to be, and I’m trying to figure out how to pull back on some of that.
That is what was new on APHINITY. On ExteNET, this is a study that we’ve seen a lot. This is a study that is looking at the role of neratinib, pan-TKI [tyrosine kinase inhibitor], in patients who had completed HER2-targeted therapy. This is a pretty old trial, so the patients typically got trastuzumab as their treatment, and it was a wide-open trial. We talked about that trial, and we thought about opening it, and it was a trial that basically allowed anyone at any time who had gotten trastuzumab. You could have been 2 or 3 years out, and then they shortened the time frame. It’s really a very wide-open trial.
What they showed us over the past couple of years is that the group that appeared to benefit from that year of neratinib after having completed trastuzumab and chemotherapy were actually the patients who had hormone receptor–positive disease. All patients with hormone receptor–positive disease also got endocrine therapy. We know there’s a lot of cross talk between those pathways, so you can think that there might be a rationale, particularly if you’re starting it later in the course.
That was really the subset that seemed to come out. The other thing is not surprising: The patients who were started more closely into completing their adjuvant trastuzumab were the other group that seemed to really get the benefit. The hormone receptor positive started within 1 year of completing their trastuzumab.
We hadn’t seen survival data and Frankie Holmes presented that at this past San Antonio Breast Cancer Symposium. Looking at that group, there was no benefit overall in terms of overall survival in the intent-to-treat population. These become exploratory analysis when they looked at the patients with hormone receptor positive. There emerged a survival benefit—about a 2% survival benefit—if you looked at the super-highest risk. The hormone receptor–positive patients who started within a year of completing their therapy, and the ones who didn’t achieve a pathologic CR [complete response]. We’re getting to really small numbers, so let’s be careful. There was actually a pretty significant benefit that emerged in that group in terms of overall survival.
It takes us back to the discussion of where we think about this drug now. What do we do with this drug in the era of KATHERINE and in the era of pertuzumab? That’s something that maybe we want to come back to as a group and talk about. That was really an interesting finding and it’s one that we debate in practice. I don’t know if you want to talk about it now, Joyce.
Joyce O’Shaughnessy, MD: Let’s do it. What do you do? Do you use neratinib in some patients?
Claudine Isaacs, MD: I’d be really interested to hear what my colleagues think. Like most of us, I was really impressed by the KATHERINE data. It showed this really big 3-year invasive disease-free survival benefit for the patients who just didn’t achieve a pathologic CR. It’s about an 11% absolute benefit. What also struck me is those patients weren’t doing that great—even the group that got T-DM1 [trastuzumab emtansine], right? At 3 years there was about 11% to 12% of them who developed a recurrence.
Joyce O’Shaughnessy, MD: Right.
Claudine Isaacs, MD: It was 3 years so it struck me that there was still room for benefit in that group. In those patients, particularly in the really high-risk patients, and particularly if they have hormone receptor–positive disease—and we all have some patients who have multiple nodes, 2 or 3 nodes—I tell them, and I do tend to give them neratinib.
I always tell people when we start on a drug, particularly 1 that has adverse effects: This is not a moving train; you can’t get off. Let’s try it, and let’s see how you tolerate it. If it’s tolerable, we may as well try to get benefit from it. If it’s not, we try it, and obviously they go on endocrine therapy and everything, but that’s the group for whom I still think about using neratinib. I recognize that we have a paucity of data to support my recommendation, except that there’s still a place for improvement in that group of patients.
William Gradishar, MD: I agree with everything that Claudine said, and the 1 other element that has to go into the mix is that it has to be a highly motivated patient partnered with a highly motivated oncologist because it’s going to take a lot to get them through it. I frankly don’t use it a lot. It would be in those patients that Claudine described. Of the handful of patients who did go on, half discontinued, and that’s even with the antidiarrheal maneuvers. It’s not for the faint of heart oftentimes.
Joyce O’Shaughnessy, MD: Yeah, and I just want to make the point about how important it is to escalate the agent. In case somebody hasn’t seen the results of the CONTROL trial, a lot of things were looked at. Loperamide, which we certainly want to use for more prn as needed with the escalation strategy, plus budesonide and colestipol. Starting at 3 or 4 pills, from 120 to 150 mg, and then every 1 or 2 weeks as tolerated, increasing it by 1 pill has made a substantial difference. In the CONTROL trial, only 2% or something stopped for toxicity. I’ve really been pleased with that. That’s really the only way to go. People are going to try to give patients a shot at this, and using the escalation strategy is really important. How about you, VK? What do you think about neratinib?
Vijayakrishna Gadi, MD: I’ve actually found myself using it increasingly of late. That’s because of the cross talk issue. I believe that ER [estrogen receptor] disease is fundamentally different from the kind that’s ER negative. If we don’t address that cross talk, and we don’t do that with T-DM1 [trastuzumab emtansine], I’m still worried about these patients having events down the road.
The other thing, and we learned this from tucatinib in the metastatic setting, having that molecule that can cross the blood-brain barrier even in this context may actually have benefit. I know that trials are underpowered for CNS [central nervous system] as a first site of recurrent type event. It’s my suspicion that those are patients who are vulnerable to those events when you have residual disease, have done T-DM1, have ER-positive disease. I’d like to give them that extra bit of coverage for that as well as for prevention for those CNS events. I’ve gradually shifted: I was not at all using it, and now I find myself more often using it. Now that we have the ability to give it, start with a few pills, work our way up…. It’s not for the faint of heart, to steal Bill’s words.
Joyce O’Shaughnessy, MD: I’ll be honest: I know practices that don’t let their doctors use it in off pathways and stuff. I’d love Bill to change this for us, the NCCN [National Comprehensive Cancer Network] has it like it’s a footnote—on the top, Bill, just as an option. It’s down in the fine print, it’s the argument that the ExteNET was done with pertuzumab and T-DM1. That’s the argument, and I totally get that.
It’s a non-cross-resistant agent, and you’ve got the cross top coming. To me, it’s like a totally different drug, and I don’t know why antecedent pertuzumab and T-DM1 make a difference. What do you guys think? Lisa, do you ever use this drug?
Lisa Carey, MD, FASCO: Rarely. The thing I struggle with is that the cross talk is certainly something that’s preclinically important. We haven’t seen that direction of effect by hormone receptors with any of the other small molecules or, in fact, with neratinib itself in the metastatic setting.
I struggle a little with it because it didn’t quite seem to hold true. That said, the ExteNET data are what they are. If I have a very high-risk patient, I have occasionally reached for it, and I’ve been happier with the option of dose escalation. In the CONTROL trial they did quite well. They escalated relatively quickly. I was actually surprised. It seemed like the low hanging fruit of managing your diarrhea, and it was the most effective 1. If I was going to do it, I would do that.
Vijayakrishna Gadi, MD: We’re going to talk about it in a little bit, but NALA and HER2CLIMB are the only studies we have in the metastatic setting. Both did not permit endocrine therapy usage. Personal opinion, it would have been nice to have studies that just said, “We are just managing HER2+, ER-positive patients with the anchored regimens with endocrine therapy.” We do have studies in the early stage metastatic setting, like in the PERTAIN trial, and you see that synergy there. I think there’s still room.
Joyce O’Shaughnessy, MD: Right, there’s more to learn.
Transcript Edited for Clarity